INTRODUCTION:

Receptor is a protein molecule which is embedded in either the plasma membrane or the cytoplasm of a cell to which one or more specific kinds of signaling and may be a peptide (short protein) or other small molecule such as a neurotransmitter, a hormone, a pharmaceutical drug or a toxin ¹.

Depending on their functions, ligands several types of receptors may be identified:-

1. Peripheral membrane proteins.

2. Transmembrane proteins: transmembrane receptors are embedded in the phospholipid bilayer of cell membranes, that allow the activation of signal transduction pathways in response to the activation by the binding molecule or ligand.

3. Metabotropic receptors: These are coupled to G-proteins and affect the cell indirectly through enzymes which control ion channels.

4. Ionotropic receptors (also known as ligand-gated ion channels): They contain a central pore which opens in response to the binding of ligand. Another major class of receptors is intracellular proteins such as those for steroid and intracrine peptide hormone receptors ².

Drug receptor interaction:

According to the Occupation theory, drug effect is directly proportional to number of receptors. Occupied drug effect ceases as drug-receptor complex dissociate Efficacy is the ability of the drug-receptor complex to initiate a response. Affinity “drug-receptor interaction” is governed by the law of mass action. Two main types of neurotransmitters and neurotransmitter receptors excitatory and inhibitory determine the response of the signal receiving neuron. Excitatory neurotransmitters and their receptors increase the neuron’s intrinsic electrical activity and excitability, whereas inhibitory neurotransmitters and their receptors reduce neuronal excitability. For optimal functioning, the brain must balance the excitatory and inhibitory influences ^{3, 4}.

GABA (Gamma amino butyric acid)-

A neurotransmitter:

GABA is the major inhibitory amino acid transmitter of the mammalian central nervous system and it is present in some 40% of all neurones. Most of the early studies, carried out with iontophoretic application of GABA in the CNS, indicated that it generally produced inhibitory hyperpolarizing responses on neurons. The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the vertebrate central nervous system. There are two classes of GABA receptors: GABA_A and GABA_B. GABA_A receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABA_B receptors are G protein-coupled receptors (also known as metabotropic receptors) ³.

1. GABA (STORAGE AND RELEASE):

GABA (Gamma amino butyric acid) occurs in brain tissue but not in other mammalian tissues except in trace amounts. GABA is formed from glutamate by the action of glutamic acid decarboxylase (GAD), an enzyme found only in GABA-synthesizing neurons in the brain. Immuno histochemical labelling of GAD is used to map the GABA pathways in the brain. GABA is destroyed by a transamination reaction in which the amino group is transferred to α-oxoglutaric acid (to yield glutamate), with the production of succinic semialdehyde and then succinic acid. This reaction is catalysed by GABA transaminase which is inhibited by vigabatrine, a compound used to treat epilepsy .GABAergic neurons and astrocytes take up GABA via specific transporters, and it is this, rather than GABA transaminase, which removes the GABA after it has been released. About 20% of CNS neurons are GABAergic. Most are short inter neurons, but long GABAergic tracts run to the cerebellum and striatum. The widespread distribution of GABA, and the fact that virtually all neurons are sensitive to its inhibitory effect, suggests that its function is ubiquitous in the brain. GABA serves as a transmitter at about 30% of all the synapses in the CNS ⁵.

Fig 1: Shows storage and release of GABA in response to various stimuli

GABA receptors: structure and pharmacology:

GABA acts on two distinct types of receptor, one (the GABA_A receptor) being a ligand-gated channel, the other (GABA_B) being a G-protein-coupled receptor ⁶.Structurally, they are pentamers, most of them composed of three different subunits (α, β, γ), each of which can exist in three to six molecular subtypes. There are a great many possible permutations, of which one (α₁β₂γ₂) is by far the most abundant overall, although dozens of other functional variants are expressed in specific regions-a familiar pattern of heterogeneity typical of neurotransmitter receptors. GABA_B receptors are located pre- and postsynaptically, and they are typical G-protein-coupled receptors but unusual in that the functional receptor is a dimmer consisting of two different subunits. Apart from minor splice variants, only a single isoform is known-also unusual among G-protein-coupled receptors. GABA_B receptors exert their effects by inhibiting voltage-gated calcium channels (thus reducing transmitter release) and by opening potassium channels (thus reducing postsynaptic excitability), these actions resulting from inhibition of adenylyl cyclase. It is believed that glutamate and GABA, and their receptors, evolved very early, so these receptors probably represent the venerable aristocrats from which upstarts such as the neuropeptide receptors evolved much later. The active site of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, barbiturates, ethanol ^[4],neuroactive steroids, inhaled anaesthetics, and picrotoxin, among others ^5,6.

Fig 2: Shows structure and different binding sites of GABA receptors.

GABA RECEPTORS: CLASSIFICATION

Ø GABA_AReceptors:

GABA_A receptors are responsible for the majority of neuronal inhibition in the mammalian CNS. Agonist activation results in the opening of their integral anion channel, generally leading to hyperpolarization of the cell membrane and thus inhibition. Electron microscopic studies of the native receptors have shown that they are composed of five subunits arranged pseudo symmetrically around the ion channel pathway which passes through the cell membrane, and the receptor appears as a doughnut with a diameter of around eight nm when viewed from the cell exterior. The receptors are generally heterooligomers ^7,8,9,10. The subunits being selected from four principle families in the human brain, molecular cloning studies have so far isolated six α subunit isoforms, three β and three γ while only a single δ isoform is currently known. Each of the subunit isoforms are encoded by a single gene although additional heterogeneity is introduced by alternative splicing in a number of cases². There are perhaps four principle receptor subtypes in the brain accounting for 70-80% of the total receptor population, but these are supplemented with fewer than ten less common subtypes. The most common GABA_A receptor of the mammalian CNS appears to comprise two subunits. However, it is clear that the precise subunit composition of the receptor subtype determines its pharmacological and gating characteristics^11,12,13. The GABA_A receptor family is the target for a number of psychoactive drugs namely benzodiazepines, barbiturates, neurosteroids and the general anesthetics with each class interacting with unique allosteric sites on the receptor. The spectrum of pharmacological activity is wide with positive efficacy of agents producing sedation/hypnosis, anxiolysis, anticonvulsant activity, muscle relaxation and anterograde amnesia. ^12,13,14.

Fig 3: Shows the GABA receptor from the extracellular space, the orientation of the subunits within the pentamer together with the location of the benzodiazepine (Bz) and low affinity GABA sites

Ø GABA_B Receptors:

The GABA_B receptor is not only located post-synaptically, but is also present on pre-synaptic terminals where its activation modulates the release of neurotransmitters. This is clearly evident in spinal cord where activation of the receptor on primary afferent terminals appears to be important in the modulation of nocciceptive inputs, and on terminals of monosynaptic inputs to motoneurons in the production of muscle relaxation ⁴. A year after this initial discovery it was realized that GABA_B1 is not expressed on the surface of cells without the support of a second receptor protein referred to as GABA_B2, which appears to couple to GABA_B1at the level of the endoplasmic reticulum in order to facilitate surface expression. GABA_B2 also has a seven transmembrane spanning and links to GABA_B1 at their intracellular C-terminals. The combination of these two proteins forms a heterodimer that is crucial for full receptor function. However, no GABA binding has been associated with GABA_B2, although it appears that this protein may be more than just a trafficker for GABA_B1. Numerous isoforms of GABA_B1 and GABA_B2 have been described with at least three forms of human GABA_B1 and GABA_B2proteins. However, whether different combinations of these isoforms produce different pharmacological characteristics is not known. Even definitive evidence for the existence of subtypes of native GABA_Breceptors have yet to be shown, although there are data which support a separation based on neuropharmacological and neurochemical analysis. A variety of proteins which are unrelated to GABA_B receptors, e.g. CREB2, have been shown to independently associate with high affinity to GABA_B1and GABA_B2 proteins although they fail to produce any receptor functionality GABA also activates metabotropic GABA receptors which are widely distributed within the central nervous system and also in peripheral autonomic terminals. Their activation causes an inhibition of both basal and forskolin stimulated adenylate cyclase activity together with a decrease in Ca and an increase in K conductance in neuronal membranes. The receptors are activated by baclofen, used in the treatment of spasticity, (R)-baclofen being the active isomer .There is evidence that GABA_Breceptors agonists may be useful in the treatment of pain and to reduce the craving for drugs of addiction. There is limited information on the therapeutic potential of GABA_B receptor antagonists but there is support for the idea that they may prove valuable in the treatment of absence epilepsy and as cognition enhancers. GABA receptors have now been identified by expression cloning using the high affinity ligand CGP-64213. Functional receptors are formed only after heterodimerization of GABA and GABA (previously known as GBR1 and GBR2) by interaction through their C-termini, the first time that this form of 1:1 stochiometry has been identified within this family. Both subunits are members of the seven-transmembrane receptor family that show over 30% sequence homology to the metabotropic glutamate receptors. A number of splice variants have been identified for both GABA and GABA. The mRNA encoding GABA is found exclusively in neurons but GABA is found in both neurons and glial. Immunoprecipitation studies suggest that GABA_B1and GABA_B2 are always found as heterodimers although the paucity of mRNA for GABA in the striatum has led to suggestions that further subunits remain to be identified . There have been suggestions that the two most widely studied splice variants GABA_B1a and GABA_B1b may be differentially located within the cell, the former being pre-synaptic while the latter is found post-synaptically. The large deletion at the N-terminus which occurs in splice variant GABA is consistent with a differential subcellular localisation and it will be interesting to see the whether or not this is region specific. Although a significant number of phosphinic acid derivatives have been synthesised as GABA receptors agonists few exceed the potency of (R)-baclofen and none has proved useful in the differentiation of the distinct receptors subtypes ^4,9,15,16. Like the metabotropic glutamate receptors, both the GABAb1 and GABAb2 subunits possess a large extracellular N-terminal tail which has been modelled by homology on the bacterial periplasmic binding protein characterized by two globular domains connected by a hinge region. It has been suggested that agonist activation relies on the closure of the two globular domains subsequent to agonist binding: the venus fly-trap model ^15,16,17.

Ø GABA_Creceptors^:

The time constants of GABA_C receptor relaxation are in the order of tens of seconds, which makes them the slowest ligand-gated channels identified to date. The chloride channels gated by GABA_Creceptors exhibit small single channel conductances (a few picosiemens). GABA_C receptors are thought to be composed of GABA ρ (rho) subunits. At least three types of GABA ρ subunits have now been cloned from retinal cDNA libraries human ρ1 and its shorter alternative spliced forms (D51 and D450); human ρ2; and rat ρ1-3. Using both Xenopus oocytes and cell line expression systems, it has been shown that these subunits can form homo-oligomeric receptors with physiological and pharmacological properties similar to those observed for GABA_Creceptors. In addition, various GABAρ subunits exhibit different expression patterns in the CNS. These results suggest that the neuronal GABA_C receptors are formed by hetero-oligomeric GABA ρ subunits, and that diverse forms of GABA_C receptors exist in the CNS. However, the exact subunit composition of the GABA_Creceptors has yet to be determined. However, molecular cloning studies have revealed that this pharmacological profile is remarkably similar to that exhibited by the subunits when expressed ectopically ¹⁰. Two homologous subunits have been identified in man and these can be expressed as homomers or heteromers, but do not co-assemble with any of the GABA receptor subunits. The DNAs are encoded on chromosome in man distinct from the clusters of GABA receptor subunit genes which are found on chromosomes 4, 5, 15 and X; the subunits are between 30 and 38% homologous to the GABA receptor subunits at the amino acid level. In the important TM2 region of the sequence, they show greater homology to the glycine subunits than to any of the GABA receptors subunits. It is assumed that they form pentameric assemblies, similar to the other members of the ligand gated ion channel family which enclose a chloride selective channel. The single channel conductance of the homomeric or heteromeric receptors composed of subunits is smaller (around seven pS) than that exhibited by the GABA receptors and the gating kinetics are quite distinct, with both the activation and deactivation time constants being very slow ^15,16,17,18.

Drugs acting on GABA receptors:

} GABA

◦ Muscimol (direct agonist); bicuculine (direct antagonist)

} Benzodiazepine (indirect agonist)

◦ Natural inverse agonist binds here (fear, tension, anxiety)

◦ Tranquilizing drugs (anxiolytics): valium, librium

◦ Likely site for alcohol

} Barbiturate (indirect agonist)

◦ Phenobarbital; pentobarbital

} Steroid (indirect agonist)

} Picrotoxin (inverse agonist):

} Zinc

} Strychnine

Table 1: Pharmacology of drugs acting on GABA receptors ⁹

Compound	GABA_A	GABA_B	GABA_C
GABA	Agonist	Agonist	Agonist
Muscimol	Agonist	Inactive	Partial Agonist
Isoguvacine	Agonist	Inactive	Antagonist
THIP	Agonist	Inactive	Antagonist
P4S	Agonist	Inactive	Antagonist
TACA	Agonist	Inactive	Agonist
CACA	Inactive	Inactive	Partial Agonist
(R)-Baclofen	Inactive	Agonist	Inactive
Bicuculline	Antagonist	Inactive	Inactive
Picrotoxine	Antagonist	Inactive	Antagonist
CGP 35348	Inactive	Antagonist	Inactive
CGP 54626	Inactive	Antagonist	Inactive
CGP 64213	Inactive	Antagonist	Inactive
SCH 50911	Inactive	Antagonist	Inactive
TPMPA	Inactive	Inactive	Antagonist

Ø GABA

A. Mechanism of action:

Stimulation of inhibitory neurons causes movement of ions that result in a hyperpolarization of the postsynaptic membrane. These inhibitory postsynaptic potentials (IPSP) are generated by the Stimulation of inhibitory neurons releases neurotransmitter molecules, such as I³-aminobutyric acid (GABA) or glycine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of specific ions, such as potassium (K+) and chloride (Cl^-) ions ^20,21. The influx of Cl^- and efflux of K+ cause a weak hyperpolarization or IPSP that moves the postsynaptic potential away from its firing threshold. This diminishes the generation of action potentials ⁵.

Figure 4: Mechanism of action of GABA on GABA receptors

Ø Benzodiazepines:

The benzodiazepines are frequently classified into three groups:

(1) short-acting,

(2) intermediate-acting, and

(3) long-acting.^20,21,22.

Ex- Short-Acting- Midazolam,Trizolam

Intermediate-Acting-Alprazolam, Estazolam, Lorazepam

Long-Acting-Clonazepam.

A. Mechanism of action–:

The molecular site of action for the benzodiazepines is at the GABAA receptors in the CNS. GABA or gamma-aminobutyric acid is an amino acid neurotransmitter that has an inhibitory effect on neurotransmission in the CNS. Therefore, an increase in the effect of GABA results in general suppression of the CNS. When GABA binds to GABA_A receptors, the result is an influx of chlorine ions into neurons through the ion channel formed by the receptor. It is the influx of chlorine that causes the negative effect on neurotransmission. On the GABA_A receptors there is also a site separate from the GABA binding site for benzodiazepines to bind at. When both GABA and a benzodiazepine is bound to a GABA_A receptor, the result is an increase in the influx of chlorine through the ion channel of the receptor .Therefore, benzodiazepines are said to increase the effect that GABA has at GABA_Areceptors when it binds. Another way to explain this is that benzodiazepines increase the agonist effect of GABA at the GABA_A receptors. Overall, this effect is said to be gabaergic because the overall effect is one of increasing the inhibitory effect of GABA in the CNS. Finally, it should be pointed out that the benzodiazepines do not have a direct effect on the GABA_Areceptor if GABA is not bound to the GABA_A receptors then benzodiazepine binding has no effect on chlorine ion influx ¹⁹.

Fig 5: Shows benzodiazepine binding site on GABA_A Receptor

B. Pharmacological Actions:

All benzodiazepines exhibit the following actions to a greater or lesser extent ²³.

· Reduction of anxiety:

· Sedative and hypnotic actions:

· Anterograde amnesia: This also impairs a person’s ability to learn and form new memories. This effect is partially, although not completely, mediated by I±1-GABA_A receptors.

· Muscle relaxation: At high doses, probably by increasing presynaptic inhibition in the spinal cord where the Î±2-GABA_Areceptors are largely located.

C. Therapeutic uses:

The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative properties. However, the duration of action varies widely among this group and pharmacokinetic considerations are often important in choosing one benzodiazepine over another ^{23, 24, 25}.

D. Pharmacokinetics:

The benzodiazepines are lipophilic and they are rapidly and completely absorbed after oral administration and distribute throughout the body. The half-lives of the benzodiazepines are very important clinically, because the duration of action may determine the therapeutic usefulness. The longer-acting agents form active metabolites with long half-lives. However, with some benzodiazepines the clinical durations of action do not always correlate with actual half-lives.

E. Adverse effects:

Drowsiness and confusion:

These effects are the two most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination such as driving an automobile. Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can occur with use of benzodiazepines. Triazolam, one of the most potent oral benzodiazepines with the most rapid elimination, often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety, along with amnesia and confusion.

Dependence:

Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and rarely seizures.

F. Drug Interactions:

Benzodiazepines should be used cautiously in treating patients with liver disease. They should be avoided in patients with acute narrow-angle glaucoma. Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines.

Ø Benzodiazepine Inverse Agonist and Antagonist:

The term inverse agonist is applied to drugs that bind to benzodiazepine receptors and exert the opposite effect to that of conventional benzodiazepines, producing signs of increased anxiety and convulsions. Diazepam-binding inhibitor is an example, and some benzodiazepine analogues act similarly. It is possible to explain these complexities in terms of the two-state model discussed by postulating that the benzodiazepine receptors exists in two distinct conformations, only one of which (A) can bind a GABA molecule and open the chloride channel. The other conformation B cannot bind GABA. Normally, with no benzodiazepine receptor ligand present, there is an equilibrium between these two conformations; sensitivity to GABA is present but submaximal. Benzodiazepine agonists (e.g. diazepam) are postulated to bind preferentially to conformation A, thus shifting the equilibrium in favor of A and enhancing GABA sensitivity. Inverse agonists bind selectively to B and have the opposite effect. Competitive antagonists such as flumazenilbind equally to A and B, and consequently do not disturb the conformational equilibrium but antagonise the effect of both agonists and inverse agonists. Some of the molecular variants of the GABA_A receptor seem to show different relative affinities for agonists, antagonists and inverse agonists, and it is possible that this reflects differences in the equilibrium between the A and B states as a function of the subunit composition of the receptor^5,20,27.

Ø Barbiturate (indirect agonist):

The barbiturates may also be divided into groups based on their duration of action.

Ex-- Short-Acting- Butobarbitone, pentobarbitone

Ultra-Short-Acting- Thiopentone, Methohexitone

Long-Acting-Phenobarbitone ²⁸

A. Mechanism of action:

} Barbiturates act throughout the CNS; nonanesthetic doses preferentially suppress polysynaptic responses.

} barbiturates promote (rather than compete with) the binding of benzodiazepines to GABA_A receptors;

} barbiturates potentiate GABA-induced chloride currents by prolonging periods during which bursts of channel opening occur rather than by increasing the frequency of these bursts as benzodiazepines do;

} only a and b (not g) subunits of the receptor/channel are required for barbiturate action; and

} Barbiturate-induced increases in chloride conductance are insensitive to mutations in the b subunit that govern the sensitivity of GABA_A receptors to activation by agonists. In addition, sub-anesthetic concentrations of barbiturates also can reduce glutamate-induced depolarization of the AMPA subtype of glutamate receptor. Thus, the activation of inhibitory GABA_A receptors and inhibition of excitatory AMPA receptors by barbiturates may explain their CNS-depressant effects ^26,29.

B. Pharmacological Actions:

} epression of CNS: At low doses the barbiturates produce sedation (calming effect, reducing excitement). At higher doses the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation) and finally coma and death. Thus, any degree of depression of the CNS is possible depending on the dose.

} Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO₂and over dosage is followed by respiratory depression and death.

} Enzyme induction: Barbiturates induce P-450 microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on P450 metabolism to reduce their concentration.

} Drug tolerance: Chronic use causes their dependence ³⁰.

C. Pharmacokinetics:

Oral absorption is rapid and nearly complete. The onset of action varies from 10–60 minutes depending on the agent and the formulation, and is delayed by the presence of food in the stomach. When necessary, intramuscular injections of solutions of the sodium salts should be placed deeply into large muscles to avoid the pain and possible necrosis that can result at more superficial sites.

D. Therapeutic Uses:

As with the benzodiazepines, selection of particular barbiturates for a given therapeutic indication is based primarily on pharmacokinetic considerations. In addition, there are some hepatic metabolic uses. Because hepatic glucuronyl transferase and the bilirubin-binding Y-protein are increased by the barbiturates, phenobarbital has been used successfully to treat hyperbilirubinemia and kernicterus in the neonate. The nondepressant barbiturate phetharbital (N-phenylbarbital) works equally well. Phenobarbital may improve the hepatic transport of bilirubin in patients with hemolytic jaundice.

Ø Steroids:

Neurosteroids are compounds that are related to steroid hormones but that act (like benzodiazepines) to enhance activation of GABA_A receptors as well as on conventional intracellular steroid receptors.

A. Mechanism of neurosteroid modulation of GABA_A receptor:

Experiments that investigated the influence of alphaxalone on the GABA-induced increase of membrane current noise in mouse spinal neurons suggested that this anesthetic acted to enhance GABA_A-receptors function by principally prolonging the mean open time of the GABA-activated chloride ion channel ³¹. Single-channel experiments arrived at the same conclusion for the related neurosteroids 3a, 50t-TH PROG or 3a, 5/3-TH PROG and additionally confirmed that these depressant steroids had no effect on the GABA-gated single-channel conductance. These studies also revealed that, at concentrations in excess of those required for GABA modulation, these depressant steroids had a second action, to directly activate the GABA_A receptors. Subsequently, a detailed quantitative kinetic analysis of the GABA-modulatory actions of neuroactive steroids was performed on mouse spinal neurons grown in cell culture ³².

Ø Picrotoxin :

It is obtained from the fish berry also blocks the action of GABA on chloride channels, although not competitively. The plants name reflects the native practice of incapacitating fish by throwing berries into the water. Picrotoxin, like bicuculline causes convulsions and has no clinical uses ³³.

Ø Bicuculline:-

It is a plant alkaloid resembles strychnine in its effects but acts by blocking receptors for GABA rather than glycine.Its action is confined to GABA_A receptors which control Cl^- permeability and it does not affect GABA_B receptors. Its main effects are on the brain rather than the spinal cord and it is a useful experimental tool for studying GABA-mediated transmission it has no clinical uses except in barbiturate poisoning ⁵.

CONCLUSION:

From the present review, we conclude that GABA (gamma amino butyric acid) is an important inhibitory neurotransmitter which has varied functions in the central nervous system. Acting as a mediator in various physiological and psychological states, it plays an important role in the overall well-being of an individual. Hence, modulation of its concentration is a key tool for the treatment of various CNS related disorders such as epilepsy, insomnia, anesthesia, anxiety and muscle tissue relaxation. Barbiturates and Benzodiazepines are the most popular and widely used drugs in this context. However the use of barbiturates is limited due to the development of tolerance and absence of an antagonist in case of overdose. In contrast to barbiturates, benzodiazepines are relatively safer and hence are widely used. The development of newer GABA modulatory agents with more safety margin particularly with mnimum tolerance and side effects is the need of future.

REFERENCES:

1. Sharma HL and Sharma KK. Principles of Pharmacology, Paras Publications, New Delhi, 2007.

2. Goodman L and Gilman A. Drugs acting on central nervous system In Goodman and Gilman`s. The pharmacological basis of therapeutics, Edited by Hardman JG and Limbird LE. McGraw-Hill, New York. 1996; 9th ed: pp. 1073-1101.

3. Katzung GB and Trevor JA. Basic and Clinical Pharmacology, McGraw-Hill, California, 2009.

4. Kenakin T. Pharmacologic Analysis of Drug–Receptor Interaction. Philadelphia, Lippincott-Raven, 1997.

5. Rang HP, Dale MM, Ritter JM and Moore PK. Pharmacology. Churchill–Livingstone, 2003: 481-488, 538-541.

6. Sieghart W. Structure and pharmacology of gamma-aminobutyric acid_A receptor subtypes. Pharmacol. Rev. 47; 2000: 181–234.

7. Chou KC. Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5. Biochem. Biophys. Res. Commun. 316; 2004: 636–642.

8. Young AB and Chu D. Distribution of GABA, and GABA, Receptors in Mammalian Brain. Potential Targets for Drug Development. 21; 1990: 161-167.

9. Dolan BP and Peter HS. Structural and functional characterization of the-Y subunit of GABA_A/benzodiazepine receptors The EMBO Journal. 9; 1999: 3261-3267.

10. Gohar O. GABA (A) Receptor Family. Modulator. 18; 2004:1-2.

11. Mertens JS. GABA_A receptor heterogeneity immunochemical and pharmacological characterization of receptor subtypes Swiss Federal Institute of Technology. 1962: 1-6.

12. Christopher JM, Stephane AB. Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits. Plos one 2(9); 2007: 894-892.

13. Xiang K, Tietze I. Chronic benzodiazepine-induced reduction in GABA_A receptor-mediated synaptic currents in hippocampalca1 pyramidal neurons prevented by prior nimodipine injection. Neuroscience 157; 2008: 153–163

14. Johnston G. GABA_A Receptor Channel Pharmacology. Current Pharmaceutical Design. 11; 2005: 1867-1885

15. Bittiger HK. GABA_B receptor antagonists: From synthesis to therapeutic applications. Trends Pharmacol. Sci. 14, 1993: 91-393.

16. Marta MM, Nung J. A Trafficking Checkpoint Controls GABA_B Receptor Heterodimerization. Neuron. 27; 2000: 97-106.

17. Mihic SJ, Harris RA. GABA and the GABAA receptor-Neurotransmitter review. Journal of Neurochemistry 62; 1998: 1635-1638.

18. Chebib MH. Analogues of γ-aminobutyric acid GABA and trans-4-aminocrotonic acid TACA substitute in the two position as GABA_Creceptor antagonists. British Journal of Pharmacology. 122; 1997: 1551-1560.

19. Baburin I, Khom S. Estimating the efficiency of benzodiazepines on GABA_A receptors comprising c1 or c2 subunits. British Journal of Pharmacology. 154(5); 2008: 1–10.

20. Panda UN. Textbook of Medicine, CBS Publishers, New Delhi, 2000: 107-108.

21. Richard AH and Pamela CC. Lippincott's Illustrated Reviews: Pharmacology, Lippincott-Raven Publishers, Philadephia, 2009:169-230.

22. Kiyomi I, Yasuhiko Y, Kouichi N. Classification of benzodiazepine hypnotics in humans based on receptor occupancy theory. Journal of Pharmacokinetics and Pharmacodynamics. 21(1); 1993: 31-41.

23. Geraldo FB and Pilowsky SL. Correlation Between Reduced in Vivo Benzodiazepine Receptor Binding and Severity of Psychotic Symptoms in Schizophrenia. American Journal of Psychiatry. 154; 1997:56-64

24. Sharkey LM and Czajkowsk S. Individually Monitoring Ligand-Induced Changes in the Structure of the GABA_AReceptor at Benzodiazepine Binding Site and Non–Binding-Site Interfaces. Mol. Pharmacol. 74(1); 2008: 203–212.

25. Nakazawa F, Cantas A, Masahiro S. PBRL, a putative peripheral benzodiazepine receptor, in primitive erythropoiesis. Gene Expression Patterns. 9; 2009:114–121.

26. Zarbin MA, Anholr RH. Benzodiazepine Receptors in the Eye. Investigative Ophthalmology and Visual Science. 32; 1991: 2580-87.

27. Arseniev AS, Baruskov IL, Bystrov BF, Lomize AL, Ovchinikov YA. 1H-NMR study of gramicidin A transmembrane ion channel. FEBS Lett. 186; 1985:168-174.

28. Tortora GJ and Derrickson BP. Principles of Anatomy and Physiology. John Wiley and Sons, USA, 2008: 448-449.

29. Kiran S, Chhabra B. Management of barbiturate poisoning – a case report. Indian J. Anaesth. 46 (6); 2002: 480-482.

30. Ho IK. Mechanism of action of Barbiturates. Ann. Rev. Pharm. Toxicol. 21; 1981: 83-111.

31. Chaudhari SK. Quintessence of Medical Pharmacology, New Central Book Agency, New Delhi, 2001: 103-106.

32. Cottrell GA, Lambert JJ, Peters JA. Modulation of GABA_A receptor activity by alphaxalone. Br J Pharmacol. 90(3); 1987: 491–500.

33. Belelli D, Lambert V. Neurosteroids: endogenous regulators of the GABA_A receptor. Nature Reviews Neuroscience. 6; 2005: 565-575.

34. Reifenstein EC. Picrotoxin in the treatment of acute barbiturate poisoning; A review of the literature with report of two cases. Annals of internal medicine. 13(6); 1939: 1013-1027.

Received on 16.04.2012 Modified on 18.05.2012

Research J. Pharm. and Tech. 5(6): June 2012; Page 721-728