Neurotransmitters Overview

Neurotransmitters

• Chemical messengers synthesized in neurons and released during neuronal excitation (dependent on calcium influx).
• Can elicit excitatory or inhibitory responses in cells or tissues.
• Act in postsynaptic, post-ganglionic, or target cells.
• Facilitate communication between neurons through chemical synapses.
• Photoreceptors are the only nerve cells active during hyperpolarization.

Functional Classification

• Excitatory: Depolarization, leading to an increase in the likelihood of a neuron firing.
• Inhibitory: Hyperpolarization, decreasing the likelihood of a neuron firing.
  • Photoreceptors are an exception to this, being active during hyperpolarization.
• Direct (Ionotropic): Neurotransmitter binds to an ionotropic receptor, causing the channel to open and allowing ions to flow across the membrane. This produces an immediate response.
• Indirect (Metabotropic): Neurotransmitter binds to a metabotropic receptor, activating a G protein. This G protein then activates an effector protein, leading to the production of second messenger molecules. These messengers activate enzymes, ultimately opening ion channels and causing a more delayed and longer-lasting response compared to ionotropic receptors.

Neurotransmitter Inactivation

• Degradation by Enzymes: Enzymes present in the postsynaptic cell or synaptic cleft break down the neurotransmitter, removing it from the synapse.
• Reuptake: Glial cells (astrocytes) or the presynaptic neuron reabsorb the neurotransmitter back into the presynaptic terminal.
• Diffusion: Neurotransmitter diffuses away from the synapse into the bloodstream.

Acetylcholine (ACh)

• Functional Regulation:
  • Movement
  • Cortical excitability
  • Heart and skeletal muscle contraction
  • Arousal and sleep
  • Cognition and reward
• Synthesis: Acetylcholine is synthesized from acetyl-CoA and choline by choline acetyltransferase (ChAT), the rate-limiting step in the pathway.
  • Acetyl-CoA is derived from glycolysis products (pyruvate) converted by pyruvate dehydrogenase.
  • Choline is obtained from reuptake after cholinesterase enzymatic degradation.
• Excitatory in skeletal muscle, inhibitory in cardiac muscle.
• Packaging: Acetylcholine is packaged into vesicles by a vesicular acetylcholine transporter (vAChT).

Dopamine (DA)

• Functional Regulation:
  • Coordination and movement
  • Attention, memory, and learning
  • Pleasure/reward
  • Arousal and sleep
  • Behavior and cognition
  • Inhibition of prolactin production
  • Nausea and vomiting
  • Inflammation and pain
• Imbalance:
  • Sleep disturbances
  • Restless legs syndrome
  • Psychosis
  • Apathy/depression
  • ADHD symptoms
• Inactivation: Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT) inactivate dopamine in the liver, presynaptic, or post-synaptic terminal (reuptake-2).
• Receptors: Dopamine receptors are classified as D1-like (D1R and D5R) and D2-like (D2R, D3R, D4R), all G-protein coupled receptors.
  • D1-like: Linked to Gs, stimulating adenyl cyclase (AC).
  • D2-like: Linked to Gi/Gs, inhibiting AC and Ca2+ channels, and activating K+ channels.

Norepinephrine (NE)

• Biosynthesis: Norepinephrine is synthesized from the same pathway as dopamine, originating from phenylalanine and tyrosine amino acids.
• Functional Regulation: Various depending on the receptor type, but generally excitatory or inhibitory.
• Location:
  • CNS: Brainstem (pons)- locus coeruleus nuclei (Ag group of neurons), Limbic system, Some areas of cerebral cortex.
  • PNS: Main neurotransmitter of postganglionic neurons in the sympathetic nervous system.
• Role in Mood: May play a role in the genesis and maintenance of mood.
• Catecholamine Hypothesis: Reduced norepinephrine activity is linked to depression, while increased activity is linked to mania.

Epinephrine (E)

• Synthesis: Epinephrine is synthesized from norepinephrine by the enzyme PNMT.
• Location: Can be synthesized in neurons or the adrenal medulla and transported back to neurons or used in tissues.
• C1 Neurons: Rostral ventrolateral medulla.
• C2 Neurons: Nucleus tracts solitarius or solitary nucleus.

Serotonin (5-HT)

• Biosynthesis: Dietary tryptophan serves as a substrate for serotonin synthesis, requiring aromatic amino acid decarboxylase.
• Functional Regulation:
  • Mainly inhibitory.
  • Indirect action via second messengers.
  • Direct action at 5-HT receptors.
• Location:
  • CNS: Brainstem (dorsal and medial raphe nuclei): midbrain, medulla, pons.
  • Projections: Hypothalamus, Limbic system, Cerebellum, Pineal gland, Spinal cord.
• Pineal Gland: Serotonin is synthesized in the pineal gland and serves as a precursor for melatonin, which regulates sleep patterns.
• Receptors: Serotonin receptors are classified into families (5-HT1-5) with subtypes.
  • Inhibitory: Receptors types 1, 5, and 6.
  • Stimulatory: Receptors types 2, 3, and 4.
  • Second Messenger: Cyclic AMP (cAMP) for all families.
• Effects: Plays a role in sleep, appetite, nausea, migraine headaches, mood regulation, and body temperature.
  • Low 5-HT levels are associated with severe depression and insomnia.
  • High 5-HT activity is associated with mania.
  • Dysfunction of 5-HT is linked to obsessive-compulsive disorder.

Glutamate

• Source:
  • Kreb's Cycle: α-oxoglutarate is converted to glutamate by α-oxoglutarate transaminase.
  • Reuptake: Glial cells or presynaptic neurons reabsorb glutamate or convert it to glutamine.
• Function: Excitatory neurotransmitter.
• Effects: Plays a role in Alzheimer's disease (AD) and neuronal loss due to overexcitation and glutamate-induced activation of NMDA receptors.
  • Namenda, an NMDA receptor antagonist, is used to treat AD.
• Retina: Glutamate circuits in the retina regulate the activation and deactivation of photoreceptors.
  • Rods: Active at night and activated by mGluR6, while cones are off at the same time.

Acetylcholine Receptors

• Nicotinic (N):
  • N1 (NM): Found at the neuromuscular junction of skeletal muscle.
  • N2 (NN): Found in autonomic ganglia, CNS, and adrenal medulla (for catecholamine release).
• Muscarinic (M):
  • M1-M5: Widely distributed in the CNS.
    • M1: Found in the autonomic nervous system, striatum, cortex, and hippocampus.
    • M2: Found in the autonomic nervous system, heart, intestinal smooth muscle, hindbrain, and cerebellum.
    • M3: Mediates pupil constriction and activation of lacrimal gland secretion (pupil constriction by CN 3, lacrimal gland by CN 7).

Acetylcholine Associated Effects

• Organophosphate Insecticides: Prolonged effects of ACh leading to tetanic muscle spasms.
• Botulinum Toxin (Botox): Inhibits ACh release by Clostridium botulinum bacteria.
• Alzheimer's Disease: Decreased ACh levels in certain brain areas.
• Myasthenia Gravis: Nicotinic ACh receptors at the neuromuscular junction are destroyed by the immune system, resulting in muscle weakness.
• Atropine: Anti-muscarinic cholinergic drug used to treat conditions like bradycardia, uveitis, and early amblyopia in children.
  • Stimulates pupil dilation (mydriasis) and paralyzes the accommodation reflex (cycloplegic), used in ophthalmic evaluation.

Alzheimer's Disease (AD)

• Cholinergic Neurons: Cholinergic neurons of the basal forebrain, involved in learning and memory, are implicated in AD.
• Neural Atrophy: Characterized by extensive neural atrophy in the brain cortex and hippocampal formation, along with significant loss of cholinergic neurons in the basal nucleus of Meynert.
• Symptoms: Memory loss, personality changes, dementia.
• Treatment (Replacement Therapy): Donepezil (Aricept), Galantamine (Razadyne ER).

Huntington's Disease/Chorea

• Degeneration: Degeneration of ACh and GABA containing neurons.
• Symptoms: Chorea (sudden, unexpected, and purposeless contraction of proximal muscles), dementia.
• Brain Atrophy: Atrophy of the brain basal ganglia and lateral ventricle enlargement.
• Juvenile HD: < 20 years, with faster progression.
• Other Symptoms: Muscle rigidity, slow or unusual eye movements, problems walking or maintaining posture, and speech and swallowing deficits.

Myasthenia Gravis

• Autoimmune Syndrome: Auto-antibodies are present against nicotinic ACh receptors (N1/NM) at the neuromuscular junction.
• Reduced Receptors: Auto-antibodies reduce the number of receptors at the neuromuscular junction, leading to paresis (weakness of voluntary movements).
• Muscle Involvement: Affects extraocular and eyelid muscles (causing diplopia and ptosis), bulbar muscles (nasal speech and jaw fatigue), and limbs (weaker proximally, stronger distally).
• Diagnosis: IV edrophonium (short and rapid-acting anticholinesterase drug) can be used to temporarily improve muscle strength.

Lambert-Eaton Myasthenic Syndrome (LEMS)

• Autoimmune Disease: Autoimmune attack of voltage-gated calcium channels at the presynaptic nerve endings, resulting in decreased ACh release at the neuromuscular junction.
• Muscle Weakness: Weakness primarily affects limb muscles.
• Association with Neoplasms: 50% of cases are associated with neoplasms (lung, breast, prostate).
• Autonomic Dysfunction: Often accompanied by involuntary autonomic dysfunction, especially dry mouth.

Dopamine Clinical Correlations

• Parkinson's Disease: Degeneration of dopaminergic neurons in the substantia nigra, reducing DA release in the caudate/putamen.
  • Symptoms: Hand tremors, rigidity, akinesia (loss of voluntary movement), dementia.
  • Treatment: L-DOPA and carbidopa (an inhibitor of dopa-decarboxylase).
• Psychotic Disorders: Most common is Schizophrenia, associated with increased activity at dopaminergic synapses.
  • Treatment: Phenothiazines and butyrophenones (reduce DA synaptic activity in the limbic forebrain).
• Cocaine Drug Abuse: Cocaine, a local anesthetic, inhibits the reuptake of DA and NE into the nerve terminals.
  • Responsible for the euphoric effects.
  • DA projections from the VTA to the NAcc contribute to the emotional reinforcement and motivation associated with cocaine addiction.

Dopamine Boosting Drugs/Abuse

• Illicit Drugs: Heroin, cocaine (crack and powder), crystal meth, ecstasy (MDMA derivative), pure MDMA, bath salts, marijuana, LSD.
• Legal Drugs: Alcohol, prescription painkillers, benzodiazepines, and caffeine.
• Withdrawal Symptoms: Prolonged use of dopamine-increasing drugs leads to withdrawal symptoms when quitting due to the brain's adaptation to high levels of dopamine.

Supplements Affecting Dopamine Levels

• Receptor Agonists:
  • Yohimbine: Used for erectile dysfunction, weight loss, and angina.
  • Ningdong Granules: A traditional Chinese herbal supplement.
• Receptor Antagonists:
  • L-theanine: Found in green tea.
  • Ginkgo biloba: Used to improve cognitive function, blood circulation, and eye health.
  • Bacopa: A traditional Indian medicinal herb.
  • Mucuna pruriens: A tropical legume known for its high L-DOPA content.

Serotonin Clinical Correlations

• Depression: Low 5-HT levels are associated with depression, which is often treated with selective serotonin reuptake inhibitors (SSRIs) like Prozac, that block the reuptake of serotonin.
• Mania: High 5-HT activity is associated with mania.
• Obsessive-Compulsive Disorder (OCD): Dysfunction of 5-HT is often linked to OCD, which can be treated with tricyclic antidepressants and SSRIs like Fluoxetine (Prozac) to increase 5-HT availability.
• Migraines: Selective serotonin receptor agonists (for 5-HT1B), like sumatriptan (Imitrex), can abort migraines due to vasoconstrictive and anti-inflammatory actions.