brain

Drugs and Pharmacology

Related topics: Synaptic Transmission and Neurotransmitters | Tectum and Tegmentum (dopamine pathways)

Drugs and Toxins at the Synapse

Preventing Action Potentials

• Local anesthetics (Novocain) and tetrodotoxin (pufferfish) block Na⁺ channels.
• Without sodium influx, no action potential can propagate.

Preventing Neurotransmitter Release

• Spider venoms (e.g., funnel-web spider) block Ca²⁺ channels → no vesicle fusion.
• Botulinum toxin (BoNT, Botox) interferes with SNARE proteins → blocks exocytosis, reduces neurotransmitter release.

Increasing Neurotransmitter Release

• Black widow spider venom (latrotoxin):
  • Creates pores for Ca²⁺ influx and neurotransmitter leakage.
  • Massive ACh release → muscle spasms.
• Amphetamines & methamphetamine:
  • Reverse transporters (dopamine, norepinephrine, serotonin).
  • Increase vesicular release.
  • Block uptake into vesicles.
  • Net effect: more neurotransmitter in the synaptic cleft.
  • Adderall produces prolonged dopamine release compared to isomers.

Preventing Reuptake

• Cocaine, Ritalin, antidepressants: block transporters for dopamine, norepinephrine, serotonin.
• Leads to increased levels in the synaptic cleft.

Preventing Deactivation

• Monoamine oxidase inhibitors (MAOIs): block MAO enzyme, preventing breakdown of monoamines.
• Organophosphates (pesticides): block acetylcholinesterase → ACh accumulates, causing overstimulation.

Blocking Receptors

• Some antipsychotics block serotonin receptors (e.g., clozapine).
• Black mamba venom blocks muscarinic ACh receptors → paralysis.

Stimulating Receptors

• LSD → binds serotonin receptors.
• Nicotine → binds nicotinic ACh receptors.
• Opiates (morphine, heroin) → bind endorphin receptors.

Mimicking Retrograde Transmitters

• THC (marijuana) mimics endocannabinoids (anandamide, 2-AG).
• Binds presynaptic cannabinoid receptors → inhibits Ca²⁺ channels, reducing neurotransmitter release.
• Chronic cannabis use can cause long-term cognitive impairments (attention, memory, information processing).

Ketamine and Antidepressant Action

• Ketamine acts on glutamate neurotransmission.
• Mechanism:
  1. Blocks NMDA receptors on GABAergic interneurons → reduces inhibition.
  2. Leads to increased glutamate release from excitatory neurons.
  3. Enhances AMPA receptor activation on glutamatergic neurons.
  4. Metabolized into hydroxynorketamine (HNK), which also contributes to effects.
• Overall effect: disinhibition and enhanced glutamate signaling, linked to its rapid antidepressant properties.

Caffeine

• Works through adenosine receptors:
  • Normally, adenosine A1 receptors reduce excitatory release.
  • A2A receptors dampen dopamine receptor activity.
• Caffeine blocks A1 and A2A receptors → increases neurotransmitter release and dopamine activity.
• Also:
  • Releases Ca²⁺ from internal stores.
  • Interferes with GABA receptors (reduces inhibition).
• Result: stimulant effect (increased alertness, arousal).

Alcohol (Ethanol)

• Complex, non-selective pharmacological effects:
  • Inhibits voltage-gated Ca²⁺ channels (reduces release).
  • Affects K⁺ channels.
  • Binds to ionotropic receptors (ACh, serotonin, GABA, glutamate).
  • Enhances adenosine signaling (slows neural activity).
  • Interferes with metabotropic receptors, cell membranes, and even gene expression.
• General effect: reduces neurotransmitter release and inhibits postsynaptic activity.

Tolerance and Withdrawal

• With repeated use, the brain compensates for drug effects (neural adaptation).
• Tolerance: same dose produces smaller effect.
• Withdrawal: opposite effect when drug is absent.
• Environmental cues can trigger anticipatory compensatory responses (classical conditioning).

Opioids (Morphine Example)

• Bind to μ (mu) opioid receptors.
• Mechanism:
  • G-protein activation inhibits Ca²⁺ channels (less release) and opens K⁺ channels (hyperpolarization).
  • Over time: receptors become desensitized via phosphorylation and arrestin signaling.
• Strongly affect the mesolimbic dopamine system:
  • Dopaminergic neurons in the ventral tegmental area (VTA) project to the nucleus accumbens.
  • This circuit underlies reward and addiction.

Addiction and Reward Pathways

• Olds & Milner (1954): rats pressed levers thousands of times to self-stimulate the septal area → discovery of “pleasure centers.”
• This parallels modern dopamine reward circuitry:
  • VTA → nucleus accumbens pathway.
  • Strongly activated by drugs, but also exploited by modern tech (e.g., Facebook’s “dopamine hit” model for likes).
• Addiction = hijacking of natural reward systems → compulsive behavior despite consequences.

Brain Changes in Addiction

• Cocaine users show reduced glucose metabolism in the prefrontal cortex.
• Indicates impaired executive function, decision-making, and impulse control.
• Addiction is not just chemical but also structural and functional brain change.