(4) Psychopharmacology and Neurotransmitter Functions

Psychopharmacology

The study of the effects of drugs on the nervous system and behavior

Drug

An exogenous chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses

Psychoactive Drug

A drug that has effects on conscious states and/or behavior

Goals of Psychopharmacology

To understand behavioral effects of drugs in the nervous system (e.g., site of reward effects, etc.), to develop novel therapeutics (e.g., to treat Alzheimer's), to understand the nervous system (as a research tool)

Pharmacokinetics

How drugs move through the body (kinetics = movement)

Route of Administration

Affects speed of absorption (e.g., fastest is intravenous injection) and blood levels

Absorption

Routes of Administration include intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, intracerebral administration, intracerebroventricular (ICV) administration, oral administration, sublingual administration, inhalation, topical administration

Distribution

Most psychoactive drugs exert effects on cells of the CNS and must pass through the Blood Brain Barrier

Best Drug Molecule Characteristics

Best if drug molecules are lipid soluble, small, and neutral

Metabolism and Excretion

Most drugs are metabolized and deactivated by enzymes in the brain and liver, and all drugs are eventually excreted, mostly by kidneys

Describing Drug Effects

A given drug can have more than one effect (e.g., morphine blocks pain and suppresses respiration) and drugs can produce same effects through different mechanisms (analgesia from morphine is not same as aspirin)

Dose-Response Curves

Effects vary with dose

Blood Brain Barrier

A selective barrier that prevents certain substances from entering the brain

Intravenous Injection

The fastest route of drug administration

Enzymes in Drug Metabolism

Enzymes sometimes transform molecules into active versions (e.g., benzodiazepines)

Classes of Neurotransmitters

Include Amino Acids (glutamate, GABA), Acetylcholine, Monoamines, Peptides, and Lipids

Actions on Receptors

Refers to how drugs interact with neurotransmitter receptors to produce effects

Deactivation and Re-uptake of Neurotransmitters

Processes that terminate the action of neurotransmitters in the synaptic cleft

Sites of Drug Actions

Locations in the body where drugs exert their effects

Intracerebroventricular (ICV) Administration

A method of drug administration directly into the brain's ventricular system

Margin of Safety

Difference between therapeutic dose and dose that produces toxicity (like respiratory suppression).

Tolerance

Decrease in drug effectiveness requiring higher doses for the same effect.

Sensitization

Drug becomes more effective.

Withdrawal symptoms

Symptoms that occur if an individual stops taking the drug, usually opposite to drug effects, indicating physical dependence.

Pharmacodynamics

Study of how drugs work at their target site, specifically the exact mechanism of action.

Agonist

Facilitates the action of a neurotransmitter.

Antagonist

Blocks or decreases the action of a neurotransmitter.

Production of neurotransmitters

L-DOPA is a precursor for dopamine (agonist).

Storage of neurotransmitters

Reserpine prevents storage of monoamines (antagonist).

Release of neurotransmitters

Botulinum toxin blocks release of acetylcholine (antagonist).

Direct Agonist

Mimics the action of the neurotransmitter when it occupies the receptor of the neurotransmitter (e.g., nicotine and acetylcholine).

Competitive Antagonist

Competes for the same binding site as the neurotransmitter but blocks the action of the neurotransmitter (e.g., chlorpromazine blocks dopamine receptors).

Indirect Agonist

Facilitates the action of the neurotransmitter without binding to the exact receptor, often seen when drug binds to receptor complex and increases the action of the neurotransmitter (e.g., Valium and GABA).

Non-competitive Antagonist

Blocks action of a neurotransmitter by binding to a different site (e.g., PCP and ion channel coupled to NMDA receptor).

Pre-synaptic auto-receptor

A receptor that, when bound by a drug, can decrease neurotransmitter release.

Post-synaptic receptor

A receptor that, when stimulated by a drug at higher doses, can increase neurotransmitter action.

Apomorphine

An agonist for dopamine receptors that at low doses binds to pre-synaptic autoreceptors and decreases dopamine release (antagonist effect) and at higher doses stimulates post-synaptic receptors (agonist effect).

Classes of Neurotransmitters

Includes Amino Acids (glutamate, GABA), Acetylcholine, Monoamines, Peptides, and Lipids.

Deactivation

The process by which neurotransmitters are broken down or removed from the synaptic cleft.

Re-uptake

The process by which neurotransmitters are reabsorbed by the presynaptic neuron after transmitting a signal.

Acetylcholinesterase

An enzyme that breaks down acetylcholine in the synaptic cleft.

Fluoxetine (Prozac)

A drug that blocks the re-uptake of serotonin, leading to increased serotonin neurotransmission.

Glutamate

The main excitatory neurotransmitter in the brain and spinal cord, released by all sensory neurons except pain.

GABA

Gamma-aminobutyric acid, an inhibitory neurotransmitter in the brain.

Glycine

An inhibitory neurotransmitter found in the spinal cord and lower brain stem.

NMDA Receptor

A complex receptor that is both chemical and voltage gated, involving Ca++ and Na+ channels.

EPSPs

Excitatory post-synaptic potentials caused by the activation of excitatory neurotransmitter receptors.

Glutamate Receptors

Three ionotropic receptors (NMDA, AMPA, Kainate) and one metabotropic receptor that respond to glutamate.

Glutamine Synthetase

An enzyme that converts glutamate into glutamine.

Astrocytes

Glial cells that play an important role in regulating glutamate neurotransmission and have glutamate transporters.

Neurotoxic

A term describing substances that are harmful or damaging to nerve cells.

Ionotropic Receptors

Receptors that are coupled to ion channels and mediate fast synaptic transmission.

Metabotropic Receptors

Receptors that are linked to signaling pathways and mediate slower, longer-lasting effects.

Excitatory Neurotransmitters

Neurotransmitters that increase the likelihood of a neuron firing an action potential.

Inhibitory Neurotransmitters

Neurotransmitters that decrease the likelihood of a neuron firing an action potential.

Presynaptic Neuron

The neuron that releases neurotransmitters into the synaptic cleft.

Synaptic Cleft

The space between the presynaptic and postsynaptic neurons where neurotransmitters are released.

Vesicles

Small membrane-bound sacs that store neurotransmitters in the presynaptic neuron.

Glutamate

Termination: Astrocytes are swell...

GABA

Main inhibitory neurotransmitter in brain; inhibitory influence keeps brain stable; Seizures may be result of lacking or poorly functioning GABA-secreting neurons or receptors; Drugs such as barbiturates, alcohol, and benzodiazepines produce their effects by enhancing GABA neurotransmission.

GABAA

Ionotropic, Cl- channel; hyperpolarizations; Multiple binding sites on surface for drugs: benzodiazepines, alcohol, barbiturates.

GABAB

Metabotropic; Also inhibitory.

GABA Transporters

Termination: GABA transporters; GABA aminotransferase.

Acetylcholine

Earliest known neurotransmitter; Neuromuscular junctions (PNS); Also in brain (CNS); Important for learning and memory.

Acetylcholine Pathways

Dorsolateral pons (REM sleep); Basal forebrain or nucleus basalis (facilitate learning); Medial septum (memory formation).

Nicotinic Receptor

Ionotropic ACh receptor is stimulated by nicotine.

Muscarinic Receptor

Metabotropic ACh receptor is stimulated by muscarine (found in the mushroom Amanita muscaria).

Acetylcholinesterase (AChE)

Deactivated by the enzyme acetylcholinesterase (AChE), present in the postsynaptic membrane; AChE inhibitors used to treat myasthenia gravis (neostigmine); memory loss associated with early stages of Alzheimer's donepezil (Aricept).

Monoamines

So named, due to a single amine group (NH2) in chemical structure; Very important psychological functions (target of many psychoactive drugs); Include: Dopamine (reinforcement, movement), Norepinephrine (attention, vigilance), Serotonin (mood, sleep), Histamine (wakefulness).

Catecholamines

Synthesized from tyrosine (Amino Acid); Series of steps (converting enzymes); Stored in vesicles; Note: L-DOPA used to treat Parkinson's; Termination: Enzymes: MAO (monoamine oxidase) & COMT; Re-uptake transporters.

Dopamine

Three main pathways.

Dopamine Receptors

Five metabotropic receptors: D1, D2, D3, D4, and D5; D1 and D5 are excitatory (increase cyclic AMP); Effects depend on location of receptors; For example, D2 receptors are found on pre-synaptic membranes (auto-receptors) but also on post-synaptic membranes; Note: Post-synaptic D2 receptors in mesocortical pathway implicated in schizophrenia (anti-psychotics like chlorpromazine block D2 receptors).

Dopamine Re-uptake

Note: Stimulant drugs like cocaine, amphetamines, block dopamine re-uptake transporters; In fact, amphetamine and methamphetamine cause transporter to run in reverse which further increases DA in synapses!

Norepinephrine

Found in Brain and PNS (sympathetic NS). Most (nearly all) brain areas receive NE from pathways originating in pons. Locus coeruleus is the major source. NE leads to increased vigilance: attentiveness to environmental stimuli.

Norepinephrine Release

NE released from varicosities (swellings) along axons.

Norepinephrine Receptors

All metabotropic. Two families: α and β. α1 (excitatory), α2 (pre-synaptic auto-receptors), β1, β2 (excitatory).

Norepinephrine Termination

Catabolic enzymes (MAO or COMT) and re-uptake.

Serotonin

Synthesis: from tryptophan (AA). Plays role in regulation of mood; control of eating, sleep, and arousal; and pain regulation. Also involved in dreaming. Major source is raphe nuclei of the midbrain, pons, and medulla.

Serotonin Release

Released from varicosities, like norepinephrine.

Serotonin Receptors

At least 7 types: 5-HT1, 5HT2, etc. Most are excitatory. 5-HT1A serves as an inhibitory auto-receptor on somas and dendrites (remote from synapse).

Serotonin Termination

Monoamine oxidase (MAO) and re-uptake: serotonin transporters on pre-synaptic neurons. (SSRI antidepressants like Prozac block reuptake). MDMA (ecstasy) causes transporter to run in reverse (like METH and DA).

Histamine

Found in only one place in the brain: the tuberomammillary nucleus, located in the posterior hypothalamus. Plays important role in wakefulness. Drugs that block histamines (antihistamines) cause drowsiness.

Histamine Production

Produced from the amino acid precursor histidine by the action of the enzyme histidine decarboxylase. Stored in vesicles and released following an action potential.

Histamine Receptors

CNS contains H1, H2, H3, and H4 receptors. Antihistamines act as antagonists at histamine receptors.

Peptides

Peptides are two or more amino acids linked by peptide bonds. Produced (cleaved) from larger precursor molecules into smaller peptides. Produced in soma, transported to nerve terminals. Often co-released with another neurotransmitter. The best known are endogenous opioids (enkephalins). High concentrations in periaqueductal gray (midbrain).

Peptide Receptors

At least 3 opioids receptors (mu, delta, kappa). Produce analgesia (reduce pain). Inhibits defensive behaviors (fight and flight). Rewarding/euphoric effects: Site of action of morphine, heroin, oxycodone, fentanyl, etc. Naloxone is a competitive opioid receptor antagonist used to reverse opioid drug overdose.

Lipids

Lipid neurotransmitters appear to be synthesized on demand, produced or released as needed. Not stored in synaptic vesicles. Best known are endocannabinoids (anandamide). Involved in pain regulation, appetite (munchies). Act as retrograde signals, released by post-synaptic neurons back onto pre-synaptic neurons.

Lipid Receptors

Two types of cannabinoid receptors, CB1 and CB2. CB1 receptors located on pre-synaptic nerve terminals and decrease activity of the pre-synaptic neuron.

THC Effects

THC exerts analgesic effects by stimulating CB1. Acetaminophen also acts on these receptors (in periphery).