PSYC 450 Drugs and Behaviour final exam tips questions to consider (from Unit 1-20) Athaba, Exams of Psychology

Download PSYC 450 Drugs and Behaviour final exam tips questions to consider (from Unit 1-20) Athaba and more Exams Psychology in PDF only on Docsity! PSYC 450 Drugs and Behaviour final exam tips questions to consider (from Unit 1-20) Athabasca University PSYC 450 Drugs and Behaviour final exam tips questions to consider (from Unit 1-20) Athabasca University Psyc 450 Study Notes Unit 1 – Read Chapter 1 of the text Questions to consider . • Define Psychopharmacology. – focuses on drug induced changes in mood, thinking, and behaviours. √ • What is meant by the term pharmacokinetics? √ • Describe the advantages and disadvantages of intravenous injection. √ • What are lipid-soluble drugs? √ • Explain the importance of the blood-brain barrier. √ • Define half-life. √ • What is meant by the term pharmacodynamics? • What are receptors? What are ligands? √ • Describe how receptors can be modified. In other words, explain the life cycle of receptors. √ • Differentiate between tolerance and sensitization. √ • Differentiate between metabolic tolerance and pharmacodynamic tolerance. √ Terms Pharmacology is the scientific study of the actions of drugs and their effects on a living organism. Neuropharmacology – is concerned with drug-induced changes in the functioning of cells in the nervous system. Psychopharmacology – emphasizes drug-induced changes in mood, thinking, and behaviour. Neuropsychopharmacology – is to identify chemical substances that act on the nervous system absorption, Inhalation Large absorption surface, very rapid onset, no injection equipment needed Irritation of nasal passages, inhaled small particles may damage lungs Topical Localized action and effects, easy to self-administered May be absorbed into general circulation Epidural Bypasses blood-brain barrier, Not reversible, needs trained very rapid effect on the CNS anesthesiologist, possible nerve damage Intranasal Ease of use, local or systemic effects, very rapid, no first- pass metabolism, bypasses blood- brain barrier Not all drugs can be atomized, potential irritation of the nasal mucosa. Transdermal Controlled and prolonged absorption Local irritation, useful only for lipid-soluble drugs Lipid-soluble drugs – drugs with high lipid solubility move through cell membranes by passive diffusion, leaving water in the blood or stomach juices and entering the lipid layers of membranes. Movement across the membranes is always in a direction from higher to lower concentration. The concentration difference on either side of a cell is called the concentration gradient. Bioactivation – dependence on the metabolism to convert an inactive drug into an active one. Blood-brain barrier – blood plasma is supplied by a dense network of blood-vessels that permeate the entire brain. This system supplies the brain with oxygen, glucose, and amino acids and carries away carbon dioxide and other waste products. CSF is a clear fluid that fills the subarachnoid space that surrounds the brain and spinal cord and also fills the hollow space and their interconnecting channels. Despite fluctuations in the blood levels, the CSF remains stable. This separation between brain capillaries and the brain/CSF constitutes what is the blood-brain barrier. Half -life- the amount of time required for removal of 50% of the drug in the blood stream. This is important because it determines dosage intervals of a medication. Pharmacodynamics – is the study of the physiological and biochemical interaction of drug molecules with target tissue that is responsible for the ultimate effects of a drug. Receptors – large protein molecules located on the cell surface or within the nucleus, producing differences in protein synthesis. Ligand – is any molecule that binds to a receptor with some selectivity. Receptor agonists – molecules that have the best chemical fit and attach most readily to the receptor. Receptor antagonists – low efficiency, they do not produce a cellular effect after binding and also bind to a receptor to block an active ligand from binding. Partial agonists – demonstrates efficiency that is less than that of a full agonist. Inverse antagonists – bind to a receptor, initiate biological action but it is an action opposite to that produced by an agonist. Not all effects of a drug show the same degree of tolerance. Several different mechanisms explain multiple forms of tolerance. Metabolic tolerance – is when repeated use of a drug reduces the amount of that drug that is available at the target tissue. Most common form is when a drug increases their own rate of metabolism. Pharmacodynamic tolerance – the most dramatic form of tolerance that develops to the central actions od certain drugs cannot be explained on the basis of altered metabolism. Withdrawal syndrome- when chronic drug users abruptly stop using the drug. Physical dependance – a physiological state in which the body adapts to chronic presence of a drug and elicits a drug-specific withdrawal symptom. Behavioral tolerance – when tolerance occurs in the same environment in which the drug was administered, but tolerance is not apparent or is much reduced in a novel environment. Sensitization – is the enhancement of particular drug effects after repeated administration of the same dose of drug. Pharmacogenetics – the study of genetic basis for variability in drug response among individuals. Unit 2 notes - questions to consider Psyc 450 Unit 2- read chapter 2 Questions to Consider. • What is a neuron? Describe these parts of a neuron: dendrites, some, axon, synaptic terminal √ • Discuss the functions of two types of glial cells √ • Describe the resting potential. √ • Define epilepsy. √ • What are the functions of the spinal cord. √ • What is the district regions of the CNS. √ • What is the function of the diencephalon? √ • List and describe the major parts of the limbic system. √ Neurons – are nerve cells that’s primary function is to transmit information in the form of electrical signals over long distances. Glial cells – supporting cells that provide metabolic support, protection, and insulation for neurons. Sensory neurons – sensitive to environmental stimuli, convert physical stimuli in the world around us and in out internal environment into an electrical signal and transmit that information to circuits of interneurons. Intraneurons – nerve cells within the brain and spinal cord. Motor Neurons – direct biobehavioral responses appropriate for the situation. Neurons have 3 major external features: Soma – the cell body contains the nucleus and other organelles that maintain cell metabolic function. Dendrites – treelike projections form the soma that receive information from other cells. Axons – the single tubular extension that conducts the electrical signal from the cell body to the terminal buttons on the axon terminals. Neurons are enclosed in a semipermeable membrane called the cytoplasm. Neurons have a mitochondria which are responsible for generating energy from glucose in the form of adenosine triphosphate (ATP). Synapse – dendrites and soma sending and receiving information from other cells across the gap between them. Chromosomes are long strands of DNA Depolarization – more positive inside the cell, membrane potential moves toward threshold, ESPS caused by : Na+( sodium) channel opening and Na+ entry, greater stimulation produces larger polarizations. ESPS = excitatory postsynaptic potentials IPSP = inhibitory postsynaptic potentials Absolute refractory period – the time in which the Sodium channels are closed and cannot be opened, regardless of the excitation, preventing another actin potential. Relative refractory potential – brief hyperpolarizing phase, it takes more excitation to first reach resting potential and further depolarization to reach threshold. Characteristics of Local Potentials and Action Potentials Local Potentials Action Potentials Graded All-or-none Decremental No decremental Spatial and temporal summation Intensity of stimulus coded by rate of firing Produced by opening of ligand-gated channels Produced by opening of voltage-gated channels Depolarization or hyperpolarization Depolarization Central Nervous System (CNS) – the brain and spinal cord Peripheral Nervous System (PNS) all nerves outside the brain and spinal cord. Breaks down into the somatic nervous system (SNS) (voluntary muscles with both spinal nerves and cranial nerves) and the automatic nervous system (ANS) which consists of autonomic nerves and some cranial nerves that control the function of organs and glands. The ANS has both sympathetic (SNS) and parasympathetic (PSNS) divisions. CNS functioning is dependent on structural features. Under the skull are three layers of meninges providing extra protection. Dura mater, the arachnoid, and the pia mater. The CNS has 6 distinct regions. Brain Forebrain Telencephalon( cereb ra l hemispheres) Neocortex Basal Ganglia Limbic System Diencephalon Thalamus Hypothalamus Midbrain Mesencephalon Hindbrain Metencephalon Cerebellum Pons Myelencephalon Medulla Spinal Cord Spinal Cord Spinal Cord Spinal Cord The spinal cord is made up of gray and white matter, Gray matters appears in a butterfly shape in a cross section. Spinal cord becomes the brain stem as we move up towards the brain. Motor neurons on one side and sensory neurons on the other side working together to receive information and then send out a muscular reaction. The Diencephalon – has two major structures the thalamus and the hypothalamus. The thalamus is a cluster of nuclei that first process and the distribute sensory and motor information to the appropriate proportion of the cerebral cortex. The hypothalamus – lies ventral to the thalamus at the base of the brain. It is much smaller than the thalamus, made up of many small nuclei that perform functions critical for survival. The hypothalamus receives a wide variety of information about the internal environment and in coordination with the structures of the limbic system initiates various mechanisms important for limiting the variability of the body’s internal states. Limbic System – multiple subcortical structures interconnected to form the limbic system which is critical for learning, memory, emotional responses, and motivation. Rich connections of limbic areas with associations areas of the cortex contribute to decision making and planning. The limbic system is a complex neural network that is involved in integrating emotional responses and regulating motivated behaviour learning. The limbic system is made up of: The limbic cortex which is located on the medial and interior surface of the cerebral hemispheres and is transitional between allocortex and the neocortex. Epilepsy – is a central nervous system disorder in which brain activity becomes abnormal, causing seizures or periods of unusual behavior, sensations and sometimes loss of awareness. Anyone can develop epilepsy. Epilepsy affects both males and females of all races, ethnic backgrounds and ages. Unit 3 notes - questions to consider Unit 3 – read chapter 3 PSYC 450 Questions to consider. What is a synapse? Give two examples. What is a neurotransmitter? What is classical neurotransmitter? How is the synaptic transmitter action of a released chemical terminated? Give two examples. Describe the two major types of receptors. Why is nitric oxide considered to be an atypical neurotransmitter? Describe four ways in which drugs can alter synaptic transmission. Describe the importance of the endocrine system. Explain the organization of the hypothalamic-pituitary axis. A synapse is neuron communication. Communication occurs in one direction. From the presynaptic cell to the postsynaptic cell. The most common synapse in the brain is axodendritic synapse. This is where the axon terminal from the presynaptic neuron communicates with a dendrite of a postsynaptic cell. There is a small gap between presynaptic and postsynaptic cells call synaptic cleft. There are many small sack like objects in the axon called synaptic vesicles. There are also axosomatic synapses which are between nerve terminal and a nerve cell body, and axoaxonic synapses that involve one axon synapsing on the terminal of another axon. The connection pint between a neuron and a muscle is called the neuromuscular junction. Neurotransmitters are chemical substances released by neurons to communicate with other Speed of action Fast Slower - Do not posses a channel or pore Both types of receptors can be affected by allosteric modulators. Second-messenger System Associated protein kinase Cyclic AMP (cAMP) Protein kinase A (PKA) Cyclic GMP (cGMP) Protein kinase G (PKG) Phosphoinositide Protein kinase C (PKC) Calcium (Ca2+) Calcium/calmodulin kinase II (CaMKII) The Endocrine System Adrenal glands – lie over the kidneys. The inner part is called the adrenal medulla it receives input from the preganglionic fibers of the sympathetic nervous system. Cells of the adrenal medulla are called chromaffin cells and they secrete epinephrine (EPI) and norepinephrine (NE). The outer part of the adrenal glands is the adrenal cortex and secretes hormones called glucocorticoids. Humans make cortisol. The endocrine system is important to pharmacologists because 1) both therapeutic and abused drugs can alter the secretion of many hormones, causing physiological changes. 2) Hormones may alter subjective and behavioural responses to drugs. 3) Hormones themselves sometimes have psychoactive properties like those of certain drugs. 4) The secretion of pituitary hormones and other hormones dependent on the pituitary is controlled by neurotransmitter system in the brain. Drugs and Synaptic Transmission Drugs can either enhance or interfere with virtually all aspects of synaptic transmission. Drugs may increase or decrease the rate of transmitter synthesis. If the drug is a chemical precursor to the transmitter that the rate of transmitter formation may be increase. A drug decreases levels of neurotransmitter by inhibiting a key enzyme needed for transmitter synthesis. Nitric oxide NO does not fit the traditional neurotransmitter Organization of the hypothalamic pituitary axis - Axon terminals of the hypothalamic releasing hormone neurons are located near blood capillaries in the median eminence, whereas oxytocin and vasopressin neurons send their axons all the way into the posterior lobe of the pituitary glad. Unit 4 - questions to consider Unit 4 – read chapter 4 PSYC 450 Questions to consider. 1. Discuss the process of stereotaxic surgery. 2. What is microdialysis? 3. What is situ hybridization? 4. Differentiate between PET and MRI. 5. Explain the utility of using knockout technology. 6. Outline the process of drug development and testing. 7. What is operant conditioning? Give an example of its use. Operant conditioning a highly sensitive method that can be used to evaluate a wide variety of behaviours including analgesia, anxiety, addiction potential, and drug discrimination. The underlying principal is that consequences control behaviours. Analgesia is the reduction of perceived pain without a loss of consciousness. Tests of learning and memory: Mazes – T-maze, Multiple T maze, Radial arm maze, Morris water maze. Delayed response test – test evaluates working memory. Measures of anxiety – light-dark crossing task, elevated plus maze, zero maze, one-chamber social interaction test, water-lick suppression test, The slice method -Visualization method – requires structures intact so it requires a slice or piece of tissue. Target Molecule Tissue Extract Assay to Quantify Brain Slice Preparation to Visualize. Receptor site Radioligand binding Receptor Autoradiography Receptor and other proteins Radioimmunoassay (RIA); Western blot; ELISA Immunocytochemistry (ICC) mRNA Dot blot or Northern blot In site hybridization (ISH) Radioligand binding – Once the section is dissected out it is ground up to make homogenate. A ligand that is radioactively labeled is incubated with the tissue under conditions that optimize its binding. Although the binding procedure is quite simple, interpretation of the results is more complex. Criteria: 1) specificity – the ligand is binding only to the receptor we are concerned with in this tissue. 2) saturability – there are a finite number of receptors in a given radioligand to a fixed amount of tissue, one would expect to see gradual increases in binding until all sites are filled. 3) reversibility and high affinity is demonstrated in binding assays because the radioactive ligand can be displaced by the same drug that is not radiolabeled.If you compare the rate of dissociation with the rate of bidning you get an estimate of receptor affinity called the dissociation constant or Kd 4)biological relevance- binding of chemically similar drugs should correlate with some measurable biochemical or behavioural effect to show the biological relevance of the receptor. In Situ Hybridization (ISH) – makes it possible to locate cells in tissue slices that are manufacturing a particular protein or peptide, in much the same manner that ICC identifies cells containing a particular protein. ISH is useful in neuropharmacology for detecting the specific messenger RNA (mRNA) molecules responsible for directing the manufacture of the wide variety of proteins essential to neuron function, such as enzymes, structural proteins, receptors, ion channels, and peptides. Imagine Techniques CT - computerized tomography -increases resolution sharpness of an x-ray and provides the image in 3D. MRI – magnetic resonance spectroscopy – further refines the image beyond a CT using computerized measurements of the distinct waves that different atoms emit when placed in a strong magnetic field and activated by radio-frequency waves. This method distinguishes different body tissues on the basis of their individual chemical composition. MRS – magnetic resonance spectroscopy – compliments MRI because it can use the MRI- generated data to calculate concentration of rain chemicals as well as evaluating metabolic changes in individuals with Alzheimers, Parkinson;s, depression, epilepsy, or other conditions. MRI shows only structure, MRS is an important tool for researchers and physicians to measure levels of specific molecules such as glutamate, choline, and neurotransmitter metabolites in discrete brain regions in living individuals. DTi – diffusion tensor imaging – depends on the ability to scan the microscopic 3Dmovement of water in neural tissue. In axon bundles that are generally myelinated with fatty sheaths, movement is restricted, and the water can diffuse only alone the length of the myelinated axons. EEG – electroencephalography – electrodes are taped to the scalp in multiple locations according to the international 10-20 system that describes the location of the scalp electrodes based on the underlying area of the cerebral cortex. PET – position emission tomography – does not create images of the brain but maps the distribution of a radioactively labeled substance that has been injected indo an individual. Radioscopes are used that decay rather quickly as to not build up. Scanning devices detectors surround the head to track these gamma photons and locate their origin. Knockout technology - a procedure in which the DNA of the organism is altered, or a foreign gene is added to the genetic material of the organism (transgenic). These procedures provide the opportunity to produce highly specific mutations in the mouse genome to study subsequent changes in brain function and behaviour. 8. What is operant conditioning? Give an example of its use. importance of reuptake for catecholamine functioning can be seen when the DA and NE transporters are missing. Metabolic breakdown – to prevent excessive neurotransmitter accumulation. The break down of catecholamines involved tow enzymes catech-o-methyltransferase (COMT) and monoamine oxidase (MAO). Two types of MAO – MOA-A and MAO-B. NE is metabolized by MAo-A in both humans and rodents, but DA is metabolized by MAO-B in humans and MAO-A in rodents. The act of COMT and Mao either together or individually gives rise to several catecholamine metabolites. In humand DA has 1 metabolite called homovanillic acid (HVA). NE break down gives rise to several important compounds including 3-methoxy-4-hydroxy-phenylglycol (MHPG) and Vanillylmandelic acid (VMA). Dopaminergic Pathways A1 – A7 are noradrenergic. A8-A16 are dopaminergic. A9 group associated with a structure called substantia nigra and the A10 group found nearby the ventral tegmental area (VTA). Two important ascending dopaminergic systems arise from cells of the VTA. Some of these neurons travel to various structures of the limbic system. Parkinson’s disease – is a disease that involves a massive loss of DA neurons in the substantia nigra and consequent DA denervation of the dorsal striatum. Parkinson’s is characterized by progressive motor dysfunction, beginning with tremors, and advancing to postural disturbances, akinesia and rigidity. There are five main subtypes of dopamine receptors organized into D1 and D2-like families. Neurotransmitter DA uses 5 main subtypes all of which are metabotropic receptors, they interact with G proteins, and they function in part through second messengers. D1 and D5 are very similar to each other. D2, D3, D4 receptors represent a separate family. D1 and D2 discovered first and are most common subtypes in the brain. D2 function as Autor receptors, also play an important role as normal postsynaptic receptors. D1 and D2 have opposite effects on the second messenger substance cyclic adenosine monophosphate. D1 and D2 receptors differ with their respect to their signaling mechanisms and their affinity for DA. D2 have significantly higher affinity for DA than D1. Apomorphine is widely used agonist that stimulates both D1 and D2 receptors. It is also used to treat erectile dysfunction. Drugs that Affect the Dopaminergic System Drug Action Dihydroxyphenylalanine (L-DOPA) Converted to dopamine (DA) in the brain Phenelzine IncreASES CATECHOLAMINE LEVELS BY INHIBITING MONOAMINE OXIDASE (MAO) a-methyl-para-tyrosine (AMPT) Depletes catecholamines by inhibiting tyrosine hydroxylase Reserpine Depletes catecholamines by inhibiting vesicular uptake 6-Hydroxydopamine (6-OHDA) Damages or destroys catecholaminergic neurons Amphetamine* Releases catecholamines Cocaine and methylphenidate* Inhibit catecholamine reuptake Apomorphine Stimulants DA receptors generally (agonist) SKF 38393 Stimulates D1 receptors (agonist) Quinpirole Stimulates D2 and D3 receptors (agonist) SCH 23390 Blocks D1 receptors (antagonists) Haloperidol Blocks D2 receptors (antagonists) • These drugs are not selective for catecholamines, as they also affect serotonin release or reuptake. The noradrenergic system has both a central and peripheral component. These cell bodies of the central noradrenergic system are found in the brainstem, and their ascending fibers innervate a wide range of forebrain structures, whereas peripheral noradrenergic neurons are an important component of the sympathetic nervous system. NE released from these cells acts on adrenergic receptors located either in the central nervous system or in peripheral target organs. Norepinephrine and epinephrine act through a- and B- adrenergic receptors. All adrenergic receptors belong to the general family f metabotropic receptors. They serve a broader role by having to mediate both neurotransmitter and hormonal actions of the catecholamines. The central noradrenergic system plays a significant role in arousal, cognition and the consolidation of emotional memories. Adrenergic receptor antagonists have varied clinical uses. A2antagonists yohimbrine helps the treatment of certain types of male sexual impotence. Drugs that affect the Noradrenergic system Drug Action Phenelzine Increases catecholamine levels by inhibiting MAO a-methyl-para-tyrosine (AMPT) Depletes catecholamines by inhibiting tyrosine hydroxylase Reserpine Depletes catecholamines by inhibiting vesicular uptake 6 Hydroxydopamine (6-OHDA) Damages or detstroys catecholaminergic neurons Amphetamine* Releases catecholamines Cocaine and Methylphenidate* Inhibits catecholamine reuptake Nisoxetine Selectively inhibits norepinephrine reuptake Phenylephrine Stimulates a1-receptors (agonist) Clonidine Stimulates a-2 receptors (agonists) Albuterol Stimulates B-receptors (partially selective for B2) Prazosin Blocks a1-receptors (antagonist) Yohimbine Blocks a2-receptors (antagonist) Propranolol Blocks B-receptors generally (antagonist) Metoprolol Blocks B1 receptors (antagonist) • These drugs are not selective for catecholamines, as they also affect serotonin release or reuptake. Adrenergic agonists are used therapeutically for various physiological and psychological disorders. suppressant), and MDMA ( recreational drug). These drugs can exert toxic effects on the serotonergic system. The serotonergic system originates in the brainstem and projects to all forebrain areas. Serotonin has been known to influence hunger and eating behaviours. 5-HT1B, 5_HT 2c receptor agonists as well as 5_HT6 antagonists produce hypophagia ( reduced food intake) and weigh loss. Serotonergic projections to the hypothalamus participate in a complex circuit involving several other neurotransmitters and neuropeptides that together regulate appetite and energy metabolism. The use of serotonergic drugs to treat obesity went through an early dark period with unfortunate results. The drugs did help with weight lose but caused disorders causing heart valve abnormalities and pulmonary hypertension. Anxiety 5-HT plays a key role in the regulation of anxiety. SSRI’s among the most commonly prescribed in the treatment of several kids of anxiety disorders. Pain Serotonergic drugs have been used to treat migraine headaches. It is also used for patients with neuropathic pain, and often associated with hyperalgesia. Learning and Memory Serotonin in the Gut 90-95% of the total body 5-HT content in located in the gut, not the brain. Some of this 5-HT can be found in neurons of the enteric nervous system, a large system of ganglia situated within the muscle walls of the intestines. This system is activated by food into the GI tract, this stimulation leads to increased peristalsis and release of fluid and hormones by secretory cells of the gut. Two types of IBS IBS-D and IBS -C Two best characterized 5-HT receptors subtypes are 5-HT1A and 5_HT2A receptors. 5-HT1A receptors have been found in the hippocampus, the septum, parts of the amygdala and the dorsal raphe nucleus. These receptors are mainly somatodenddritic auto receptors on the serotonergic neurons themselves. In other brain areas 5-HT1A receptors are found on the postsynaptic neurons that receive serotonergic input. The most widespread use of AChE inhibitors is for the treatment of mild to moderate Alzheimer’s disease. Alzheimer’s disease is a significant loss of forebrain cholinergic neurons, and this loss contributes to the profound cognitive deficits suffered by the patients. There are two acetylcholine receptor subtypes: nicotinic and muscarinic. Nicotinic receptors are highly concentrated on muscle cells at neuromuscular junctions, or ganglionic neurons of both the sympathetic and parasympathetic systems and on some neurons within the brain. They are ionotropic receptors which means that they possess an ion channel as an integral part of the receptor complex. When Ach binds to the nicotine receptor, the channel opens very rapidly and sodium and calcium ions enter the neuron or muscle cell. This causes depolarization of the cell membrane, thereby increasing excitability of the cell. If the responding cell is a neuron, firing is increase, if it is a muscle cell, it responds by contracting. Each nicotinic receptor contains 5 subunits. Which are proteins that are assembled and then inserted into the cell membrane. Ionotropic receptors, all ion channels can exists in three different states: open, closed or desensitized. Muscarinic receptors - represent another family of ACh receptors. Muscarinic receptor are all metabotropic. There are 5 different muscarinic receptors desginated from M1-M5 have been identified, each with specific pharmacological characteristics and coded for by a different gene. They operate through several different second messenger systems. Some activate the phosphoinositide second messenger system, while others inhibit the formation of cyclic adensosine monophosphate. They also stiumate potassium channel opening. This leads to hyperpolarization of the cell membrane and a reduction of cell firing. Widely distributed throughout the brain. Current opthamologists use atropine to dilate pupils of patients. Unit 8 notes - questions to consider Unit 8 – read chapter 8 PSYC 450 Glutamate and GABA Questions to consider. 1. What is glutamate? How is it synthesized? 2. Describe what ionotropic glutamate receptors are. 3. Describe the functions of metabotropic glutamate receptors. 4. Discuss the role of glutamate receptors in long-term potentiation. How is this model relevant? 5. What is GABA? How is it synthesized? 6. Describe the structure and function of the GABAA receptor. 7. What are anxiolytics drugs? How do they work? 8. Describe the structure and function of the GABA receptor. Nootrpoics – cognitive enhancing compounds that act on the cholinergic system. Others such as amphetamine and methylphenidate work primarily through catecholaminergic activation. Glutamate – is the ionized form of the amino acid glutamic acid. Glutamate is used by all our cells to make new proteins. It is the most abundant amino acid in the brain. Glutamate and aspartate are the two principal members of excitatory amino acid neurotransmitters. All neurons and glial cells contain significant amounts of glutamate, cells that use glutamate as a transmitter possess even greater amounts. Glutamatergic neurons are thought to segregate the pool of glutamate that they use for transmission from the pool of glutamate used for other cellular functions. Glutamate can be synthesized by several different chemical reactions. Most molecules of gluatamate are derived ultimately from the normal metabolic breakdown of sugar glucose. Neurons can transform glutamine into glutamate using an enzyme called glutaminase. Glutamate packaging into vesicles and uptake after release are mediated by multiple transport systems. Glutamate is packaged in and released from synaptic vesicles. Proteins that package glutamate into vesicles VGLUT1, VGLUT2and VGLUT3. VGLUT1 gene expression occurs in the cortex and hippocampus. Knockout mice survive birth but begin to die around week 3 of life. VGLUT2 gene expression is found in subcortical structures. Knockout mice do not survive birth. VGLUT3 mice survive but are completely deaf. Ionotropic glutamate receptors depolarize the membrane of the postsynaptic cell, which leads to an excitatory response. For AMPA and Kianate – this is caused by the flow of sodium ions into the cell through receptor channels. For NMDA it is caused by sodium and calcium. Similar to nicotinic receptors ionotropic receptors are made of subunits (4). One widely used antagonist called NBQX can block both AMPA and KAINATE receptors but has no effect on NMDA receptors. Glycine and D-Serine are considered coagonists with glutamate at the NMDA receptor. Metabotropic Glutamate Receptors There are 8 different glutamate receptors. They are designated mGluR1-mGluR8. These 8 are further divided into 3 subgroups based on their amino acid sequences, subcellular localization and signaling pathways. mGluR1 and mGluR5 are located postsynaptically and mediate excitatory responses by activating the phosphoinositide second messenger system. mGluR2 and mGluR3 are group 2 mGlur4, mGluR6 mGluR7 and mGluR8 are group 3. They signal by inhibiting cyclic adenosine monophosphate formation. Many of the group 2 and group3 receptors are located presynaptically where they function as auto or heteroreceptors to inhibit release of glutamate or other neurotransmitters. Widely distributed throughout the brain and participate in many normal functions such as locomotor activity, motor coordination, cognition, mood, and pain perception. AMPA and NMDA receptors play a key role in learning and memory. Many neuropsychiatric disorders are associated with cognitive impairment, and dysregulation of glutamate receptors including intellectual disability, autism, and schizophrenia. Fragile X syndrome and Metabotropic Glutamate Receptor Antagonist. Fragile X is caused by mutations in the FMR1 gene which is located on the X chromosome. It is a congenital disorder that is thought to be the leading cause of intellectual disability and autistic symptoms. The core feautrs of the syndrome are cognitive deficits (memory and language), impaired attention, socioemotional problems. Additionally, there are concerns with anxiety, irritability, hyperactivity, aggression, and self-injury. GABA and Glycine GABA’s only function is to serve as a neurotransmitter. GABA is synthesized from glutamate in a single biochemical step which is catalyzed by the enzyme Glutamic Acid Decarboxylase (GAD). Gad is localized specifically to GABAergic neurons,and can be found by staining for GAD. Several drugs are known to block GABA synthesis. A significant reduction to GABA leads to convulsions. Three different transporters GAT-1, GAT-2, GAT-3. Gat-1 and GAT-2 appear to be expressed in both neurons and astrocytes. Where GAT-3 is found on astrocytes only. Vigabatrine is an irreversible inhibitor of GABA-T (GABA aminotransferase). Administration of this drug leads to build up of AGABA levels within the brain. GABA is co-released with several other classical neurotransmitters. Such as glycine, acetylcholine, dopamine, and glutamate. This is accomplished in part by co-expression of the vesicular transporters for multiple transmitters in the same neuron. Some GAGAergic neurons are interneurons while others are projection neurons. Other areas rich in GABA are cerebellum, striatum, globus, pallidus and olfactory bulb. GABA is found in lare numbers of local interneurons. GABAergic projection neurons that carry inhibitory information longer distances within the rbain. The actions of GABA are primarily mediated by ionotropic GABAA receptors. GABA makes both ionotropic and metabotropic receptors. However only 1 type of each is sed. The GABA A receptor is ionotropic and the GABAB receptor is metabotropic. GABA A receptors are ion channels that permit Cl-ions to move across the cell membrane from outside to inside. This causes inhibition of the postsynaptic cell as a result of membrane hyperpolarization. More Cl-ions flow through open GABAA receptor channels when the membrane has previously been depolarized by excitatory synaptic input. Each GAGAA receptor contains 5 subunits. 3 or 4 different kind of subunits may be found within a particular GABAA receptor complex. These subunits are designated by Greek letters α β ϒ δ2. Most GABA receptors are thought to contain two subunits α, two β and one ϒ. The classic agonist for GABAA receptor is a drug called muscimol. This compound is found in the mushroom Amanita muscaria. Bicuculline is best known competitive antagonist for GABA A receptor. It blocks the binding of GABA to GABAA receptor and when taken systemically can have convulsive effects. Anxiolytic ( anti anxiety) Drugs of abuse may be defined as psychoactive substances that have the potential to be used in a problematic way, usually because the substance affects mood, or behaviour in a manner that is desirable to the user. The medicalization of addiction has two compnoents : that addiction was now thought of as a disease and that drug addicts should be treated by the medical establishment. By the beginning of the 20th century there was widespread use of cocaine, opium, and heroin in over the counter or patent medications. The Food and Drug act in 1906 mandated the accurate labeling of patent medicines so that a consumer would be aware of the presence of alcohol, cocaine, opiates, or marijuana in such products. History of federal Drug Legislation in the US Name of Law Year enacted Purpose Pure Food and Drug Act 1906 Regulated labeling of patent medicines and created the FDA Harrison Act 1914 Regulated dispensing and use of opiod drugs and cocaine Eighteeth Constitutional Amendement (Prohibition) 1920 Banned alcohol sales except for medicinal use (repealed in 1933) Marijuanna Tax Act 1937 Banned nonmedical use of cannabis ( overturned by US Supreme Court in 1969) Controlled Substances Act 1970 Established the schedule of controlled substances and created the DEA The Harrison Act used these provisions: 1) Use of these substances for non medical purposes was prohibited. 2) Pharmacists and physicians were required to register with the treasury department and to keep records of their inventory of narcotics. 3) Retail sellers of narcotics and practicing physicians had to pay a yearly $1 tax to the federal government. 4) Patent medicines containing small amounts of opium, morphine, heroin, or cocaine remained legal and could continue to be sold by mail order or in retail establishments. Every time the government became more involved in drug regulation, the action resulted in an increase in drug use and /or perceived societal dangers posed by such use. Description of addiction – “Certain individuals use certain substances in certain ways thought at certain times to be unacceptable by certain individuals for reasons both certain and uncertain” Burglass and Shaffer (1984). Drug addiction is considered to be a chronic relapsing behavioral disorder. Some drugs such as alcohol and opiates can create strong physical dependence and severe withdrawal symptoms in dependent individuals. Modern conceptions of addiction - focus more on behaviours specifically the compulsive nature of drug seeking and drug use in the addict. The addict is often driven by a strong urge to take the drug called craving. Secondly addiction is thought as a chronic relapsing, disorder. The individual remains addicted for long periods of time. Drug free periods (remissions) are often followed by relapses in which drug use recurs despite negative consequences. Current view of addiction is – drug addiction can be defined as a chronically relapsing disorder, characterized by compulsion to see and take the drug, loss of control in limiting intake and emergence of a negative emotional state when access to the drug is prevented. The DSM-5 says substance-related disorders instead of addictions that cover 10 designated classes of drugs 1) alcohol 2) caffeine 3) cannabis 4) hallucinogens 5) inhalants 6) opioids 7) sedative-hypnotic and anxiolytic drugs 8) stimulants 9) tobacco 10) other substances. The DSM-5 states all of these substances share the ability to activate the neural circuitry that mediates “reward”. It is further broken down into substance use disorders and substance- induced disorders. Substance use disorders – a cluster of cognitive, behavioural, and physiological symptoms indicating that the individual continues using the substance despite significant substance-related problems. Substance-induced disorder – the development of a reversible substance-specific syndrome due to recent ingestion of a substance. Intoxication, withdrawal, and other substance/medication-induced mental disorders (substance-induced psychotic disorders, substance-induced depressive disorder). There are two types of progression in drug use: In one type the youth starts by taking legal substances such as alcohol or tobacco, then later progresses to marijuana and in a small percentage moves to cocaine, heroin, or other illicit drugs. This is called the gateway theory. conducted under drug-free conditions. If the drug produced a reward, the animal will spend more time in the drug compartment than in the other compartments. Electrical self-stimulation - an electrical stimulus is sent to the brain’s reward centre. The threshold for rewarding brain stimulations is reduced when animals have been treated acutely with various drugs of abuse. Certain drugs can lead to physical dependence when taken repeatedly such as alcohol, and opiates. Once an individual has become dependent, attempts at abstinence lead to highly unpleasant withdrawal symptoms. This motivates the user to take the drug again to alleviate the symptoms. Addictions changes from an impulse stage where the drug motivation is a positive reinforcement of the high from the drug to a compulsive stage where the drug use is a negative reinforcement to alleviate the withdrawal symptoms. Genetic factors contribute to the risk for addiction. Common disease-common variant hypothesis – the genetically based susceptibility to a particular neuropsychiatric disorder stems from a pool of risk-conferring gene alleles that are possessed in common through the population. Each of these “ risk alleles” that you carry confers a small increase in susceptibility to developing the disorder. Your genetic based susceptibility is based on the sum of all the risk alleles you carry. Common disease-rare variant hypothesis – different individuals diagnosed with the same disorder may carry vastly different genetic profiles. Therefore, a significant portion of the genetic risk for a neuropsychiatric disorder stems from rare mutations or other genetic anomalies such as copy number variations. Three main approaches are used to study the genetics of neuropsychiatric disorders. Candidate gene analysis, Linkage analysis, and Genome-wide association studies. Psychosocial variables also contribute to addiction risk. Risk factors Sociodemographic variables Exhibiting conduct disorders during childhood Having substance using friends/peers Occurrence of stressful life events Addicts and alcoholics are often diagnosed with an anxiety, mood or personality disorder in addition to their drug problem. These can lead to self-medication to treat their unknown conditions. It is predicted that those with anxiety tend to seek out alcohol or other sedative anxiolytic drugs where as depressed people seek out stimulant medications such as cocaine, of amphetamine. It is also possible that it occurs in a reverse order where the substance disorder leads to symptoms of anxiety/depression behaviours. Shared etiology – is a combination of genetic and environmental factors contribute to elevated risk for addiction. Protective Factors An absence of various risk factors The development of addiction has been conceptualized as a repeating spiral of three stages associate with substance use. 1) Preoccupation with and anticipation of obtaining and using the substance. 2) Binge use and intoxication from the substance 3) Withdrawal and the associated negative affect when coming down from the drug. This framework has been used to better understand the neurobiology of addiction including the neural circuits and neurotransmitters implicated most directly in each stage. Psychostimulants such as cocaine and amphetamines exert their rewarding effects by directly releasing DA from dopaminergic terminals in the NAcc and / or by blocking DA reuptake after its release. Opioid drugs such as morphine or heroin activate the reward circuit by stimulating opiod receptors in the VTA, NAcc, and AMG. Opioid reward is mediated by a combination of DA- independent mechanisms. Alcohol enhances the action of ϒ-aminobutyric acid (GABA) on GABAA receptors, and this enhances DA release in the NAcc and opioid peptides release in the VTA, NAcc, ad AMG. Nicotine derived from tobacco activates the reward circuit by stimulating nicotinic cholinergic receptors in the VTA, NAcc and AMG THC derived from Marijuanna are rewarding because of the stimulation of cannabinoid receptors in the VTA, NAcc and AMG. Both nicotine and THC enhance the DA release in the NAcc through local mechanisms and/or acting within the VTA. The dopaminergic system is essential for drug reward for some substances like cocaine, or amphetamine nit not for others such as heroin or alcohol. Opioids or THC provoke very little DA release in the ventral striatum. 3. What are DT’s? 4. Discuss the neurotoxic effects of heavy alcohol consumption. 5. Describe the effects of alcohol in other body organ systems. 6. How does alcohol affect glutamate? 7. Discuss the major psychological factors associated with alcoholism. 8. What are the two major pharmacotherapeutic approaches in treating alcoholism? Describe the drugs used in these approaches. Alcohol is the most commonly used psychoactive drug in America and is the drug that is most abused. Alcohol use began with the very first immigrants. Ethyl alcohol is the alcohol we are most familiar with. An ethyl molecule has 2 carbon atoms, a complement of hydrogens plus the -OH (hydroxyl group). Methyl or wood alcohol have even simpler chemical structures but are highly toxic if consumed. Yeast converts each sugar molecule into 2 molecules of alcohol. Alcohol is easily absorbed by the GI tract and diffuses throughout the body, entering most tissues, including brain. The rates of absorption, distribution and clearance of alcohol are modified based on many factors all od which contribute to the highly variable blood levels that occur after the ingestion of a fixed amount of alcohol. For this reason, behaviours are based on a blood alcohol concentration (BAC) rather than the amount ingested. It takes .02% (20mg of alcohol per 100 ml of blood) to produce measurable behavioural effects. Since oral administration is about the only way this drug is used recreationally, absorption will necessarily occur form the GI tract: about 10% from the stomach and 90% from the small intestine. The small molecules move across the membrane barriers by passive diffusion from the higher concentration on one side to the lower concentration on the other (blood). Carbonated alcoholic beverages are absorbed more quickly because carbination speeds the movement of materials from the stomach to the intestines. Gender differences also exist in the absorption of alcohol from the stomach bc certain enzymes that are present in gastric fluid are about 60% more active in men than women, leaving a higher concentration of alcohol that will be absorbed more rapidly in women. Of alcohol that reaches the general circulation, approx. 95% is metabolized by the liver before excreted as carbon dioxide. The remaining 5% is excreted by the lungs and can be measured in one’s breath by using a breathalyzer. Alcohol metabolism is different from that of most other drugs in that the rate of oxidation is constant over time and does not occur more quickly when the drug is more concentrated in the blood. The average rate is approx. 1 to 1.5 ounces or 12-18 ml of 80-proof alcohol per hour. Several enzyme systems in the lover are capable of oxidizing alcohol. Most important is alcohol dehyogenase, which is found in the stomach and reduces the amount of available alcohol for absorption. This enzyme converts alcohol to acetaldehyde, a potentially toxic intermediate, which normally is rapidly modififed further by aldehyde dehydrohease (ALDH) to form acetic acid. The ALDH gene a marker for low risk of alcohol use disorder. The 2nd class of enzymes is cytochrome P450 family. The enzyme of importance in this family is CYP2E1 which is something called microsomal ethanol oxidizing system (MEOS). These enzymes metabolize many drugs aside form alcohol. In contrast to the acute effect, when alcohol is consumed on a regular basis, these liver enzymes increase in number which increases the rate of metabolism of alcohol as well as other drugs. This process is called induction of liver enzymes and serves as the basis for metabolic tolerance. Chronic alcohol use leads to both tolerance and dependence. The effects of alcohol are significantly reduced when the drug is administered repeatedly. This creates tolerance. There is also cross-tolerance with a variety of other drugs in the sedative- hypnotic class, including barbiturates and benzodiazepines. Acute tolerance - occurs within a single exposure to alcohol. Many binge drinkers do not recognize their alcohol levels and are responsible for about 80% of alcohol impaired accidents each year. Metabolic Tolerance- chronic alcohol use significantly increases the P450 lover microsomal enzymes that metabolize the drug. More rapid metabolism means the blood levels of the drug will be reduced, producing diminished effects. Pharmacodynamic tolerance - neurons also adapt to continued presence of alcohol by making compensatory changes in cell function. Behavioural tolerance - animals and humans are able to learn to adjust their behaviours when allowed to practice while under the influence of alcohol. Classical conditioning may also contribute to behavioural tolerance. vesicles. For women it caused disrupted ovarian function and higher than normal incidence of menstrual disorders. Gastrointestinal System - increases salvation and secretion of gastric juices, which in turn increased appetite and aid digestion, although higher concentrations irritate stomach lining and chronic use produces inflammation of the stomach and esophagus. Heavy alcohol use causes diarrhea, inhibits utilization of proteins, and reduces absorption and metabolism of vitamins and minerals. Liver - liver dysfunction. Fatty Liver - involves the accumulation of triglycerides inside the liver cells. When alcohol is present, it metabolizes that first and leaves the fat for storage. Alcohol also effects adipose tissue. Alcohol causes inflammation of the tissue along with increased breakdown of fat into fatty acids. These changes release fatty acids into the blood which contributes to the increased deposit of triglycerides by liver cells. Alcohol-induced cirrhosis – a scar tissue develops blood vessels carrying oxygen are cut off leading to cell death. Effects on Fetal Development - Alcohol passes the placental barrier. The baby will reach the same BAC as the mother. The damaging developments effects of the prenatal exposure leads to fetal alcohol syndrome. FAs is the most preventable cause of intellectual disability. Diagnostic signs of FASD are : Intellectual disability and other developmental delays, low birth weight, neurological problems, distinctive craniofacial malformations, other physical abnormalities. There are no cures for FASD but identification before age 6 can help to improve the outcome for the child developmentally as therapies can be started early. Effects of alcohol on neuronal membranes – alcohol acts at both specific and nonspecific sites including membrane phospholipids, ligand-gated channels and second messenger systems. 1. Nonspecific – alters lipid composition. 2. Nonspecific – interacts with polar heads of phospholipids. 3. Nonspecific – disturbs the relationship of protein in membrane. 4. Specific – acts at neurotransmitter binding site. 5. Specific – modifies gating mechanism inside channel. 6. Specific – interacts directly with channel protein. 7. Specific – stimulates Gs, which is linked to adenylyl cyclase. Glutamate – all glutamate receptors are inhibited by acute alcohol exposure but some are only affected by high concentrations. Alcohol has the greatest effect on the NMDA receptor which is a ligand-gated channel that allows positively charged ions to enter and cause localized depolarization. In adult brains, repeated use of alcohol leads to a neuroadaptive increase in the number of NMDA receptors in response to reduced glutamate activity. GABA – Alcohol modulates GABA function both directly via GABA A receptors and indirectly by stimulating GABA release. Role of Selected Neurotransmittersin cellular and behavioural effects of alcohol Neurotransmitter Acute cellular effects Chronic cellular effects Behavioural effects Glutamate • Receptor antagonis m and reduced glutamate release • • • • Up-regulation of receptors and rebound increase in glutamate release • Extreme hyperexcitabili ty and massive Ca2+ influx (rebound) • Memory loss • Rebound hyperexcitabili ty of the abstinence syndrome • • Brain damage GABA • Increase in GABA- induced Cl- influx to hyperpolariz e • • • Neuroadaptiv e decrease in GABA function without change in receptor number • Sedative effects, anxiety reduction, sedation, incoordination , memory impairment • Tolerance and signs of hyperexcitabili ty during withdrawal (seizures, tremors) Dopamine • Increase in dopamine transmission in mesolimbic tract • • • Reduced firing rate, release metabolism • Reinforcement • Negative affect as a sign of withdrawal Opioids • Increase in endogenous opioid synthesis and release • • Neuroadaptiv e decrease in endorphin levels • Reinforcement • Dysphoria Alcohol Use Disorder – (AUD) (previously called alcoholism) is a serious and complex phenomenon that consists of psychological, neurobiological, genetic, and sociocultural factors, making it both difficult to define and treat. Unit 11 notes - questions to consider Some narcotic drugs are semisynthetic because they require chemical modifications on the natural opiates. Hydromorphone ( Dilaudid) and heroid are modifications of the morphine molecule. Propoxyphene (Darvon) , Meperidine ( Demeroll) are completely synthetic. Natural narcotic s Opium Morphine Codeine Thebaine Semisynthe ti c Narcotics Heroin Hydromorph o ne Oxycodone Buprenophine Totally Syntheti c Narcotic s Pentazoci n e Demerol Fentanyl Methadone LAAM Propoxyphe n e Endogenou s Neuropepti d es Enkephali n s Endorphines Dynorp hi ns Endomorphi ns Nociceptin/ orphan in FQ Opioids have the most important effects on the CNS and the GI tract. Modified opioid molecules such as loperamide, which was designed so that is cannot cross the blood-brain barrier. It slows the GI tract but has no effects on the CNS. Opioids drugs produce biobehavioural effects by binding to specific neuronal receptors. Four opioid receptor subtypes µ(mu) – is the receptor that has a high affinity for morphine and related opioid drugs. The location has been mapped by autoradiography in several species. Distribution is in the brain (medial raphe, medial thalamus, periaqueductal gray,) and clusters within the spinal cord. Other high density areas suggest a role in feeding and positive reinforcement(nucleus accumbens), cardiovascular and respiratory depression, cough control, nausea and vomiting and sensorimotor integration. δ(delta) – distribution similar to the mu receptor but are more restricted. Predominently in the forebrain structures such as the neocortex, striatum, olfactory areas, substantia nigra and nucleus accumbens. Possible roles in modulating olfaction, motor integration, reinforcement, and cognitive function. κ(kappa) – have very distict distribution compared to the mu and delta. Found on the straitum and amygdala but also has distribution in th hypothalamus and pituitary. May participate in the regulation o fpain perception, gut motility, and dysphoria but also modulate water balance, feeding, temperature and neuroendocrine function. FQ (NOP-R) – are widely distributed in the CNS and peripheral nervous system. Found in high concentration in the cerebral cortex and the limbic areas including the amygdala, hippocampus, and hypothalamus as well as periaqueductal gray, thalamus and brainstem nuclei. Suggestive role in analgesia, feeding, learning, motor function and neuroendocrine regulation. The first peptide enkephalin Soon many peptides were found and called endorphins. Locations, functions, and endogenous ligands for opioid receptor subtypes Receptor Subtype Endogenous ligands (prohormone sources) Locations (most dense) Functions µ (mu) Endormorphins (unknown), endorphins (POMC) Thalamus, periaqueductal gray, raphe nuclei, spinal cord, striatum, brainstem, nucleus accumbens, amygdala, hippocampus. Analgesia, reinforcement, feeding, cardiovascular and respiratory depression, antitissue, vomiting, sensorimotor integration δ (delta) Enkephalin (proenkephalin) Endorphins (POMC) Neocortex, striatum, substantia nigra, nucleus accumbens, spinal cord, hippocampus, amygdala, hypothalamus Analgesia, reinforcement, cognitive function, olfaction, motor integration κ Dynorphins (prodynorphin) Pituitary, hypothalamus, amygadala, striatum, nucleus accumbens Neuroendocrine function, water balance, feeding, temperature control, dysphoria, analgesia NOP-R Nociceptin/orphanin FQ (pronociceptin/orphanin FQ) Cortex, amygdala, hypothalamus, hippocampus, periaqueductal gray, thalamus, substantia nigra, brainstem, spinal cord. Spinal analgesia, supraspinal pronociception, feeding, learning, motor function, neuroendocrine function. Four opioid receptor subtypes are linked to the G proteins. Neuropeptides reduce synaptic transmission in three principal ways 1) by postsynaptic inhibition, through axoaxonic inhibition, and via presynaptic autoreceptors. The two components of pain have distinct features First or early pain represents immediate sensory component and signals the onset of noxious Unit 12 notes - questions to consider Unit 12 – read chapter 12 PSYC 450 Psychomotor Stimulants: Cocaine, Amphetamine, and Related Drugs. Questions to consider. 1. What is cocaine? What is crack? 2. Describe the mechanism of action of cocaine. 3. Briefly discuss dopamine’s role in the behavioural effects of psychostimulant drugs. 4. Explain what sensitization is and describe its phases. 5. How can pharmacotherapy be sued in treating cocaine dependence? 6. What is amphetamine? How is it used therapeutically? 7. Describe the behavioural effects that amphetamine can have on users. 8. What is MDMA? How can it affect brain pathways? Psychomotor stimulants – cocaine, amphetamine, and related compounds. Marked sensorimotor activation that occurs in response to drug administration. . They have an ability to increase alertness, heighten arousal, and cause behavioural excitement. Cocaine is an alkaloid found in the leaves of the shrub Erythroxylon coca. The shrub is native to south America. 92% of cocaine entering the US comes from Columbia. Coca paste contains about 80% cocaine, the alkaloid is then converted to hydrochloride salt and is crystalized. It is water soluble so much be taken orally, intranasally, or by IV injection. It can be converted back into “freebase” by dissolving in water and add an alkaline solution such as ammonia, and then extract the resulting cocaine base with an organic solvent. A safer way is taking cocaine base, mixing it with baking soda, heating it and then drying it. Extremely rapid absorption occurs from IV injection and smoking. Cocaine is lipophilic and passes through the blood brain barrier quite readily. Rapid entry into the brain is believed to be a reason crack is so easily addictive. Cocaine half life is about 30 mins to 60 mins. Cocaine interacts with several neurotransmitter systems. Most of the behavioural and physiological actions can be explained by the fact that cocaine can block reuptake of three monoamine neurotransmitters: the two catecholamines dopamine (DA) and norepinephrine (NE) and also serotonin (5-HT). The stimulant methylphenidate exerts similar behavioural profile to cocaine but the DA uptake blockers mazindol nomifensine, vanoxerine do not produce euphoria and lack cocaine’s abuse potential. At high concentrations cocaine also blocks voltage-gated Na+ channels, which leads to a local anesthetic effect. Cocaine stimulates mood and behaviour. Typical aspects of cocaine high are: exhilaration, euphoria, a sense of well-being, enhanced alertness, heightened energy and diminished fatigue and great self- confidence. Cocaine is considered a sympathomimetic drug – meaning is produces symptoms of sympathetic nervous system activation. The physiological symptoms consequences of acute cocaine use includes increase heart rate, narrowing of blood vessels, increased blood pressure. At low does these changes are not usually harmful but at higher doses it can be very toxic or fatal. Nucleus accumbens DA has also been implicated in cocaine reward by using paradigms that test for drug- seeking behaviour as a model of relapse in previously abstinent individuals. Chronic Abuse and the effects of chronic cocaine exposure. Therapies currently in practice to help with cocaine addiction. Psychosocial treatment programs Cognitive behavioural therapy Relapse prevetion therapy Amphetamines Amphetamine - is the parent compound if a family of synthetic psychostimulants. Available in two chemical forms L-amphetamine (Benzedrine) and D-amphetamine (Dexedrine). Another key member of this family is methamphetamine. Two naturally occurring plant compounds have structures similar to those of amphetamine and methamphetamine are cathinone and ephedrine. Amphetamine is typically taken either orally or by IV or by sub cue injection. Street names include uppers, bennies, dexies, black beauties, and diet pills. It may take up to 30 mins for behavioural effects after a typical dose of 5-15 mg. IV injection is more rapid and intense than oral consumption. Methamphetamine is more potent in its effects on the CNS. Street names are meth, speed, crystal, crack, zip, and go. It can be snorted, injected IV, or smoked. The drug vaporizes at a low temperature is not readily broken down by heat. Both are metabolized by the liver although at a slow rate. Both are indirect agonists of catecholamine systems, blocking reuptake and also release it from nerve terminals. Heighten alertness, increased confidence, feelings of exhilaration, reduce fatigue, and generalized sense of wellbeing, improved performance on simple repetitive tasks, a delay in sleep onset, and reduction of needed sleep time. Therapeutic uses Treatment of narcolepsy. Treatment of ADHD Unit 13 notes - questions to consider Unit 13 – read chapter 13 Nicotine and Caffeine Questions to consider. 1. What is nicotine? How does it work? 2. Describe the effects nicotine at high doses. 3. Describe the abstinence syndrome associated with nicotine. 4. Discuss two kinds of nicotine-replacement therapies. 5. What is caffeine? What are its main behavioural and physiological effects? 6. What is caffein’s mechanism of action? 7. Describe the pattern of tolerance with chronic use of caffeine. 8. What is caffeinism? Nicotine is an alkaloid found in tobacco leaves. A typical tobacco cigarette contains 6-11mg of Nicotine, although no more than 1-3mg enter the blood stream. Tobacco can be smoked, chewed, or snorted. Tobacco enters the smoker’s lungs on particles called tar. A typical smoker takes about 10-15 puffs per cigarette at intervals of 30-60 seconds apart. E-cigarette’s “vaping” About 70-80% of nicotine in the body is transformed into the principal metabolite cotinine by a specific liver enzyme known as cytochrome P450 2A6. Nicotine half life is about 2 hours. Nicotine works mainly by activating nicotine acetylcholine receptors. Nicotine is found to increase calmness and relaxation in recently abstinent smokers. Nonsmokers may feel nauseous, lightheaded and dizzy after smoking. Nicotine exerts both reinforcing and aversive effects. Under the right experimental conditions experienced smokers will self administer pure nicotine by IV injection. This shows nicotine itself can be reinforcing. Smoking a cigarette stimulates the adrenal glands to release epinephrine and norepinephrine. These hormones along with direct nicotine-induced activation of sympathetic hanglia lead to symptoms of physiological arousal. Nicotine is toxic and can be fatal at high doses. Chronic exposure to nicotine leads to tolerance and then dependence. Interventions to quit smoking Behavioural and Psychosocial interventions. Warnings on cigarette packs Self-help programs Web based cessation programs Pharmacological interventions. Nicotine replacement therapy -first was created was a gum, delivers nicotine continually at lower does to reduce cravings. Next available as a patch, nasal spray and lozenge. Non-nicotine drugs aimed at reducing tobacco cravings and withdrawal symptoms. Bupropion and varenicline. Antinicotine vaccines. Caffeine Coffee comes from coffea arabiaca plants. Tea contains both caffeine and theophylline. Both are members of a wider group of plant derived chemicals called methylxanthines. Caffeine can increase arousal, enhance cognitive function. Regular use of caffeine can produce tolerance and dependence. Excessive ingestion can pose significant health risks. Caffeine intoxication - recent high doses of caffeine (more than 1000mg) symptoms of restlessness, nervousness, insomnia, and physiological disturbances (increased heart rate, muscle twitching, GI upset). Caffeine dependence syndrome (caffeine use disorder) - a cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include strong desire to take the drug again, difficulties in controlling use, persisting in its use despite harmful consequences, higher priority given to the drug use than other activities and obligations, increased tolerance, and sometimes physical withdrawal. Regular coffee consumption of 3-4 cups per day reduces the risk of developing type 2 diabetes. Caffeeine properties are mediated rimarily by its ability to block A1 and A2a receptors from the neurotransmitters adenosine. Unit 14 – read chapter 14 PSYC 450 Marijuana and the Cannabinoids Questions to Consider. 1. What are cannabinoids? What are endocannabinoids? 2. What does THC do? 3. Discuss the therapeutic uses of cannabinoids. 4. Describe the behavioral and physiological effects of cannabis consumption. 5. Are cannabinoids reinforcing to non-human animals? Explain. 6. Describe the dependence and withdrawal characteristics of chronic cannabinoid use. 7. Discuss the limitations of research investigation chronic cannabis use and cognition deficits. 8. Describe potential health concerns with chronic cannabis use. Cannabis plants contain 70unique compounds that are collectively known as phytocannabinoids. The psychoactive properties of some of these compounds is called THC. Cannabis originated in central Asia and was used for medical and religious reasons. A non-psychoactive ingredient is CBD and is used to treat a variety of neuropsychological and neuropsychiatric disorders. Inhaled THC is quickly absorbed by the lungs and enters circulation where oral consumptions yields slower plasma peak. THC is extensively metabolized in the liver and the metabolites are excreted in the feces and urine. Cannabinoid receptors CB1 and CB2 – found in the immune system and in the tissues of bone, and adipose tissue and GI tract. CB1 0 in the brain, expressed at high density in the basal ganglia, cerebellum, hippocampus and cerebral cortex. CB2 – first identified in the immune system, found in other tissues and in the brain where it is mainly localized in microglial cells. Cannabinoid receptors belong to the G protein coupled receptor superfamily. Receptor activation can inhibit cAMP formation, inhibit voltage sensitive Ca2+ channels and activate K+ channels. Agonists at the receptor (CB1) include synthetic full agonists CP-55-940 and WIN 55, 212-22 and the partial agonist THC. CB1 agonists also impair learning and memory consolidation in several different kinds of tasks. CB2 receptor activation in the immune system causes cytokine release and change sin immune cell migration toward inflammatory site. The brain synthesizes several substances call endocannabinoids that are neurotransmitter-like agonists at cannabinoid receptors. Anandamide was the first endocannabinoid to be discovered but 2-AG is present in the brain at higher levels. Endocannabinoids are generated on demand from arachidnic acid-containing membrane lipids by a Ca2+ dependent mechanism and are relweaseed from the cell by a process that does not involved synaptic vesicles. Endocannabinoids usually function as retrograde messengers that are sunthesized and released from postsynaptic cells to activate CB 1 receptors. The endocannabinoids system plays a complex role in learning and memory of hippocampal- dependent tasks. Oral spray with both THC and CBD for neuropathic pain and spasticity in patients with MS. Characteristics of Cannabis intoxication Euphoria, disinhibition, relaxtation, altered senations, increased appetite. Cannabis acutely causes impairment in episodic verbal memory and working memory, attention, inhibition control, and psychomotor function. Cannabis use disorder – estimated 10% of users will become dependent. Neuroimaging studies of regular cannabis users have reported structural and biochemical changes in certain brain regions including reduce volume of the hippocampus and parts of the PFC and defictis in white matter integrity. Health consequences of heavy marijuana smoking include – respiratory problems, increased risk of myocardial infraction, interference with reproductive systems, suppression of immune system, andverse effects on offspring. NBOMes – a new class of synthetic hallucinogens. Distributed in a single dose on blotter paper. Usually taken sublingual or buccal routes of administration. Very potent which makes overdose very easy and possible. Salvia – is a member of the mint family native to Oaxaca. Historically used in religious rituals. Recreational users may chew fresh salvia leaves, smoke dried and crushed leaves or consume concentrated salvinorin. Few psychoactive effects occur when ingested orally. It is however quicklu absorbed by the lungs when smoked and yields rapid and intenstexperiences. It dissipates rapidly typically lasting 15 mintues. Routes of Administration and Potency of Various Hallucinogenic Drugs Drug Usual route of administration Typical dose range LSD Oral 50-100µg (.05-.10 mg) 25I-NBOMe Sublingual/buccal 250-800 µg (.25-.80 mg) Psilocybin (Shrooms) Oral 10-20 mg Mescaline Oral 200-500 mg DMT Smoking 20-50 mg Salvinorin A (Salvia) Smoking 200-1000µg (.2-1.0 mg) LSD trip divided into 4 phases – onset (within 30 mins), plateau (2 hours), peak(generally after hour 3 and lasts 2-3 hours) and comedown ( may last 2 hours) Most hallucinogenic drugs share a common indoleamine or phenethylamine structure. Despite the relative lack of addictive potential hallucinogens still cause serious problems for some users. Hallucinogenic drugs disrupt the normal electrical oscillations measured in the cerebral cortex. PCP and Ketamine PCP also known asd phencyclidine – was first tested as a potential anesthetic agent. Street names like angel dust and hog. Generally a pill form and can be ingested orally, snorted, or injected by IV. Many users add it to tobacco or pot. Ketamine – was considered a safer alternative than PCP . Used for sedation for children and by veterinarians. Currently marketed legally as a prescription medication under the trade names Ketalar, Ketaset and Vetalar. Sold as a liquid, that manufacturers evaporate down into a powder that is snorted or compressed into a pill. Sold as street names special K, K or cat valium. PCP and Ketamine bind to a site within the NMDA receptor channel, thereby acting as noncompetitive receptor antagonists. A secondary consequence of NMDA receptor blockade in increased presynaptic glutamate release which may contribute to the behavioral and subjective effects of PCP and ketamine. Unit 16 notes - questions to consider Nitrites – used to heighten sexual arousal and pleasure. Nitrites produce subjective effects by dilating blood vessels and causing muscle relaxation. Also known as poppers. Abused inhalants are rapidly absorbed and readily enter the brain. Effect occur quickly and dissipate quickly as well. They are measured in the particles in the air is units of ppm. Exposures higher than 500ppm are believed to be potentially dangerous to a person’s health. Inhalants have complex effects on the CNS function and behavioral activity. Toluene acutely enhances the function of inhibitory GABAA and glycine receptors, whereas it inhibits the activity of excitatory NMDA. Health Risks have been associated with inhalant abuse. Sudden sniffing death syndrome. Damage to the liver, kidneys, respiratory tract and bone marrow. Gamma-Hydroxybutyrate (GHB) GHB is closely related structurally to the important inhibitory neurotransmitter GABA. GHB can be taken up into GABAergic vesicles by the vesicular inhibitory amino acid transporter. Street names are liquid X, liquid E, Georgia home boy, grievous bodily harm, heaven, cherry meth, organic quaalude and natures quaalude. Users take the drug for the relaxation, euphoria and sexual arousal. GHB is known as the club drug and also the date rape drug because of its sedation effects at high doses. In 2000 it became a schedule 1 controlled substance. GHB containing solutions are clear, odorless and almost tasteless. It is rapidly absorbed in the GI tract and enters the bloodstream and crosses the blood-brain barrier. GHB is used therapeutically for the treatment of narcolepsy and alcoholism. Anabolic-Androgenic Steroids (AAS) Doping agents are performance enhancing steroids. AAS – are steroid hormones that increase muscle mass and also have masculinizing or testosterone-like properties. AAS are structurally related to testosterone. Often taken orally or by intramuscular injection. AAS prescribed for medicinial purposes are sometimes formulated for buccal or transdermal patch absorption or topical gel. Intramuscular injection is developed to last 7 days to 3 weeks. AAS are taken in specific pattern and combinations. They use a pattern called cycling and cycles last 6-12 weeks in duration. They use cycling because: To minimize the development of tolerance to the drug To reduce the occurrence of adverse side effects To maximize performance at an atheletic competition To avoid detection of a banned substance. Cycling is sometimes is combined with pyramiding, in which steroids dose is gradually increased until the midpoint of the cycle and then is gradually decreased. Stacking refers to using 2 or more steroids at the same time. AAs all have androgenic action, which means they are all agonists at the androgen receptor. AAS exert several additional effects that contribute to muscle growth. One in the increase in proliferation of so-called satellite cells that are necessary for the formation of new myotubes. The 2nd is promotion of differentiation of local stem cells into muscle cells while inhibiting an aternate differentiation pathway into adipose cells. Many adverse side effects are associated with AAS. Abnormalities in heart structure and function, high blood pressure, and reduce high-density lipoprotein cholesterol. Liver toxicity ranges from mild to hepatitis and lover tumors. Severe impairment in renal function, skin and hair problems and high outbreaks of acne. Severe effects on reproductive systems. Depressed mood, irritability, violent outburst (roid rage), muscle dysmorphia. Men show suppressed release of LH and FSH from the pituitary gland bc of androgenic properties of AAS activate negative feedback system that controls gonadotropin release. Testosterone has an important role in the treatment of hypogonadism. This is when the teste are unresponsive to LH and FSH, which result in low testosterone levels, which can cause poor libido, ED, sterility, and loss of muscle mass and bone density.