PSY1BNA Lecture 8: The Chemistry of Behaviour 2 Neuropharmacology

Key Concepts and Understanding

  • Basic neuropharmacology: Includes understanding binding affinity, efficacy, and dose-response relationships.
  • Drug effects on synaptic transmission.
  • Classes of drugs: antipsychotics, antidepressants, and anxiolytics.
  • Common recreational drugs.

Recommended Readings

  • Breedlove, S.M., & Watson, N.W. (2023). Behavioral Neuroscience (10th ed.). Sunderland, MA: Sinauer Associates, Inc. (Chapter 4; pp. 111-134).
  • Breedlove, S.M., & Watson, N.W. (2020). Behavioral Neuroscience (9th ed.). Sunderland, MA: Sinauer Associates, Inc. (Chapter 4; pp. 106-126).
  • Breedlove, S.M., & Watson, N.W. (2017). Behavioral Neuroscience (8th ed.). Sunderland, MA: Sinauer Associates, Inc. (Chapter 4; pp. 103-121).

Introduction

  • Neurochemistry: Focuses on the chemical composition and processes within the nervous system.
  • Neuropharmacology: Study of compounds that selectively affect the nervous system.

Binding Affinity and Drug Effectiveness

  • Binding Affinity: The degree to which a drug molecule binds to a receptor.
    • Higher-affinity drug: More likely to bind to the receptor than a lower-affinity drug.

Receptor Regulation

  • Down-regulation: A cell decreases the quantity of its receptor to a molecule like a hormone or neurotransmitter, reducing the cell's sensitivity to the molecule.
    • Occurs in response to agonists.
  • Up-regulation: Increase in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another signal.
    • Occurs in response to antagonists.

Drug Effects on Presynaptic Mechanisms

  • Drugs can affect various presynaptic mechanisms including:
    • Transmitter production.
    • Transmitter release.
    • Transmitter clearance.

Drug Effects on Postsynaptic Mechanisms

  • Drugs can affect the postsynaptic receptors:
    • Acting as agonists, antagonists, or modulators.
    • Influencing intracellular processes.
    • Examples include:
      • Haloperidol: affecting dopamine receptors.
      • Nicotine: affecting ACh receptors.
      • LSD: affecting Serotonin 5-HT2A receptors.
      • Lithium: affecting intracellular processes.

Antipsychotics

  • Antipsychotics (neuroleptics): Used to treat schizophrenia.
    • Typical antipsychotics: Selective dopamine D2 antagonists, reducing positive symptoms like delusions and hallucinations (e.g., chlorpromazine, haloperidol, loxapine).
    • Atypical antipsychotics: Block some serotonin receptors, reducing negative symptoms like social withdrawal and blunted emotional responses (e.g., clozapine).
    • Third-generation antipsychotics: Target novel synapses, such as glutamate.

Antidepressants

  • Monoamine oxidase (MAO) inhibitors: Prevent the breakdown of monoamines at the synapses, increasing their availability.
  • Tricyclic antidepressants: Increase norepinephrine and serotonin levels at the synapses by blocking their reuptake into presynaptic axon terminals.
  • Selective serotonin reuptake inhibitors (SSRIs): (e.g., Prozac, Zoloft) allow serotonin to accumulate in the synapses, with fewer side effects than tricyclics.

Anxiolytics

  • Anxiolytics (tranquilizers): Depressants that reduce nervous system activity to combat anxiety.
  • Benzodiazepine agonists: Act on GABAA receptors, enhancing the inhibitory effects of GABA.
    • Example: Barbiturates.

GABA Receptors

  • GABA receptors have multiple binding sites that can enhance or inhibit GABA's effects.
  • Benzodiazepines bind at an orphan receptor (no known endogenous ligand).
  • Allopregnanolone: A steroid elevated during stress, has calming effects.
  • Neurosteroids: Steroids produced in the brain may act on GABAA sites.

DREADDs

  • Designer Receptors Exclusively Activated by Designer Drugs (DREADDs).
  • Clozapine-N-oxide (CNO) is used to selectively activate these receptors.
    • Can cause Excitation or Inhibition via G proteins.

Opiates

  • Opiates relieve pain.
  • Opium (from poppy seeds) contains morphine, an effective analgesic and painkiller.
  • Morphine and heroin are related and highly addictive, binding to opioid receptors in the brain, especially in the locus coeruleus and periaqueductal gray.

Endogenous Opiates

  • Endogenous opiates: Peptides produced in the body that bind to opioid receptors and relieve pain; also addictive.
    • Examples: Enkephalins, endorphins, dynorphins.
  • Three main types of opiate receptors (all metabotropic):
    • Delta (δ)
    • Kappa (κ)
    • Mu (μ)

Cannabinoids

  • Marijuana is derived from Cannabis sativa; its active ingredient is Δ9-tetrahydrocannabinol (THC).
    • Effects vary: relaxation, mood alteration, stimulation, hallucination, and paranoia. Sustained use can cause addiction.
  • The brain contains cannabinoid receptors to mediate the effects of THC and other compounds.
    • Concentrated in the substantia nigra, hippocampus, cerebellar cortex, and cerebral cortex.

Cannabinoid Receptors

  • Two kinds of cannabinoid receptors (both G protein-coupled metabotropic receptors):
    • CB1 receptors: found only in the CNS and mediate the rewarding properties of cannabinoids.
    • CB2 receptors: prominent in the immune system.
  • Endocannabinoids: Homologs of marijuana produced in the brain; act as retrograde messengers, may influence neurotransmitter release from the presynaptic neuron.
  • Anandamide: An endocannabinoid with many effects:
    • Alters memory formation, stimulates appetite, reduces pain sensitivity, protects from excitotoxic brain damage, lowers blood pressure, combats nausea, lowers eye pressure (glaucoma).

Chronic Marijuana Use

  • Chronic or heavy marijuana use has negative effects:
    • Transient amnesia, stimulation and paranoia are possible, respiratory problems, addiction, cognitive decline, psychiatric disorders.
  • Use of marijuana in adolescence is correlated with the development of psychosis in adulthood.

Stimulants

  • Stimulants increase nervous system activity, have an alerting, activating effect.
  • Many naturally occurring and artificial stimulants are widely used, including amphetamine, nicotine, caffeine, and cocaine.
  • Khat (qat): An African shrub that acts as a stimulant; amphetamine-like stimulants (cathinones) are released when chewed.

Nicotine

  • Nicotine (from tobacco):
    • Increases heart rate, blood pressure, hydrochloric acid secretion, and bowel activity.
    • Acts as an agonist on nicotinic ACh receptors in the body and brain.
    • Rewarding effects are mediated by receptors in the ventral tegmental area.
    • Nicotine in one cigarette can occupy 88% of the brains nicotinic receptors.

Cocaine

  • Leaves from the coca shrub alleviate hunger, promote endurance, and enhance the sense of well-being.
  • Cocaine is the purified extract.
    • Can be used as an anesthetic.
    • Increases catecholamine stimulation.
    • Is highly addictive.
    • Crack cocaine is smoked and enters the brain more rapidly.
  • Cocaine blocks monoamine transporters (especially dopamine), slows reuptake of neurotransmitters, enhancing their effects.
  • Dual dependence: Addiction to the effects of the interaction of two drugs.
    • Example: Cocaine metabolized in the presence of ethanol (alcohol) yields an active metabolite called cocaethylene.

Amphetamine

  • Amphetamine and methamphetamine: Synthetic stimulants resembling catecholamine transmitters (norepinephrine, epinephrine, and dopamine) in structure.
    • Cause the release of neurotransmitters, even in the absence of action potentials, and potentiate release with action potentials.
    • Enhance activity by:
      • Blocking the reuptake of catecholamines into the presynaptic terminal.
      • Providing an alternative target for the enzyme (monoamine oxidase) that normally inactivates catecholamines.

Effects of Amphetamine Use

  • Short-term effects: Alertness, euphoria, and stamina.
  • Long-term effects: Sleeplessness, weight loss, and general deterioration of mental and physical condition.
  • Prolonged use may lead to symptoms resembling those of paranoid schizophrenia: compulsive, agitated behavior and irrational suspiciousness.

Alcohol

  • Alcohol’s effects are biphasic: An initial stimulant phase followed by a depressant phase.
    • Activates GABAA receptors, increases inhibitory effects (social disinhibition and loss of motor coordination).
    • Stimulates dopamine pathways (euphoric effects).
  • Alcohol abuse damages nerve cells; the frontal lobes are the most affected by chronic alcohol use, yet some effects are reversible.
  • Periodic overconsumption (bingeing) may cause brain damage and reduces neurogenesis.
  • Fetal alcohol syndrome: Result of pregnant women abusing alcohol, causing permanent damage to the fetus.

Hallucinogens

  • Hallucinogens alter sensory perception and produce peculiar experiences.
    • Examples: LSD (acid), mescaline (peyote), and psilocybin (magic mushrooms).
      • Have mainly visual effects.
    • Have diverse neural actions, including those on the noradrenergic (e.g., mescaline), serotonergic (e.g., mescaline, psilocybin, and LSD), Ach (e.g., muscarine), and opiate (e.g., Salvia) systems.
    • LSD acts as a serotonin agonist or partial agonist, especially on 5-HT2A receptors, found in high concentrations in the visual cortex.

Functional Classes of Drugs

  • Ketamine (Special K): Blocks NMDA receptors in the prefrontal cortex.
    • Classified as a dissociative: Produces detachment and depersonalization at moderate doses, transient hallucinogenic effects and psychotic symptoms at high doses.
  • MDMA (Ecstasy): Hallucinogenic amphetamine derivative; its major actions are increases in serotonin levels and changes in dopamine and oxytocin levels.
    • Effects: Positive emotions, empathy, sense of well-being, colorful visual phenomena.
    • Chronic use: Causes depression, memory disturbances, and alters the structure and function of serotonergic neurons.

Clinical Applications of Hallucinogens

  • Different hallucinogens show potential clinical applications:
    • Psilocybin: May offer improvements in OCD, cluster headache, and anxiety in terminal cancer patients.
    • LSD: May treat alcoholism, other addictions, and debilitating anxiety.
    • Ketamine: Shows a potent antidepressant effect, even in treatment-resistant cases.
    • MDMA: May reduce PTSD symptoms, especially with psychotherapy

Drug Abuse and Addiction

  • Substance abuse and addiction affects millions, disrupting lives.
  • Social costs:
    • Huge expenses for medical and social services.
    • Millions of hours lost in the workplace.
    • Elevated rates of crime associated with illicit drugs.
    • Scores of children damaged by parents’ substance abuse behavior.

Substance-Related Disorders

  • Dependence (addiction): The desire to self-administer a drug of abuse; criteria include patterns of consumption, craving, time/energy spent, and impact on ones life.
    • More severe than substance abuse, which is a pattern of use that does not fully meet the criteria for dependence.
  • Many addictive drugs cause dopamine release in the nucleus accumbens.
    • Axons terminating here originate in the ventral tegmental area (VTA) and are involved in the reward pathway. Addictive power of drugs may come from stimulating this pathway.
    • Another pathway may involve the insula. People with damage to this area have been able to stop smoking effortlessly.
    • Reciprocal connections between the VTA and the insula suggest that these two regions normally interact to mediate addiction.

Factors in Susceptibility to Addiction

  • Biological: sex, genetic predisposition.
  • Family situation: family breakup, poor relationships, sibling drug users.
  • Personal characteristics: aggressiveness, emotional control.
  • Environmental factors: peer pressure, social factors.
  • Environmental stimuli can become associated with the effects of drugs.
    • Cue-induced drug use is the increased likelihood of using a drug because factors are present that were also present when the drug was last used.

Medications to Treat Drug Abuse

  • Lessening the discomfort of withdrawal: Benzodiazepines and drugs that suppress central adrenergic activity to help ease withdrawal symptoms or cravings.
  • Providing alternatives to the addictive drug: Agonist or partial agonist analogs partially activate the same pathways, such as methadone or nicotine patches.
  • Directly blocking the actions of the addictive drug: Blocks effects of the abused drug but may produce harsh withdrawal symptoms.
  • Altering the metabolism of the abused drug: Changing breakdown of drug can change, reduce, or reverse its rewarding properties.
    • Antabuse causes nausea-inducing metabolites to be formed from alcohol in the body.
  • Blocking the brains reward system: Blocks rewarding effects of the abused drug, but may produce a lack of all pleasurable feelings.

Vaccination

  • Vaccination may be effective for prompting the immune system to reject and remove targeted drugs.

Concluding Remarks

  • The effects of a drug depend on its site of action and dose.
  • Drugs affect each stage of neural conduction and synaptic transmission.
  • Antipsychotic, antidepressant, and anxiolytic drugs.
  • Opiates are potent painkillers.
  • The effects of stimulant drugs.
  • Hallucinogens alter sensory perception.
  • Substance abuse and addiction are major health problems.
  • Treating drug abuse.