Neurotransmitters and Neuropharmacology

Neurotransmitters and Synaptic Communication

Synapses pass info using neurotransmitters.

Neurotransmitters meet strict identification criteria.

Acetylcholine = first neurotransmitter discovered.

Monoamines: mood, attention, motor control.

Amino acids: GABA, glutamate, glycine, aspartate.

Neuropeptides: endorphins, enkephalins, substance P.

Gases: nitric oxide diffuses backwards.

Receptors: diverse subtypes, unique brain distributions.

Neuropharmacology: Principles and Mechanisms

• Targets for Neuropharmacological Compounds: Every step in synaptic transmission presents a potential target for neuropharmacological intervention. These steps include:

  • Neurotransmitter synthesis.

  • Axonal transport.

  • Presynaptic effects.

  • Postsynaptic effects.

• Parallel Discovery of Drugs and Receptors: The discovery of new drugs and the characterization of new receptor types often occur simultaneously.

  • Brain receptors are sometimes found by binding with exogenous drugs.

  • Brain receptors are sometimes found by binding with exogenous drugs.

Every synaptic step = drug target.

Drugs + receptors often discovered together.

Brain receptors sometimes identified with drugs.

Drug Bioavailability and Tolerance

• Bioavailability Factors: active drug proportion in circulation, influenced by multiple factors:

  • Route of Administration: How the drug is introduced into the body (e.g., oral, intravenous, inhalation).

  • Biotransformation: The metabolic processes that chemically alter the drug within the body, often involving the liver.

  • Pharmacokinetics: The study of drug absorption, distribution, metabolism, and excretion.

  • Dose-Response Curves: The relationship between the dose of a drug and the magnitude of its effect.

  • Blood-Brain Barrier (BBB): The selective permeability barrier that separates circulating blood from the brain extracellular fluid. A drug must be able to cross this barrier to exert central nervous system (CNS) effects.

• Tolerance: Repeated use of certain drugs can lead to tolerance, meaning frequent doses of the same amount of drug produce progressively less effect.

  • Metabolic Tolerance: Occurs when organ systems (e.g., liver) become more efficient at metabolizing and clearing a drug from the body, thus reducing its concentration.

  • Functional Tolerance: Involves adaptive changes at the cellular level, such as the up-regulation (increase) or down-regulation (decrease) of synaptic receptor density, altering the responsiveness of target cells to the drug.

Presynaptic and Postsynaptic Drug Actions

• Presynaptic Drug Effects: Drugs can influence various aspects of presynaptic function:

  • Alteration in Transmitter Production:

    • Changes in neurotransmitter synthesis.

    • Modifications in the transport of neurotransmitter precursors or finished neurotransmitters.

    • Alterations in the storage of neurotransmitters within vesicles.

  • Alteration in Transmitter Release:

    • Changes in axon potential propagation.

    • Direct alterations in the release of neurotransmitters into the synaptic cleft.

    • Modulations through autoreceptors, which are receptors located on the presynaptic neuron that regulate its own neurotransmitter release.

  • Alteration in Transmitter Clearance:

    • Changes in reuptake (the reabsorption of neurotransmitters by the presynaptic neuron).

    • Alterations in enzymatic degradation of neurotransmitters within the synaptic cleft.

• Postsynaptic Drug Effects: Drugs can also affect many different aspects of postsynaptic function:

  • Activation of Postsynaptic Receptors: Mimicking the neurotransmitter and directly binding to and activating receptors.

  • Blockage of Postsynaptic Receptors: Preventing the neurotransmitter from binding and activating its receptors.

  • Alteration of Second Messenger Activity: Modifying the intracellular signaling pathways initiated by receptor activation.

  • Alteration in Gene Expression: Influencing the transcription and translation of genes, leading to long-term changes in cellular function.

  • Up- and Down-regulation of Postsynaptic Receptor Density: Changing the number of receptors present on the postsynaptic membrane, similar to functional tolerance mechanisms.

Specific Classes of Neuropharmacological Agents

Antipsychotics

• Revolutionary Impact: The development of antipsychotic drugs in the mid 20th century significantly changed psychiatry and the treatment of schizophrenia.

• First-Generation Antipsychotics: Primarily functioned by selectively blocking dopamine D2 receptors.

• Second-Generation Antipsychotics: More recently developed, these drugs exhibit both dopaminergic (affecting dopamine systems) and non-dopaminergic actions, often with a broader receptor profile.

Antidepressants (Affective Disorders Treatment)

• Historical Treatment: Initially, affective disorders were treated with monoamine oxidase inhibitors (MAOIs).

• Current Treatments: Today, the most common treatments include:

  • Tricyclic Antidepressants.

  • Selective Serotonin Reuptake Inhibitors (SSRIs).

  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs).

• Common Mechanism: All these contemporary antidepressants increase synaptic transmission by either inhibiting the reuptake of neurotransmitters (norepinephrine, serotonin, or both) or by preventing their enzymatic degradation.

Opioids

• Endogenous Opioid Peptides:

  • Enkephalins.

  • Endorphins.

  • These are naturally occurring peptides that bind to opiate receptors and possess morphine-like analgesic (pain-relieving) properties.

• Exogenous Opiates: Substances like morphine (the active component in opium) are powerful analgesics and are commonly abused.

• Opiate Receptors: Several distinct types of opiate receptors have been identified, along with a number of endogenous opiate peptides.

Nicotine

• Active Ingredient: Nicotine is the psychoactive component in tobacco.

• Pharmacokinetics: When inhaled via cigarettes, nicotine rapidly enters the brain.

• Mechanism of Action: It primarily binds to and activates nicotinic acetylcholine receptors.

• Receptor Distribution and Effects: These receptors are found in both the periphery and the central nervous system, mediating a wide range of effects, including:

  • Enhancement of certain aspects of cognitive performance.

  • Activation of reward pathways in the brain.

Alcohol

• Biphasic Psychoactive Effect: Alcohol's effect on the nervous system is characterized by two phases:

  • An initial stimulant phase.

  • A more prolonged depressant phase that follows.

• Chronic Abuse Effects: Long-term alcohol abuse leads to alterations in both the function and structure of the brain.

• Reversibility: Many of the brain-related effects of chronic alcohol abuse can be reversible upon cessation of alcohol use.

Cannabis

• Active Ingredient: Delta-9-tetrahydrocannabinol (THC) is the main psychoactive compound in cannabis.

• Mechanism of Action: THC exerts its effects by acting on cannabinoid receptors.

• Endocannabinoid System: The endogenous cannabinoid anandamide is responsible for many of the familiar physiological and psychological effects associated with marijuana use, including:

  • Improved mood.

  • Pain relief.

  • Lowered blood pressure.

  • Relief from nausea.

  • Improvements in glaucoma symptoms.

Stimulants

• Diverse Mechanisms:

  • Some stimulants, like nicotine, imitate excitatory synaptic transmitters by directly activating receptors.

  • Others, such as amphetamine, cause the enhanced release of excitatory synaptic transmitters and simultaneously block their reuptake.

  • Cocaine primarily causes the synaptic accumulation of neurotransmitters, especially dopamine, across large areas of the brain, by blocking their reuptake.

Hallucinogens

• Nature of Effects: Hallucinogenic drugs primarily alter or distort existing sensory perceptions rather than provoking true hallucinations (perceiving things that are not there).

• Mechanism of Action: The majority of hallucinogens act as serotonin receptor agonists or partial agonists, particularly at 5- HT2A receptors.

Models of Drug Abuse and Treatment

• Complexity of Dependency: While several models of drug abuse have been proposed, none fully explains all the complex phenomena associated with drug dependency and addiction.

• Positive Reward Model: This model has received significant support from drug self-administration studies (experiments where animals or humans self-administer drugs).

  • It emphasizes the activation of a dopamine-containing reward mechanism in the basal forebrain.

  • This pathway specifically projects from the ventral tegmental area (VTA) to the nucleus accumbens, a key circuit involved in motivation and reward.

• Other Contributing Models: The moral, disease, and physical dependence models each offer insights and contribute to understanding the complexities of substance use and abuse, but none alone fully accounts for addiction's multifaceted nature.

• Pharmacological Interventions: Recent advancements in understanding the neurophysiological bases of drug abuse have led to the proposal of several pharmacological interventions for treating substance-related disorders. These aim to target specific neural mechanisms underlying addiction to aid recovery.