L15 - Psychoactive Drugs

Psychoactive Drugs

Learning Objectives

• Describe the mechanism of action of psychoactive drugs:

  • Psychomotor stimulant drugs

  • Psychedelic drugs

  • Central nervous system depressant drugs

  • Dissociative drugs

Definition

• Psychoactive drugs: Substances that affect mental processes including:

  • Perception

  • Consciousness

  • Cognition

  • Mood

  • Emotion

• Common types:

  • Psychomotor stimulants

  • Psychedelics

  • Dissociatives

  • Depressants

Psychomotor Stimulants

• Stimulate the central nervous system (CNS).

• Produce:

  • Euphoria

  • Excitement

  • Increased energy

  • Motor activity

• Facilitate monoamine neurotransmitters (dopamine, noradrenaline, serotonin) activity in the CNS.

• Caffeine: Inhibitor at adenosine receptors.

• Uses:

  • Stimulants

  • Performance enhancers

  • Recreational drugs

• Clinical Uses:

  • Counteract hypotensive effects of general anaesthesia

  • Management of bronchospasm

  • Management of behavioural disorders (ADHD)

Common Psychomotor Stimulant Drugs

Points of Action

• Cocaine: Inhibits dopamine and noradrenaline reuptake transporters.

• Amphetamines: Taken up by noradrenaline and dopamine reuptake transporters, facilitating the release of noradrenaline and dopamine.

Amphetamines (Detailed)

• Main effects:

  • Increased motor activity

  • Euphoria

  • Excitement

  • Insomnia

  • Anorexia

• Mechanism:

  • Substrate for dopamine and noradrenaline transporters on presynaptic neuron.

  • Taken up into presynaptic cleft; noradrenaline and dopamine released.

  • Taken up into storage vesicles (VMAT) and displace endogenous monoamines into the cytoplasm.

  • Increase dopamine and noradrenaline concentrations in the synapse.

• Highly addictive; amphetamine psychosis can develop after prolonged use.

• Tolerance: Due to depletion of dopamine in the nerve terminals or dopamine receptor desensitization.

Cocaine (Detailed)

• Binds to and inhibits reuptake transporters:

  • Noradrenaline reuptake transporter (NET)

  • Dopamine reuptake transporter (DAT)

  • Serotonin reuptake transporter (SERT)

• Increases levels of monoamines in the synapse.

• Marked psychomotor stimulant; enhances peripheral effects of sympathetic nervous system.

• Highly addictive; unclear if continued use induces tolerance and physical dependence fully.

• Associated with cardiac dysrhythmias, aortic dissection, and myocardial/cerebral infarction or haemorrhage with persistent use.

Nicotine (Detailed)

• Acts on nicotinic acetylcholine receptors (widely expressed in the brain, cortex, hippocampus).

• Causes influx of calcium and sodium ions and efflux of potassium ions.

• Increases firing rate and phasic activity of dopaminergic neurons in the ventral tegmental area (reward pathway).

• Highly addictive; regular use induces tolerance.

Psychedelics

• Affect thought, perception, and mood without marked psychomotor stimulation or depressive effects.

• Associated with sensory distortion and hallucinations.

• Mechanism: Action on 5-HT_{2A} receptors.

  • Agonists of 5-HT_{2A} receptors in cortical neurons.

  • Activation affects glutamatergic signaling and thus sensory input.

  • Leads to altered gene expression and cellular function, causing complex changes in consciousness.

• Low tendency for addiction; tolerance develops quickly.

• Hallucinogen binding to 5-HT_{2A} receptors in various brain regions (e.g., reticular nucleus, prefrontal cortex) leads to:

  • Altered serotonergic tone

  • Altered glutamatergic transmission

  • Altered GABAergic transmission

• Currently being investigated for potential antidepressant effects due to impact on neuroplasticity.

  • Activation of neurobiological pathways by 5-HT_{2A} receptor activation upon the binding of psychedelics

  • Affects both the serotonergic and the glutamatergic tone within the brain, particularly in the cortical layers.

  • Activation of the 5-HT_{2A} receptor activates intracellular signalling pathways such as PLC, PLA, and PKC

  • Activation of these pathways leads to alterations in gene expression, though to be linked to synaptic plasticity and primarily through the increase of calcium release and through the upregulation of AMPA receptors on the pyramidal neurons in the cortical layers.

  • The activation induces a change in synaptic plasticity that could have some clinical significance in terms of being able to treat depression.

Dissociative Drugs

• Make a user feel out of control or disconnected from their body or environment.

• Examples: Ketamine and PCP.

• Ketamine:

  • Non-competitive antagonist of the NMDA receptor.

  • Clinical research supports further research of sub-anaesthetic doses of ketamine in depression, bipolar disorder, anxiety, substance use disorders and eating disorders.

  • Management of chronic pain due to its changes on NMDA receptor signalling.

Central Nervous System (CNS) Depressants

• Ethanol (alcohol) is the major CNS depressant.

• Clinical utility:

  • Benzodiazepines and Z-drugs: Treatment of anxiety and insomnia.

  • Gabapentin and pregabalin: Treatment of epilepsy and neuropathic pain.

  • Propofol: Anaesthesia.

Ethanol (Detailed)

• No clinical utility asides from recreation. Depresses inhibitions resulting in behavioural stimulation at lower concentrations, but at higher concentrations it's associated with the depression.

• Depresses neuronal activity by enhancing GABAergic neurotransmission and inhibiting excitatory NMDA receptors.

  • Ethanol interacts with GABA receptors, facilitating chloride ion influx and hyperpolarization.

  • Ethanol inhibits glutamatergic signaling by targeting NMDA receptors, preventing sodium and calcium influx.

• Reward pathway:

  • Alcohol causes opioid neuropeptides to be released, which leads to the disinhibition of dopamine release in the nucleus accumbens.

  • Action on the mu opioid receptor causes opioid neuropeptides to release.

• Withdrawal syndrome:

  • Due to neuronal adaptations, particularly at the ion channels.

  • Long-term consequences: Brain damage and liver damage.

Ethanol Metabolism

• Rapidly absorbed, mostly from the stomach.

• 90% metabolized, 5% excreted unchanged.

• Ethanol is broken down either by mixed function oxidases, or alcohol dehydrogenase primarily, which provides acetaldehyde, which is then broken down by aldehyde dehydrogenase to form acetic acid.

• Occurs almost entirely in the liver.

• Involves successive oxidations: ethanol → acetaldehyde → acetic acid.

Opioids

• Mu receptor agonists: Morphine, codeine, fentanyl, heroin.

• Agonism at opioid receptors causes analgesia, increased prolactin release, respiratory depression, sedation, drug dependence, and immunosuppression.

• Heroin and other opioids leads to increased synaptic dopamine levels due to disinhibition of dopaminergic neurons involved in the reward system.

• Activation of the reward pathway occurs with opioid receptor activation.

Opioid addiction

• Opioid use, reduced GABAergic interneuron levels, which results in disinhibition of dopamine levels, or dopaminergic neurons.

• Chronic recurrent disease of the central nervous system.

• Associated with personality disorders, comorbidity, and premature death.

• Chronic morphine abuse leads to physical and psychological dependence.

• Chronic exposure to morphine induces phosphorylation of opioid receptors by G protein coupled receptor kinases.

  • Phosphorylation prepares opioid receptors for arrestin binding (beta arrestin binding).

  • Beta arrestin binding blocks further G protein-mediated signaling, inducing desensitization of opioid receptors.

• Ordinary Opioid use (treatment of pain):

  • Opioid receptor activation results in decreased level of cyclic AMP, increased PKA activation and CREB gene expression

• Chronic Opioid Use:

  • Causes opioid receptor phosphorylation and beta arrestin signaling, which is associated with desensitization of the opioid receptors to opioids binding to that particular mu receptor and is associated with one of the molecular mechanisms of opioid dependence.

Cannabis

• Main psychoactive constituent: THC, generates a pharmacologically active metabolite (11-hydroxy metabolite).

• Induces euphoria and relaxation.

• Impairs learning, memory, and motor function.

• Mechanism: Cannabinoids bind to the CB_1 receptor (G protein-coupled receptor).

  • Activation inhibits neurotransmitter release: inhibiting adenyl cyclase and voltage gated calcium channels.

  • Activation of potassium channels, which leads to hyperpolarization.

  • Decreased GABA release, leading to disinhibition of dopaminergic neurons, increasing synaptic dopamine levels.

• Tolerance can develop; physical dependence is uncommon.

• Cannabidiol (CBD) is a major non-psychotropic constituent of C. Sativa (cannabis).

  • It's non-psychotropic, but that can induce pain relief, relaxation, and have many effects on neurotransmitter release without those psychotropic effects

• Activation of the CB_1 receptor is associated with inhibition of adenyl cyclase, also with activation of potassium channels, decrease of calcium influx, and also increased MAK kinase signaling, which can lead to altered gene expression.

Overview of Mechanisms of Action

Summary

• THC and the active constituent of cannabis acting on the CB1 and CB2 receptors this is associated with psychological, psychomotor and cognitive effects.

• Cocaine is associated with increases in extracellular dopamine in a euphoric rush.

• Ethanol acts on the NMDA receptors in GABA levels, and it's associated with depressed neuronal activity and sedation.

• MDMA can act on the synaptic vesicle storage area of the monoamine transporters and then the turn can increase levels of noradrenaline and dopamine.

• The opioids acting on the mu receptor, which are associated with decreased levels of cyclic AMP and decreased excitability and neurotransmitter release which is associated with respiratory depression dependence, analgesia and anti anxiety effects

Recent Data (Australia)

Recap

• Psychoactive drugs: Substances affecting mental processes (perception, consciousness, cognition, mood, emotion).

• Include psychomotor stimulants, depressants, psychedelics, and dissociative drugs.

• Most are subject to substance abuse; some have medicinal properties.

• Substances of abuse have wide-ranging behavioral, biochemical, and toxic consequences, particularly on the brain due to their impact on neurotransmission.