Drugs and Behaviour Study Guide PDF

Drugs and Behaviour Study Guide Opioids Opiate – a drug derived from opium, primarily used for pain relief and sedation Opioid – opiate-like drugs that mimic the effects of opiates, acting on the same receptors Semisynthetic opioids – modification of morphine - 10x more lipid soluble, Diacety...

Drugs and Behaviour Study Guide Opioids Opiate – a drug derived from opium, primarily used for pain relief and sedation Opioid – opiate-like drugs that mimic the effects of opiates, acting on the same receptors Semisynthetic opioids – modification of morphine - 10x more lipid soluble, Diacetyl morphine (heroin) Opioid agonists – drugs that promote (activate) opioid receptors - Methadone, oxycodone, Percocet, oxycontin Opioid antagonists – block opioid effects - Naltrexone, naloxone Partial/mixed agonists – agonist for one or more receptor but also an antagonist for one or more receptors - Buprenorphine, cyclazocine  Opioids are weak bases  Mu is the primary receptor for opioid drugs  Opioids have a rapid tolerance, withdrawal symptoms similar to severe stomach flu, peak after 1-3 days and end within a week  Opioid receptors concentrated in the basal ganglia, amygdala, and periaqueductal grey - Metabotropic receptors linked to inhibitory G-proteins - Closes calcium (Ca2+) channels on presynaptic neuron, reducing transmitter release - Opens potassium (K+) channels on postsynaptic neuron, leading to hyperpolarization  Opium poppy is the primary source for opium, contains two active ingredients: - Morphine: approx. 10% of opium - Codeine: approx. 0.5% opium Endogenous opiates – naturally produced peptides synthesized in the brain - Endorphins: work similar to morphine, universal binding affinity to all receptors - Enkephalins: highest affinity for delta receptor (DOP) - Dynorphins: highest affinity for kappa receptor (KOP) Brief pain survey  Types of pain: - Thermoceptive pain: pain caused by extreme hold or cold - Mechanical pain: pain due to physical damage of the muscles and skin - Visceral nociception: pain associated with organ damage  Pain not only involves sensation, but also emotional stimulus   When asked about the intensity of pain and how unhappy they were having their hand in cold water, participants distracted from pain reported lower rating for intensity of pain, however, this does not affect how unpleasant it feels for them Allodynia – where neurol alterations or injury make touch that is normally pleasant feel unpleasant and painful - Opioids produce high tolerance, and can sometimes develop into OIH  OIH: Opioid-Induced-Hyperanalgesia Reward System and Effects  Mu receptors increase dopamine in nucleus accumbens causing euphoria  Kappa receptors decrease dopamine leading to dysphoria  Depressant effects on respiratory system, pinpoint pupils, vomiting - Tolerance develops to effects not the drug itself  No effect on memory or cognitive performance (cerebellum)  Animal behaviour: - Low doses increase activity - High doses decrease activity leading to sedation and catalepsy  Catalepsy: decreased sensitivity to pain and muscles become rigid - Slows avoidance without disrupting escape Punishment-suppressed behaviour – normal behaviour reduced due to punishment - Opioids do not increase punishment-suppressed behaviour (no effect on memory) Antipsychotics Dopamine theory of schizophrenia – overactivity of dopamine D2 receptors in the mesolimbic pathways causes positive symptoms - Underactivity in mesocortical pathway may cause negative symptoms Glutamate theory of schizophrenia – low NMDA receptor activity contributes to all symptom types - May cause dopamine imbalances in different areas of the brain Diathesis-stress model of schizophrenia – suggests that schizophrenia develops from a genetic predisposition combined with early environmental stress such as birth complications and malnutrition  Weak bases  Dopamine D2 primary receptor  Characterized by a loss of touch with reality (schizophrenia)  Generally safe drugs with high LD50  Positive symptoms: things that are present in the person that shouldn’t be - Hallucinations, delusions  Negative symptoms: things that are missing compared to normal behaviour  - Flat affect (reduced emotional expression), attentional deficits  Animal model of schizophrenia can be modelled: - “Executive” function – working memory, decision making - Sensorimotor gating as assessed by prepulse inhibition - Stress-related behaviours  Neonatal Ventral Hippocampal lesion model of schizophrenia - Researchers created lesions in the ventral hippocampus of baby rats around 7 days old using a NMDA receptor antagonist - Rats are assessed again when they reach adulthood - Increases dopamine activity in mesolimbic pathway and decreases GABA function in the prefrontal cortex later in development - The hippocampus regulates activity in other brain activity regions including the prefrontal cortex, VTA, and nucleus accumbens  How can you suppress dopamine activity in the mesolimbic dopamine system without blocking dopamine activity in the nigrostriatal system?  Typical and atypical antipsychotics  Typical antipsychotics have high affinity for D2 receptors - Effects tend to be related to motor movement (parkinsonian symptoms), 40% people experience these symptoms (dulled facial expression, tremors in limbs etc.) - Akathisia, restlessness, constant compulsive movement, 20% of individuals - Generalize only to other typical antipsychotics  Atypical antipsychotics have high affinity for D3 and D4 receptors - Effective in treating negative symptoms of schizophrenia - D3 receptors found in nucleus accumbens - D4 receptors found in cortex, amygdala, and hippocampus - Higher affinity for 5-HT2A receptor than D2 receptor  Tardive dyskinesia – presentation of repetitive, involuntary, purposeless movements - Lip smacking, puckering, or pursing of the lips, rapid eye blinking, rapid movements in limbs - Often becomes more apparent when antipsychotic is withdrawn  Other effects on the body include poor temp. regulation (D3 receptors), seizures, reduced food intake, dry mouth, blurred vision  Tolerance shows after 2 weeks - Some recent studies show an improvement in cognition in schizophrenics after using antipsychotic drugs Antidepressants  Weak bases - First generation antidepressants (too broad, lots of side effects)  Tricyclic antidepressants: block the reuptake of serotonin and norepinephrine receptors increasing their levels in the brain, improving mood  Monoamine Oxidase Inhibitors (MAOIs): inhibit the monoamine oxidase enzyme preventing the breakdown of monoamines such as dopamine, serotonin, and  norepinephrine, increasing their levels in the brain alleviating depressive symptoms  MAO-A: enzyme for dopamine, norepinephrine, and serotonin  MOA-B: enzyme for dopamine  Newer drugs act on MOA-B - Typicals: Second generation antidepressants  Selective Serotonin Reuptake Inhibitors (SSRIs): blocks serotonin transporter, not selective to the subtype of serotonin receptor they bind to  Antidepressant effects result from alterations to 5-HT1A receptor  Unpleasant effects result from alterations to 5-HT2A receptor - Atypicals: Third generation antidepressants  Norepinephrine Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors (NARIs or SNRIs): block the reuptake of serotonin and norepinephrine  Dopamine Reuptake Inhibitors: e.g., Bupropion  Third generation do not alter muscarinic receptors; therefore, they do not produce some of the side effects associated with older antidepressants  All cross blood-brain and placental barriers - Oral administration, max. concentration after 1-3 hours, 4-8 for SSRIs - MAOIs need to be taken a few times a day, SSRIs one dose a day  MAOIS: short half-life of 2-4 hours  SSRIs: most of have a half-life of 15-20 hours  Individual may report having depressed mood or others may observe and report indictors such as fearfulness - Children and adolescents may express these feelings in the form of irritability - Appetite and weight gain or loss, sleep disturbance, psychomotor disturbance, feeling tired or devoid of energy, sense of worthlessness, inability to focus, occurring thoughts of death or suicide  More activity in the amygdala, less in prefrontal cortex during depressive episode  The Glucocorticoid Theory of Depression - Suggest that chronic stress leads to overactivation of the HPA axis, increasing cortisol levels  HPA: hypothalamic-pituitary-adrenal axis - High cortisol levels for a long time can cause damage to brain structures, particularly the hippocampus (regulates mood and provides negative feedback to stop stress) - Chronic stress leads to high cortisol, resulting in brain changes that may lead to depression  Monoamine Theory of Depression - Depression is a result of reduced monoamine levels - Monoamine fibres from midbrain project to limbic and cortical regions: this is called the medial forebrain bundle  Norepinephrine – locus coeruleus  Serotonergic – raphe system  Dopaminergic – VTA  - Evaluation: 1. Monoamine theory is wrong 2. There is some sort of delay in the development of a crucial monoaminergic connection  Alleviation of depressive symptoms between 4-6 weeks, however it can take up to 12 weeks before they reach their full effectiveness - Individuals with no personal or family history of depression, tryptophan depletion has no effect on mood (tryptophan precursor for serotonin)  Depression enhances brain matter and number of brain cells in the hippocampus  Non-life-threatening effects - Dry mouth, constipation, dizziness, irregular heartbeat, confusion, weight gain - Cognitive, memory, and psychomotor impairment related to sedation - No motor impairment with SSRIs  Effectiveness: - Placebo group: 29.7% - Antidepressant group: 50.1% Cannabis  Weak acid, pKa of 10.8  THC is the primary active ingredient in cannabis, however, active ingredients depend on preparation and the route of administration  CB1 and CB2 primary THC receptors - CB1: located primarily in the CNS on presynaptic neurons, mediate psychoactive effects of THC and modulate neurotransmitter release via. retrograde signalling  Retrograde signalling:  Occurs when cannabinoids travel backwards from postsynaptic neuron to presynaptic neuron 1. Endocannabinoids produced in postsynaptic neuron and released into synaptic cleft 2. Cannabinoids bind to CB1 receptors o presynaptic neuron 3. Activation of CB1 reduces calcium influx which decreases neurotransmitter release - CB2: located primarily in the PNS on lymphocytes and white blood cells  Phytocannabinoids are synthesized within the cannabis plant’s trichomes - Highest concentration of cannabinoids found on the buds of a female plant  THC: psychoactive, analgesic, antiemetic, appetite-stimulating effects  CBD: does not produce psychoactive effects, anticonvulsant, anti-inflammatory, neuroprotective, antipsychotic - Many of the medical benefits of cannabis derived from CBD content - Not specific to cannabinoid receptors  Endocannabinoids: endogenous cannabinoids - Produced by the body  - Anandamide (‘internal bliss”) first discovered followed by 2-AG - Act as neuromodulators, produced in CNS and PNS - Helps to maintain homeostasis  GABAergic neuron (inhibitory) released; binding is DSI  Glutamatergic neuron (excitatory) released; binding is DSE  Adding oils can increase absorption, peak concentration after 1-3 hours, low bioavailability and individual variability - Inhalation: joints, bongs, pipes  Cannabinoids distributed throughout entire body, however, depends on the rate of blood flow to tissues and organs - Half-life: 30-80 minutes - Concentrated in heart, lings, kidney, liver, body fat, not concentrated in brain  Most cannabinoids are broken down in the liver - 11-hydroxy-delta 9 primary metabolite (potent agonist) - CBD can block this enzyme, prolonging THC action - CBN may increase metabolism, shortening its action - CBD and CBN may alter distribution by displacing THC receptors from binding sites  Initial phase – THC blood levels fall rapidly, 30-minute half-life  Later phase – slower metabolism, half-life of 20-30 hours  How do cannabinoids regulate behaviour? - Depression-related effects result from dorsal raphe serotonergic systems - Anxiety associated with CB1 and TRPV1 receptors in amygdala and PAG - Cognitive and memory effects related to glutamatergic function in prefrontal cortex and hippocampus - Pain associated to action on CB1 receptors in the PAG or spinal cord  Effects of marijuana tend to be dose-related, higher THC will produce greater effects - People experience time passing more slowly - Temporal disintegration: Loss of the ability to retain and coordinate information for a purpose - Intensification of mirror surroundings and mood of others - Level of activation in prefrontal cortex associated with task increased in cannabis users - No effect on reaction time but does impair drivers’ ability to focus on the road  Recent studies indicate doubling the risk of car accident  Therapeutic applications: - FAAH: fatty amino acid hydrolase, enzyme responsible for anandamide breakdown - FAAH -/- mice that lacked the enzyme showed reduced anxiety-like behaviour compared to WT mice - Administration of FAAH increases endocannabinoid availability in synapse  Rimonabant: CB1 receptor antagonist effective in reducing drug-seeking behaviour - Glaucoma, antiemetic, anticonvulsant, movement, and spasticity disorders  Amotivational Syndrome – systemic changes in motivation and related phenomena   Cannabis use may double the likelihood of anxiety disorders, no significant effect on depression Hallucinogens, Phantasticants, and Club Drugs Phantasticants – feelings of emotional significance Psychedelics – mind manifester, surreal sensory experiences Empathogenics – feelings of insight Psychotomimetics – stimulating psychosis, delusions, and hallucinations  Monoamine-like psychedelics increase serotonin, dopamine, and norepinephrine transmission in varying amounts - LSD (primarily serotonergic) - MDMA (ecstasy) - Psilocybin (mushrooms)  LSD, psychoactive hallucinogen/psychedelic - Effects vary by dose, mood of individual, and the environment in which the drug is taken, common effects may include mental and physical stimulation, perceptual distortions, positive mood states - 5-HT2A primary receptor, partial agonist at post-synaptic receptors - Increases glutamate in the prefrontal cortex - Repeated administration leads to rapid tolerance, downregulation of 5-HT2A receptors, non-addictive and non-toxic - Due to rapid tolerance drug is generally not continuously consumed - Normally no withdrawal symptoms (lack of effect on dopaminergic neurons) - Harmful effects:  Acute freak out, flashbacks, trailing phenomena, combined with MAOIs more dangerous - Generally, not self-administered by non-humans except monkeys with MDMA history  MDMA (ecstasy, molly) stimulant - Synthesized by modifying amphetamine - Inhibits transporter proteins such as dopamine, serotonin, and norepinephrine  increases neurotransmitter activity in the synaptic cleft - Acts on serotonin receptor more potently than other transporters - Increases alertness and positive mood - Strong feeling of trust, openness, and closeness with others - Effects such as depression, impulsivity and hostility dissipate after 6 months drug is stopped   Increased body temperature may lead to heatstroke, kidney failure, brain swelling resulting in epileptic-like seizures - Self-administered by animals  Dissociative-anaesthetics, PCP, and ketamine  Ketamine, antidepressant, and analgesic (pain-relieving, veterinary use) - NMDA receptor antagonists, act as reinforcers, net decrease in dopamine release - Metabolized into norketamine metabolite - Improve symptoms within hours, lasting up to 2 weeks, tolerance develops when used everyday - Withdrawal symptoms include vocalizations, grinding of teeth, difficulty staying awake, anxiety, tremors, etc. - New synapse formation in prefrontal cortex and hippocampus, regulate stress and mood - Rats and monkeys self-administer ketamine - Popular in cities, not much elsewhere, used among high school students  Other hallucinogens  Salvia - K-opioid receptor agonist, D2 receptor partial agonist  GHB - Binds to GHB receptor site on the GABA_B receptor - Modulates dopamine and GABA - Used to treat narcolepsy - Concentrated on cortex and hippocampus (memory impairment)  Psychedelics are fast acting compared to conventional antidepressants  Psilocybin and depression, Davis et al., (2020) study - Participants assigned to immediate treatment group or delayed treatment control group - Psilocybin administered twice, supportive psychotherapy - Depression severity was assessed using the GRID-HAMD, structured version of Hamilton Depression Rating Scale - Results: psilocybin therapy when combined with psychotherapy led to rapid and significant reductions in depressive symptoms, compared to the control group