monoanines:dopamine, serotonin

MONOAMINES: DOPAMINE, SEROTONIN

Chapter 5, 6

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THINGS YOU WILL LEARN TODAY

  • Key Learning Objectives:

    • What was Mahatma Gandhi’s tranquilizer?

    • Why is cocaine addictive?

    • What drug did the US Army experiment with to create a “truth drug” for subject interrogation?

CATECHOLAMINES

  • Definition: A subgroup of monoamines that consist of a catechol group and an amine group.

    • Examples include:

    • Dopamine (DA)

    • Norepinephrine (NE) (also functions as a hormone)

    • Epinephrine (EPI) (also functions as a hormone)

DOPAMINE (DA)

  • Discovery:

    • First identified in the brain by Katharine Montagu in 1957.

    • Recognized as a neurotransmitter.

    • Further research by Arvid Carlsson in 1958, who won the Nobel Prize in 2000 for his contributions to the understanding of dopamine.

  • Chemical Structure: Refer to the corresponding chemical structure diagrams for specificity.

NOREPINEPHRINE (NE)

  • Discovery:

    • Recognized as a neurotransmitter by Ulf von Euler in 1945.

    • Awarded the Nobel Prize in 1970 for his discoveries related to norepinephrine.

  • Chemical Structure: Similar to dopamine but distinguished by the presence of an additional hydroxyl group (OH).

SYNTHESIS

  • Process Overview:

    • Catecholamines must be synthesized and packaged into vesicles prior to their release into the synapse.

    • Tyrosine, an amino acid primarily acquired from diet, is essential in this process.

    • Positive correlation exists between tyrosine consumption and working/episodic memory performance.

  • **Enzymes Involved:

    • Tyrosine is converted to DOPA by Tyrosine Hydroxylase (TH):**

    • Characteristics of TH:

    • It is the rate-limiting enzyme in the synthesis pathway.

    • Operates at a slower rate compared to other enzymes in the pathway.

    • Its activity is regulated by the levels of DA and NE present in the axon terminal (inhibition) as well as by the rate of neuron firing (stimulation).

  • L-DOPA:

    • Also known as the left-handed version of DOPA, is a drug administered to patients with Parkinson's disease, known for its ability to cross the blood-brain barrier (BBB), unlike DA itself.

SYNTHESIS (Continued)

  • Further Conversions:

    • DOPA is converted to DA by Aromatic Amino Acid Decarboxylase (AADC).

    • DA is subsequently converted to NE by Dopamine β-hydroxylase (DBH).

  • Chemical Structures:

    • Refer to the molecular diagrams for visual representation:

      • Tyrosine - Chemical formula: C9H11NO3

      • DOPA - Chemical formula: C9H11NO4

      • Dopamine - Chemical formula: C8H11NO2

      • Norepinephrine - Chemical formula: C8H11NO3

PACKAGING

  • Catecholamines are transported to synaptic vesicles for future release.

    • This process prevents neurotransmitters (NTs) from being degraded by enzymes.

    • Vesicular Monoamine Transporter 2 (VMAT2):

    • A protein responsible for transporting DA, NE, and serotonin (5-HT) to vesicles.

    • Reserpine:

      • A drug known to block VMAT2 activity, leading to diminished levels of DA, NE, and 5-HT in the brain, which can result in symptoms such as sedation or depressive states.

RELEASE

  • Autoreceptors:

    • These receptors regulate the release of DA and NE, providing feedback inhibition.

  • Certain drugs can induce the release of DA independently of action potentials, examples include amphetamines and methamphetamines.

    • Effects include increased alertness, energy, euphoria, and insomnia.

    • Adderall:

    • Amphetamine-based medication commonly prescribed for ADHD; known for its potential for addiction and stereotyped behaviors.

REUPTAKE

  • Mechanism:

    • DA reuptake occurs via DA or NE transporters, with some being repackaged for reuse.

  • Several drugs inhibit the reuptake of DA and NE, enhancing DA functionality, such as:

    • Amphetamines (Adderall) and methamphetamines.

    • Methylphenidate (Ritalin):

    • Another stimulant that blocks the reuptake of DA, NE, and serotonin (5-HT), including cocaine.

METABOLISM

  • Breakdown of DA and NE occurs intracellularly within neurons, primarily through the actions of two key enzymes:

    • Monoamine Oxidase (MAO)

    • Catechol-O-methyltransferase (COMT)

  • Certain drugs can inhibit the enzyme breakdown of DA and NE, a property seen in classical antidepressants. MAO inhibitors, while effective, are used less frequently due to potential adverse side effects.

DA AND NE RELEASE ZONES

  • General Configuration:

    • DA and NE axons often exhibit synaptic structures known as varicosities, which contain vesicles loaded with NT for release.

DA PATHWAYS

  • Origin:

    • DA pathways originate in the midbrain and include:

    • Nigrostriatal Tract:

      • Connects substantia nigra (A9) to the striatum, pivotal for controlling voluntary movement. Damage in this area is linked to Parkinson's disease.

    • Mesolimbic Tract:

      • Runs from the ventral tegmental area (VTA, A10) to various limbic system structures, including the nucleus accumbens, amygdala, septum, and hippocampus.

    • Mesocortical Tract:

      • Projects from VTA (A10) to the cortex, specifically influencing the prefrontal cortex.

DA PATHWAYS (Continued)

  • Dopamine and Pleasure:

    • It's essential to recognize that dopamine release does not merely equate to the sensation of pleasure; rather the activity of dopaminergic neurons correlates more with the expectancy of a reward rather than its sheer size, being at its most active when a reward is unexpected.

DA PATHWAYS (Continued)

  • Updating Value in Decision-Making:

    • The ability to update value based on changing environmental conditions or personal preferences over time is critically tied to mesocortical DA tract activity.

  • Reinforcer Devaluation Paradigms:

    • Implications for behavioral economics and decision-making.

DA PATHWAYS (Continued)

  • Prediction Error Signals:

    • These signals represent the difference between the obtained reward and what was anticipated (anticipated outcomes in classical conditioning experiments).

  • Signaling Process:

    • In experimental setups:

    • When a cue (CS) is consistently presented alongside an unconditioned stimulus (US), dopaminergic activity in the VTA is recorded:

      • 1) Initially, a substantial increase in response is triggered by the US.

      • 2) This response diminishes over repeated exposure to the US.

      • 3) Dopaminergic firing aligns with positive prediction errors while contrary activity corresponds with negative prediction errors, ultimately leading to extinction behavior.

DA PATHWAYS (Continued)

  • Aversive vs. Rewarding Stimuli:

    • Stressful stimuli activate VTA dopaminergic neurons via input from the lateral habenula (LHb) projecting to the medial prefrontal cortex (mPFC).

    • In contrast, pleasurable stimuli engage the same dopaminergic neurons through pathways from the laterodorsal tegmentum (LDT) to the nucleus accumbens (NAc).

DA RECEPTORS (POSTSYNAPTIC MEMBRANE)

  • Types of Receptors:

    • All DA receptors are classified as metabotropic:

    • D1-like Family: Includes D1 and D5 receptors.

    • D2-like Family: Includes D2, D3, and D4 receptors.

    • Notably, D1 and D2 receptors are predominant in the striatum and nucleus accumbens, with a greater prevalence of D1 in the prefrontal cortex.

  • Clinical Relevance:

    • Implications for cognition and the development of antipsychotic drugs used in the treatment of schizophrenia through D2 receptor antagonists.

DA RECEPTORS (POSTSYNAPTIC MEMBRANE) (Continued)

  • Opposing Effects:

    • The D1-like and D2-like families function oppositely within the neuronal circuitry:

    • D1 Receptor Effect: Stimulation of adenylyl cyclase, leading to increased cAMP levels.

    • D2 Receptor Effect: Inhibition of adenylyl cyclase, resulting in decreased cAMP levels.

SEROTONIN

  • Introduction to Serotonin:

    • Also Known As: 5-hydroxytryptamine (5-HT).

    • Discovery Highlights:

    • Discovered by Vittorio Erspamer in 1935 (originally referred to as enteramine, known for its intestinal contracting effects).

    • Later identified by Betty Twarog in 1953 as existing in the brain.

  • Chemical Structure: Refer to the chemical structure illustration for clarity.

SYNTHESIS

  • Serotonin Synthesis:

    • The production of serotonin requires it to be synthesized and packaged prior to its utilization.

    • Tryptophan:

    • This amino acid is crucial and must be obtained exclusively through diet.

  • Conversion Process:

    • Several enzymes conduct the conversion from tryptophan to serotonin:

    • Tryptophan Hydroxylase (TPH): Acts as the rate-limiting enzyme, converting tryptophan to 5-HTP.

    • Aromatic Amino Acid Decarboxylase (AADC): Converts 5-HTP to serotonin (5-HT).

    • Notably, the AADC enzyme is the same as that used in producing dopamine from DOPA.

SYNTHESIS (Continued)

  • Dietary Impact:

    • An increase in dietary tryptophan does not guarantee augmented tryptophan levels in the brain due to competition with other amino acids in crossing the blood-brain barrier (BBB).

    • A high-protein, low-carbohydrate meal does not enhance serotonin levels in the brain, while a low-protein, high-carbohydrate meal is effective in increasing brain serotonin levels.

PACKAGING

  • Mechanism of Packaging:

    • Serotonin is transported to synaptic vesicles for future release, protecting it from degradation by enzymes.

  • Role of VMAT2:

    • Vesicular monoamine transporter 2 (VMAT2) orchestrates this process.

    • Reserpine also blocks VMAT2, leading to decreased levels of DA, NE, and 5-HT in the brain.

RELEASE

  • Regulation of Release:

    • Autoreceptors inhibit the release of serotonin.

  • Drug-Induced Release:

    • Certain drugs, such as MDMA (ecstasy), stimulate the release of serotonin without the triggering of action potentials.

    • Increases in use were observed during the 1980s associated with rave culture in the 1990s, fostering heightened arousal, euphoria, perceptual awareness, and prosocial effects.

    • Entactogens: Promote feelings of empathy and connection.

  • Serotonin Syndrome Risk:

    • Symptoms: Include hyperthermia, unstable blood pressure, respiratory complications, seizures, and delirium, especially with single doses of MDMA or combinations of MDMA with SSRIs.

REUPTAKE

  • Mechanism of Reuptake:

    • 5-HT reuptake occurs through the serotonin transporter (SERT), with some serotonin being repackaged for reuse.

  • Drug Effects:

    • Certain medications, such as fluoxetine (Prozac) classified as selective serotonin reuptake inhibitors (SSRIs), inhibit this reuptake process, prolonging serotonin action in synapses.

METABOLISM

  • Breakdown of Serotonin:

    • Occurs within neurons, primarily through monoamine oxidase (MAO-A) which converts serotonin into its inactive metabolite, 5-Hydroxyindoloacetic acid.

5HT PATHWAYS

  • Location:

    • 5-HT pathways are predominantly initiated from raphe nuclei located along the midline of the brainstem. They project extensively to all areas of the forebrain.

  • Active Locations:

    • Dorsal Raphe Nucleus (DRN): Predominantly active during waking states with a steady firing rate.

    • REM Sleep: During REM sleep, the firing rate drops to about 2 spikes per second and may become abolished.

5HT RECEPTORS (POSTSYNAPTIC MEMBRANE)

  • Types of Receptors:

    • At least 14 different serotonin receptors exist, most being metabotropic with the exception of 5-HT3, which is a well-known excitatory ionotropic receptor.

    • Most Notable: 5-HT1A and 5-HT2A receptors have significant roles in neurotransmission.

5HT RECEPTORS (POSTSYNAPTIC MEMBRANE) (Continued)

  • 5-HT1A Receptors:

    • Located primarily in the hippocampus, amygdala, and DRN; they inhibit adenylyl cyclase activity, thereby reducing intracellular cAMP and decreasing postsynaptic cell firing.

    • Buspirone:

    • An anti-anxiety medication acting as a 5-HT1A agonist.

  • 5-HT2A Receptors:

    • Found in the striatum, nucleus accumbens, and other areas; they enhance calcium influx, activating protein kinase C (PKC).

    • Hallucinogenic Drugs Influence:

    • Example: Lysergic acid diethylamide (LSD) serves as a potent 5-HT2A agonist, with notable historical relevance tied to Albert Hofmann's discovery in 1943, commemorated as “Bicycle Day.”