Gabaa receptor pharmacology

The 60 Second Panic Solution

Treatments for Anxiety and Panic Attacks

Get Instant Access

GABAA receptors are classically defined by their sensitivity to the antagonist bicuculline. Other widely used antagonists include SR-95531 (gabazine), picrotoxin, and cage convulsants such as TBPS (t-butylbicyclophosphorothionate). Like bicucul-line, SR-95531 is a competitive antagonist acting at the GABA binding site while picrotoxin and TBPS are non-competitive, acting at a site which may be more closely associated with the chloride ion channel. Of these antagonists, only bicuculline is selective, as the others also act at GABAC receptors (see below). Similarly, no truly selective GABAA agonist is known. Muscimol is commonly used to activate GABAA receptors but it is also a partial agonist at GABAC receptors, while THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a partial agonist at GABAA receptors and an antagonist at GABAC receptors (Chebib and Johnston 2000). In addition to these agonists and antagonists, an enormous range of structurally diverse compounds can affect GABAA receptors. The most important of these are the benzodiazepines, barbiturates, neuroactive steroids and various general anaesthetics. The various sites of action of these drugs are depicted schematically in Fig. 11.6.

Benzodiazepines

Benzodiazepines such as chlordiazepoxide (Librium) and diazepam (Valium) were discovered in the early 1960s and found to have clinically important anxiolytic,

Figure 11.5 Chloride distribution and the GABAa response. The change in membrane voltage (Fm) that results from an increase in chloride conductance following activation of GABAA receptors is determined by the resting membrane potential and the chloride equilibrium potential (Eh)- (a) Immature neurons accumulate Cl~ via NKCC, while mature neurons possess a Cl~-extruding transporter (KCC2). (b) In immature neurons GABAA receptor activation leads to Cl~ exit and membrane depolarisation while in mature neurons the principal response is Cl~ entry and hyperpolarisation. This is the classic inhibitory postsynaptic potential (IPSP)

Figure 11.5 Chloride distribution and the GABAa response. The change in membrane voltage (Fm) that results from an increase in chloride conductance following activation of GABAA receptors is determined by the resting membrane potential and the chloride equilibrium potential (Eh)- (a) Immature neurons accumulate Cl~ via NKCC, while mature neurons possess a Cl~-extruding transporter (KCC2). (b) In immature neurons GABAA receptor activation leads to Cl~ exit and membrane depolarisation while in mature neurons the principal response is Cl~ entry and hyperpolarisation. This is the classic inhibitory postsynaptic potential (IPSP)

anticonvulsant and muscle relaxant properties. It was not until the late 1970s, however, that their mode of action was established. Then, in studies of cultured neurons, benzodiazepines were found to increase the conductance change produced by GABA, shifting the GABA concentration-response curve to the left. They had no effect on conductance in the absence of GABA. At approximately the same time, specific high-affinity binding sites for benzodiazepines were identified in the CNS using radiolabelled compounds. A significant correlation between the binding affinity of various benzodiazepines and their potency in behavioural tests suggested that these sites mediated the central effects of benzodiazepines. A close association between benzodiazepine binding sites and the GABA receptor was indicated by the discovery of increased binding of benzodiazepines in the presence of GABA and increased binding of GABA in the presence of benzodiazepines.

The term 'benzodiazepine' refers to a specific chemical structure. Numerous benzodiazepine-receptor ligands exist which have different structures. These include the ;6-carbolines (e.g. methyl-6,7-dimethoxy-4-ethyl-^-carboline 3-carboxylate; DMCM), triazolopyridazines (e.g. CL 218872), imidazopyridines (e.g. zolpidem), and pyrazolo-quinolinones (e.g. CGS 8216). In experimental animals these compounds produce

Bicucuiline

SR-95531

Antagonists

GABA site

Picrotoxin site

Barbiturate site ctiannel

Anaesthetic site(s)

Steroid site

Benzodiazepine site

Muscimol

GABA o

THIP

Agonists a-THDOC Ganaxalone

OMCM

GL 213672

CGS B216

Propofol Etomidata

Halotharw Isollurane

Br Cl F

Picrotoainin TflPS

PhonobarbitaƤ

Thiopental

Flumazenll

Was this article helpful?

0 0
Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

Get My Free Ebook


Post a comment