PS231: Neuropharmacology III

GABA

an amino acid neurotransmitter, and the primary inhibitory neurotransmitter of the brain

GABAergic neurons

widespread, and found throughout the CNS (red arrows)

Action of GABA at the synapse

terminated by reuptake into the presynaptic nerve terminals by GABA transporters (GATs)

Three major GABA receptors

GABAA (ionotropic), GABAB (metabotropic) and GABAC receptors (ionotropic)

Fast Inhibitory Neurotransmission: GABA-A Receptor

GABA & Inhibitory GABAA Receptor Neuropharmacology

• The nervous system needs a balance between excitation (GLU) and inhibition (GABA)

  • Too much inhibition, brain shuts down; too little, run-away excitation (epilepsy/seizures)

• The amount of chloride current that the channel is capable of conducting can be modulated by activity at other binding sites

Benzodiazepines, barbiturates and ethanol

potent sedatives/anxiolytics that bind to their own separate binding sites to increase the probability that the channel opens when GABA binds and/or keep the channel open longer

Neurosteroids

can enhance or suppress inhibitory function (e.g. pregnenolone)

GABA Reuptake/Signaling Termination

1. Enzymatic breakdown (e.g. ACh)

2. Reputake by astrocytes (e.g. GLU)

3. Reuptake by presynaptic neuron (e.g. GABA)

Excess GABA in the synaptic cleft

reabsorbed into the presynaptic terminal by the action of GABA transporters (GATs) where it is recycled back into synaptic vesicles for re-release

Acetylcholine

an excitatory neurotransmitter in the brain and the NMJ, but has inhibitory effects on cardiac muscle (mAChRs)

Glutamate

the primary excitatory NT of the brain

GABA

the primary inhibitory NT of the brain

Rule

Each receptor binds a single neurotransmitter, but neurotransmitters can bind to multiple receptors

Chemical synapses

use neurotransmitters for chemical communication

Neurotransmitters

packaged in small, membrane bound organelles called synaptic vesicles

Synaptic vesicles

fuse with the presynaptic membrane to release neurotransmitter across the synaptic cleft–the space between the preand post-synaptic neuron

Receptors

neurotransmitters bind to these on the postsynaptic membrane, resutling in EPSPs or IPSPs, depending on the neurotransmitter system

Calcium

• is necessary for vesicular fusion/NT release

• binds to synaptotagmin, which catalyzes the fusion of the vesicular membrane with the axon terminal membrane, causing the release of neurotransmitter

Postsynaptic receptors

ligand-gated and when activated, allow the passage of ions (ionotropic/directly or metabotropic/ indirectly)

Multiple species of ion

pass through an open receptor channel—many are not selective to one ion species (much unlike ion channels on the axon)

Postsynaptic potentials

can be either excitatory (e.g. glutamate) or inhibitory (e.g. GABA), causing EPSPs or IPSPs, respectively

Acetylcholine, glutamate, and GABA

very important neurotransmitters that have different functions and act on different receptors throughout the nervous system, and excitatory/inhibitory balance in the brain is crucial

Drug

a non-nutritional substance that alters our physiology and/or behavior, taken either recreationally or pharmaceutically to treat a disorder or medical condition

Psychoactive substances/drugs

compounds that affect our feelings, perceptions, states of consciousness and behavior

Illicit drugs

illegal, heroin, cocaine, methamphetamine

Licit drugs

legal, alcohol, caffeine, nicotine, many prescription medications

Ingestion

• Depends on absorption by the gut, which is somewhat slower than most other routes, and is affected by digestive processes and the presence of food

• Slow to moderate

Inhalation

• Nicotine, cocaine, organic solvents, variety of prescription drugs and hormone treatments

• Take advantage of the rich vascularization of tthe nose and lungs to convey drugs directly into the bloodstream

• Moderate to fast

Peripheral injection

• Subcutaneous, sloweest effects because drugs must diffuse into nearby tissue in order to reach the bloodstream
  Intravenous injections have very rapid effects because the drugs are placed directly into the circulation

• Moderate to fast

Central injection

• Injection directly into the CNS and are used in order to circumvent the blood-brain barrier, to rule out peripheral effects, or to directly affect a discrete brain location

• Fast to very fast

How fast drugs get into the blood (onset) and how much of it (bioavailability) depends on the route of administration

Bioavailability

the proportion of substance/drug consumed that becomes completely available to its intended biological target(s)

Blood brain barrier

• A highly selective, semi-permeable border of cells that prevents substances in the circulating blood from crossing into the central nervous system (where neurons reside)

• Endothelial cells provide a solid lipid barrier, so that non-lipid soluble substances cannot get into the brain

• Protects the brain from foreign pathogens, toxins, etc.

Two factors important in crossing the blood brain barrier

• The size and lipid solubility 

• Most psychoactive drugs are small and fat soluble, these pass through the BBB test

Colchicine and reserpine

alter different aspects of neurotransmitter production

Tetrodotoxin and Verapamil

alter different aspects of neurotransmitter release

Cocaine and MAO inhibitors

alter different aspects of neurotransmitter clearance/reuptake from the synaptic cleft

Effects on transmitter receptors

Effects on cellular processes

Summary

Describe the complexity of the ionotropic GABAA receptor.

• Ligand gated ion channel

• Five different ions that permeate the receptor

• Multiple binding sites

Which ions permeate the GABAA receptor, and what is the effect on the neuron's membrane potential?

The GABAA receptor is primarily permeable to chloride ions (Cl⁻). When GABA binds, Cl⁻ flows into the neuron, making the inside more negative. This causes an Inhibitory Post-Synaptic Potential (IPSP), or hyperpolarization, which makes it more difficult for the neuron to generate an action potential.

Which other agonists can bind to the GABAA receptor? Are they competitive or noncompetitive?

Other agonists include benzodiazepines (e.g., diazepam) and barbiturates. These are generally noncompetitive agonists (allosteric modulators). They bind to sites distinct from the GABA-binding site, enhancing the effect of GABA without directly opening the channel themselves.

What class of psychoactive drugs do GABAA receptor agonists generally fall under?

Sedatives/anxiolytics (CNS depressants)

How is GABA signaling in the synaptic cleft terminated?

GABA signaling is primarily terminated by rapid reuptake of GABA from the synaptic cleft back into the presynaptic neuron and surrounding glial cells by specific transporter proteins. Once inside the cells, GABA can be degraded by the enzyme GABA transaminase.

What is meant by the term "bioavailability"?

Bioavailability is the fraction or percentage of an administered drug that reaches the systemic circulation unchanged and is thus available to produce a biological effect.

How does the route of administration affect a drug's bioavailability?

• Ingestion: slow to moderate

• Inhalation: moderate to fast

• Peripheral injection: moderate to fast

• Central injection: fast to very fast

• Different routes determine how much of the drug is absorbed

Which route of administration has the fastest onset, which has the slowest, and why?

• Fastest: Central injection, directly into the CNS and the bloodstream

• Slowest: oral, must be absorbed through gastrointestinal tract then to the liver

What is the blood-brain barrier (BBB) and how does it differ from peripheral blood vessel membranes?

The BBB is a highly selective semipermeable border of endothelial cells that line the brain's capillaries. Unlike peripheral capillaries, which have small gaps (fenestrations), the BBB endothelial cells are tightly joined together by tight junctions, preventing most substances from passively diffusing from the blood into the brain.

What role does the BBB play in the distribution of psychoactive drugs to the brain?

The BBB protects the brain by restricting the passage of toxins, pathogens, and many drugs from the blood. It acts as a major gatekeeper, controlling which psychoactive substances can enter the brain to exert their effects.

Can psychoactive drugs cross the BBB? Why or why not? If so, how?

Yes, most psychoactive drugs can cross the BBB. To do so, they must be lipophilic (fat-soluble). They primarily cross via passive diffusion through the lipid membranes of the endothelial cells. A few may use active transport systems.