GABA receptors: are cellular differences reflected in function?

Bruin Research Reviews, 14 (1989) 203-225

203

Elsevier BRESR 90099

GABA receptors:

are cellular differences reflected in function? Rae R. Matsumoto

Brown University, Department of Psychology, Providence,

RI (U.S.A.)

(Accepted 14 February 1989) Key words: y-Aminobutyric

acid; y-Aminobutyric

acid receptor; Feeding; Analgesia; Cardiovascular regulation; Depression; Epilepsy; Anxiety

CONTENTS 1. Introduction

............................................................................................................................................

203

2. GABA receptors ...................................................................................................................................... 2.1. GABA, receptors .............................................................................................................................. 2.2. GABA, receptors .............................................................................................................................. 2.3. Distribution of GABA, and GABA, receptors ...................................................................................... 2.4. Mechanisms of action ......................................................................................................................... 2.5. Summary ..........................................................................................................................................

204 204 205 205 206 207

3. Physiological effects of GABA ................................................................................................................... 3.i.Feeding ............................................................................................................................................ 3.2. Analgesia ......................................................................................................................................... 3.3. Cardiovascular regulation .................................................................................................................... 3.4. Depression ........................................................................................................................................ 3.5. Epilepsy ........................................................................................................................................... 3.6. Anxiety ............................................................................................................................................ 3.7. Other behaviors .................................................................................................................................

207 208 209 212 213 215 216 216

..................................................................................................................

4. Summary

.......................................................................................................................................

Acknowledgements References

..l.... .......................

..................................................................................................................................................

1. INTRODUCTION

Gamma-aminobutyric acid (GABA) is present in virtually every area of the brain and is active at approximately 20-40% of brain synapses”. GABA binds to two different subtypes of the GABA receptor and is involved in a variety of physiological responses. Although both receptor sites mediate neuronal inhibition, they differ in their pharmacological profiles, distribution, and interactions with Correspondence:

R.R. Matsumoto,

217 217 217

ions and nucleotides. These differences at the cellular level may be reflected in function as different behavioral and physiological profiles for the two receptor subtypes. Such a pattern has been reported in other transmitter systems: one form of the receptor to which the transmitter binds mediates only some of the functions of that ligand while another form of the receptor mediates a different subset of responses. Since GABA can influence almost every system in the central nervous sytem, it

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204 is of interest to examine whether different subtypes of the GABA receptor are associated with different functions. The first part of the paper describes the various sites and mechanisms of action of GABA. It draws on in vitro studies and focuses on the distinct and shared features of the two GABA receptor subtypes. The second part of the paper discusses some of the functional effects associated with GABA. The differential involvement of the two subtypes of the GABA receptor in various behavioral and physiological responses

is emphasized.

effects of benzodiazepines

the GABA, receptor to be biphasic. High affinity sites can be labeled with [3H]muscimol’43 and are thought to be associated with the GABA recognition site. The low affinity sites, on the other hand, can be labeled

with [3H]bicuculline

The behavioral effects produced by GABA stem from a cascade of events that follows the binding of the transmitter to its receptors. GABA interacts with two types of sites in the central nervous system. These sites are referred to as GABA, and GABA, receptors. Much of the information on GABA receptors comes from binding studies. Therefore, it should be noted that binding experiments can be plagued with variability and high affinity binding sites may not always be physiologically significant. These concerns, however, do not appear to be a serious problem in the GABA system; much of the evidence outlined below has been confirmed or supported by findings in a number of laboratories. 2.1. GABA, receptors The GABA, receptor is the classical GABA receptor. It is a complex protein with multiple recognition sites. The GABA, receptor contains minimally, a GABA binding site coupled to a Clchannel. The GABA receptor may also contain binding sites for benzodiazepines, barbiturates and convu~sants30,‘64,‘92’229.242 The sequence and binding profiles of the GABA, receptor suggest that the different recognition sites are distinct and separate parts of the GABA, receptor. Benzodiazepines, barbiturates and convulsants have non-competitive interactions with [3H]GABA1”“,224,243. This strongly suggests that the drugs do not bind directly to the GABA recognition site. Instead, these compounds have an indirect influence on the actions of GABA, an interpretation that is supported by the lack of GABA mimetic

+ thiocyanate’43.

The

distribution of low affinity sites parallels the presence of benzodiazepine binding but contrasts with the distribution of high affinity sites32,39.143,2s2,262. The low affinity

2. GABA RECEPTORS

in the absence of GABA43.

In addition, the presence of at least two different recognition sites on the GABA, receptor is suggested by biochemical data which show binding at

sites are therefore

believed

to be

distinct from the high affinity sites but associated with the benzodiazepine recognition site. These findings emphasize the distinction between different recognition sites on the GABA, receptor complex. It is likely that GABA, benzodiazepines, barbiturates, and convulsants act at different recognition sites on the same receptor complex rather than at separate receptor proteins. The most direct evidence comes from the structure of the GABA, receptor which was recently cloned by Schofield et a1.212. The GABA, receptor has a subunit structure of a2p2 that is centered around a Cl- ionophore (Fig. 1). The /3 subunit carries the GABA recognition site while the a subunit contains the recognition site for benzodiazepines212. The two domains appear to have distinct structures since only a fraction of monoclonal antibodies raised against the receptor recognizes both a and /3 subunits36.2’2. Recognition sites for barbiturates and convulsants have not been as well characterized as those for benzodiazepines and GABA. However, the non-competitive, but facilitatory, actions of these compounds on the effects of GABA support the notion of a complex receptor with multiple binding sites’3’,‘s7. The binding of compounds to recognition sites on the GABA, receptor alters membrane permeability to Cl-. Although different types of Cl- channels exist10i.2h1, it is not known whether they are associated with different binding domains of the GABA, macromolecule. In general, however, GABA agonists increase membrane permeability to Clwhile antagonists block or reduce Cl- conductance. The binding of GABA and the GABA agonist, muscimol, to recognition sites on the GABA, receptor opens Cl- channels in the cell membraneg9%

205 (e.g.

isoguavacine,

3-aminopropanesulphonic

piperidine-4-sulphonic

acid,

acid,

4,5,6,7-tetrahydrobarbiturates and ben-

isoxazolo[5,4-clpyridin-3-ol), zodiazepines 28p30*98 . Instead, GABA, receptors are stereospecifically activated by (-)baclofen (B-p-chlorophenyl GABA, trade name Lioresal), a compound that is inactive at GABA, receptors29,45,50,98,162. GABA, receptors are also not affiliated with a Cl- ionophore. Stimulation of GABA, receptors fails to alter Cl- conductances and changes in Clconcentration have no effect on GABA or baclofen binding 25-55 . GABA, receptors appear to be coupled, instead, to Ca*+ and K+ channels7*27v42*98.

Fig. 1. A schematic model of the GABA, receptor. Each subunit (a and &I contains 4 membrane spanning helices which are shown as cylinders in the diagram. Two copies of each subunit structure are thought to come together to form the receptor molecule. The helices are thought to be aligned such that portions of the membrane spanning regions form the inner walls of the chloride ionophore (Schofield et al.‘iz).

‘16*14*. Benzodiazepines stimulate the actions of GABA by increasing the frequency of Cl- channel openings’34*228 while barbiturates act by prolonging the open-state of the channels4~‘04~‘63. In contrast, the two most common antagonists at the GABA, receptor complex, bicuculline and picrotoxin, decrease membrane permeability to Cl-. Bicuculline, a highly selective competitive antagonist, reduces Cl- conductance by competing with GABA and other agonists for recognition sites*l*. Picrotoxin, on the other hand, acts directly at Clchannels to promote their closure5,‘34. 2.2. GABA, receptors GABA, and GABA, receptors have only recently been established as distinct binding sites for GABA. The GABA, receptor appears to have only one recognition site, a binding site for GABA. This recognition site appears to be on a separate protein from the GABA, receptor since its sensitivity to various drugs, ions and guanyl nucleotides contrasts sharply with responses at the GABA, receptor. GABA, receptors have a distinct pharmacological profile from GABA, receptors. GABA, receptors are insensitive to bicuculline, many GABA mimetics

(-)Baclofen and GABA decrease the amplitude of Ca*+ currents639’93 and increase K+ conductance75, 156. This contrasts with the GABA, system, where agonists increase Cl- conductance. In addition, GABA, binding is inhibited by the presence of GTP or GDP. GABA, receptors are insensitive to these nucleotides2’gW. These data suggest that two distinct subclasses of the GABA receptor exist: the GABA, and GABA, receptor. Their differences are summarized in Table I. 2.3. Distribution of GABA, and GABA, receptors In addition to having different pharmacological profiles and sensitivities to ions and guanyl nucleotides, GABA, and GABA, receptors are differen-

TABLE I Differences between GABA,

Ligands (-)Baclofen Barbiturates Benzodiazepines Bicuculline Isoguavacine Muscimol Picrotoxin THIP Ions and nucleotides Ca*+lMg*+ GTP Channels ClCa*+ K+

and GABA,

receptors

GABA,

GABA,

N/E inc binding inc binding antagonist agonist agonist Cl-channel blocker agonist

agonist N/E N/E N/E N/E weak agonist N/E N/E

N/E N/E

dependent dec binding

inc I,, not related not related

not related dec I,, inc I,

I, conductance; N/E, no effect; THIP, 4,5,6,7_tetrahydroisoxazolo[5,4-clpyridin-3-01.

206 tially distributed

in the brain and spinal cord. High

affinity GABA, sites have been labeled [‘H]muscimol. They are found in especially

with high

concentrations in the superficial laminae of the cerebral cortex (layers I-III), thalamic nuclei (especially the medial and lateral geniculate) granule layer of the cerebellum’43,‘70. In contrast, low affinity GABA, with [3H]bicuculline + thiocyanate bicycloorthobenzoate trated most heavily

and in the

sites, labeled or [3H]t-butyl-

([3H]TBOB), are in layer IV of the

concencerebral

cortex, cingulate cortex, hippocampal region (CA1 and molecular layer of the dentate gyrus), amygdala, anterior and medial hypothalamus, superior colliculus, substantia nigra pars reticulata, periaqueductal gray, and molecular layer of the cerebellum’4”. ls9. Although low affinity sites are thought to be associated with the benzodiazepine recognition site, benzodiazepine binding sites are also found in areas devoid of low affinity GABA, binding’43. Therefore, the presence of benzodiazepine activity may not always parallel activity of GABAergic systems. The chloride ionophore of the GABA, receptor can be labeled with potent, picrotoxin-like ‘cage’ convulsants (e.g. TBPS (t-butylbicyclophosphorothionate), TBOB). These sites exhibit relative permeabilities to various anions in a manner that would be expected of a GABA-gated chloride channely4. As expected, the distribution of [3”S]TBPS- and [3H]TBOB-labeled sites also parallels the presence of GABA, receptors’“‘. GABA, receptors can be labeled with [3H](-)baclofen. They are heavily concentrated in the superficial laminae of the cerebral cortex (layers I-III), interpeduncular nucleus, superior colliculus, and molecular layer of the cerebellum77~‘43,251. Several differences in the distribution of GABA, and GABA, receptors are noteworthy. Certain areas of the brain have especially high GABA,: GABA, ratios: the molecular layer of the cerebellum, the medial nucleus pars medullaris (thalamus), and the interpeduncular nucleus. In the spinal cord, GABA, binding is also concentrated in the dorsal horn while GABA, binding is more evenly distributed between dorsal and ventral areas143. Therefore, in these areas of the central nervous system, the actions of GABA may be mediated primarily by GABA, receptors. Areas with high GABA,:

GABA,

ratios include the lamina molecularis

of the

olfactory bulb and the granule layer of the cerebellum143,‘70. GABA, receptors may thus be of particular functional significance in these areas. Although

this review concentrates

sites of GABA, and GABA, ceptor types are also found 25.X1~108~132,154~166,204~2~~225~ The

on the central

receptors, both rein the periphery’,

widespread

yet

differ_

ential distribution of GABA, and GABA, receptors suggests that these receptors are distinct and functionally

significant

binding

sites for GABA.

2.4. Mechanisms of action Electrophysiological studies show that stimulation of GABA receptors results in neuronal inhibition4’. 46. This effect can be mediated either pre- or postsynaptically and by either GABA, or GABA, receptors. Postsynaptic inhibition at the GABA, receptor occurs when GABA or a GABA agonist binds to the postsynaptic receptor, resulting in the opening of Clchannels. The influx of Cl- into the cell hyperpolarizes the membrane and thus inhibits the neuron. Postsynaptic inhibition can also be mediated by GABA, receptors. Bath-applied baclofen hyperpolarizes hippocampal pyramidal cells by increasing K+ conductance7,75*‘s6. The efflux of K’ drives the membrane potential down, resulting in neuronal inhibition. Thus, GABA, receptors mediate the same

t Fig. 2. Presynaptic inhibition mediated through GABA, receptors. Axon 1 contains GABA which is released onto axon 2. Axon 2 has GABA, receptors and releases an excitatory neurotransmitter onto neuron 3. Axon 1 thus inhibits the excitation caused by neuron 2 and the net result is inhibition of neuron 3.

207

overall effect as GABA, different mechanism.

receptors

but through

a

The mechanism through which presynaptic inhibition is mediated by GABA, receptors is illustrated in Fig. 2. The release of GABA from axon 1

GABA

inhibits

excitatory

influences.

2.5. Summary Two distinct classes of GABA

receptors

exist: the

hyperpolarizes axon 2. Thus, action potentials through neuron 2 are smaller than usual and less

GABA, and GABA, receptor. The two types of receptors differ in their pharmacological profile, sensitivities to ions and nucleotides, and anatomical

transmitter

distribution.

is released

carries an excitatory less excited in the

onto neuron

3. If neuron

neurotransmitter, presence of the

2

neuron 3 is GABAergic

presynaptic neuron (neuron 1) than if only neuron 2 (the neuron containing the excitatory transmitter) were present. The net effect of the presynaptic GABAergic neuron is an inhibition of the cell postsynaptic to neuron 2 (i.e. neuron 3). This mechanism has been observed in the spinal cord, cuneate and gracile nuclei, and thalamus31. The mechanism through which GABA, receptors mediate presynaptic inhibition is much simpler. GABA, receptors appear to be localized on presynaptic nerve terminals26 and stimulation of GABA, receptors reduces Ca*+ conductance’93. Therefore, less Ca*+ enters the presynaptic cell, resulting in decreased release of neurotransmitter. Such an effect has been demonstrated in cerebellar, striatal and cortical slices of rat brain. Stimulation of GABA, receptors with GABA, (+)baclofen or (-)baclofen reduces K+ evoked release of [3H]dopamine, [3H]serotonin, and [3H]norepinephrine in rat brain slices26. These effects are insensitive to 3acid, bicuculline, and aminopropanesulphonic (+)baclofen (inactive isomer), strongly suggesting a GABA, effect. Although these presynaptic GABA, receptors inhibit neurotransmitter release, they are not autoreceptors since they do not regulate the release of GABA itself. GABA autoreceptor mechanisms are generally thought to involve GABA, receptors34*148 although recent evidence suggests that GABA, autoreceptors may also exist’85. Regardless of whether GABA acts pre- or postsynaptically or at GABA, or GABA, receptors, the net result is inhibition of neurons. It should be noted, however, that although GABA always inhibits neurons, this action may either lead to an overall excitation or inhibition of a system. An overall excitation of a system may result when GABA inhibits inhibitory neurons in that system and conversely, inhibition of a system may result when

Although

the mechanism

of action

of

the two receptor types differ, GABA-stimulation of both types of receptors results in neuronal inhibition. 3. PHYSIOLOGICAL EFFECTS OF GABA

A description

of the role of GABA

in various

behavioral and physiological effects is difficult since these outcomes involve complex, multilevel interactions between numerous neurotransmitters. The GABA system in particular acts extensively with other neurotransmitter and hormonal systems. GABA has been reported to interact with acetylcholine82*215,230, adenosine48*‘75,196, angiotensin catecholamines”9,“4,16O,*O9,*49, II78 cholecystokinm41.53, gly&eZO,

231-233,

opioid

87,147,183208,263,

norepinephrine'9,54,80,8',99,*15.

peptides21,'*R,'50,"9,*19,

somatostatin53.“5’**7,*41,*54

serotonin',

and

sub_

stance Pr81. Most of these actions occur at the synapse, but they may also happen intracellularly (e.g. via guanyl nucleotides, cyclic adenosine monophosphate (CAMP) generating systems)7’66,99,233,256. Such interactions hamper the interpretation of the role of GABA in various behavioral effects since GABA may have a secondary role in fine-tuning the actions of other neurotransmitters without being crucial for producing the behaviors per se. In this portion of the review, I hope to describe some physiological effects in which GABA appears to play an important role and the mechanisms through which GABA exerts its actions. It is a given that manipulations of other neurotransmitter systems may also have similar effects. Such redundancy in producing a given physiological action can be explained by multiple parallel pathways or by interacting parts of a single pathway. A comprehensive description of the neurochemistry of all the physiological systems to be discussed will be avoided since a primary goal of this paper is to determine whether different types of GABA receptors are associated with different functions. In each of the following

208 sections,

data are reviewed

ability of GABA

to produce

which demonstrate

the

a given behavior

and

the absence of GABA to diminish that effect. Given the apparent importance of GABA in these systems, the possible

mechanism

through

will also be described. Particular given to (1) the possible type(s)

which GABA

acts

attention will be of GABA recep-

tor(s) involved in each effect and (2) the neural networks that may underlie each behavior. The paper will now turn to various behavioral and physiological

effects

that involve

GABA.

The re-

view is not meant to be comprehensive and will concentrate on behavioral effects that have been reported

in mammals.

3.1. Feeding GABA, receptors in the hypothalamus appear to be involved in appetite regulation. It should be noted that other neurochemicals in the hypothalamus (e.g. cholecystokinin, somatostatin, substance P, enkephalin, thyrotropin-releasing hormone) also alter feeding behavior and GABA can affect appetite through at least one other area of the brain as

wel1151. This review focuses on the actions of GABA in the hypothalamus, however, since little is known about the effects of GABA on feeding in other areas of the brain. The hypothalamus is a major control center for appetite

regulation.

Studies

using lesions

and elec-

trical stimulation show that the ventromedial hypothalamus (VMH) is a satiety center in the brain and that the lateral hypothalamus (LH) is a feeding center6~35~52.95~‘37~‘90~239. The two structures are also connected

by neuronal

projections64,‘51,

suggesting

that activity in one structure may affect or be conveyed to the other antagonistic structure. The anatomical location of VMH and LH is shown in Fig. 3. Given the inhibitory actions of GABA, one would expect GABA or a GABA agonist in the LH (feeding center) to inhibit feeding. GABA in the VMH, on the other hand, would be expected to induce feeding (i.e. inhibit satiety). This is observed. Muscimol (GAB A, agonist), flurazepam dihydrochloride (benzodiazepine), and pentobarbital (barbiturate) all induce feeding when microinjected into

CORTEX HIPPOCAMPUS

Fig. 3. Coronal section through the midbrain showing the location of the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH). The hatched areas indicate regions where damage alters food intake. Damage to the lateral hypothalamus produces aphagia while damage to the ventromedial hypothalamus causes hyperphagia. AMG, amygdala; F, fornix; IC, internal capsule; LH, lateral hypothalamus; STR, striatum; VMH, ventromedial hypothalamus.

209

the VMH,

anterior

hypothalamus

(AH),

paraven-

tricular hypothalamus (PVH), and preoptic (PO) area of normal rats, satiated rats and sheep=‘ 85.““,‘11. These effects are blocked by bicuculline mechand picrotoxin”3~x5~‘1’, suggesting a GABA, anism . Since GABA has tonic influences the brainzs3, the effect of a GABA,

in some areas of antagonist alone

the indirect

effects of B-endorphin

rine on feeding

are also blocked.

muscimol

do not depend

important

rats92.“0.i’9.‘20

These findings strongly suggest the involvement of hypothalamic GABA, receptors in mediating appetite regulation. GABA, agonists increase feeding in areas involved in satiety (PVH, PO, AH, VMH) but decrease feeding or are inactive in feeding centers the distribution of (I-H) 11’.119.120. Furthermore, GABA and GABA receptors in active hypothalamic sites also suggests the involvement of a GABA, mechanism. High levels of GABA and GABA, receptors have been reported in the anterior and medial hypothalamus, whereas only negligible amounts of GABA, receptors are present in these areas113q*43.159.Therefore, the pharmacological specificity and active sites of GABA-induced feeding in the hypothalamus suggest that this behavior involves activation of GABA, receptors. The neural circuitry through which GABA is thought to act is shown in Fig. 4. GABA is thought to inhibit serotonergic efferents from the hypothalamusr5’. Furthermore, at least two other neurochemicals tj!%endorphin and norepinephrine) are thought to indirectly induce feeding through interactions with GABA when injected into the ventromedial hypothalamus”. Feeding produced by injections of ~-endo~hin and norepinephrine into the VMH can be antagonized by bicucuIlineKs although bicuculline does not act directly at opiate or adrenergic receptors. Thus, neurons containing ,8-endorphin and norepinephrine are thought to synapse onto GABAergic neurons which in turn induce feeding. When the actions of GABA are blocked,

or opiate

Alterations of GABA activity in the hypothalamus alone have observable effects on food intake.

overall effect of this would be to unmask

in normal rats, hyperphagic mother rats, and insulin-, 2-deoxyglucoseand serotonin-induced hyperphagic

on adrenergic

outflow.

Therefore, although also affect feeding,

expected, when bicuculline and picrotoxin are injected into the VMH or PVH, food intake is reduced

It is noteworthy

that muscimol-induced feeding is not blocked by naltrexone (opiate antagonist) or phentolamine (adrenergic agonist) ” . This suggests that the actions of

may be to block inhibition. In hypothalamic satiety centers, one would expect GABA, antagonists to inhibit the GABA-induced inhibition of satiety. The satiety. As

and norepineph-

other transmitter GABA appears

role in appetite

actions with GABA, satiety centers.

regulation

receptors

systems may to have an through

inter-

in hypothalamic

3.2. Analgesia GABAergic ligands produce analgesia under many different conditions. These effects are probably mediated by GABA, receptors or through other transmitter systems. The GABA, agonist baclofen produces antinociception in a variety of species in combination with different administration routes and testing conditions. Baclofen produces analgesia under the following conditions: hot plate test in mice (Lp., s.c.) and rats (i.t.); tail immersion test in mice (i.p.); tail flick test in rats (s.c., it., i.c.) and mice (i.c.); PbQ writhing test in mice (p.0.); arthritis pain test in rats (p.0.); shock titration test in monkeys (s.c.); thermal probe test in cats (i.t.); and stretch test in mice (s~c~)47.100,121.122.187,247.255 (see Table II), These stud-

+ :-== phen i SATiETY

Fig. 4. Involvement of GABA in hypothalamic feeding. GABA stimulates feeding by inhibiting serotonin-mediated satiety. The stimulatory effects of b-endorphin and norepinephrine on food intake is mediated by GABA. B-END, &endorphin; bit, bicuculhne; BZD, benzodiazepines; 5-HT, serotonin; nal, naloxone; NE, norepinephrine; phen, phentolamine (adapted from Morley”‘).

210 ies indicate that baclofen has robust and reproducible effects on pain sensitivity. Microinjection studies show that active sites in-

antagonized antagonist), or naloxone

clude areas involved

in both the transmission

inhibition

the

effect is especially ligands have been

of pain:

spinal

periaqueductal gray (PAG), and in and near the nucleus However, magnus, inhibition

cord,

the

and caudal

the caudal aqueduct, gigantocellularis’22~zss.

the area in and around

the nucleus

raphe

a structure involved in the descending of pain, is inactive’22. Although autora-

diographic studies have not specifically addressed the distribution of GABA receptors in sites such as the nucleus raphe magnus and nucleus gigantocellularis, high levels of GABA, receptors have been reported in the PAG and dorsal spinal cord77.‘4’. The distribution of active sites in both ascending and descending pain pathways suggests that GABA, receptors may be involved in both the gating of noxious stimuli in ascending tracts and the descending inhibition of pain. Pharmacological data further support the involvement of GABA, receptors in the analgesic effects of baclofen. Baclofen is a selective agonist at GABA, receptors and the analgesic actions of baciofen are insensitive to bicuculline and picrotoxin, two GABA, antagonists 10,2073247.However, it is not clear whether activation of GABA, receptors is sufficient to produce analgesia since the actions of baclofen are influenced by some transmitter systems but not others. Several lines of evidence suggest that baclofen does not act by inhibiting opiate or cholinergic systems. The analgesic actions of baclofen are not

TABLE II

Analgesiaproduced by baclofen Type of test

Administration

Species

Arthritispain Hot plate PbQ writhing Shock titration Stretch test Tail-flick Tail immersion Thermal probe

p.0. i.p..i.t.,s.c. p.0.

rats mice, rats mice monkeys mice mice, rats mice cats

S.C. S.C.

i.c.,i.t.,s.c. i.p. i.t.

i.c., intracerebral; i.p., intraperitoneal, parenteralioral; s.c., subcutaneous.

i.t., intrathecal: p.o.,

by atropine methylnitrate (muscarinic mecamylamine (nicotinic antagonist), (opiate antagonist)247,255. The latter noteworthy since GABAergic reported to influence opiate

analgesia203. The failure of naloxone to block baclofen analgesia suggests that although opiate analgesia is influenced

by GABAergic

actions.

baclofen

does not produce analgesia indirectly through opioid peptides. In further support of an opiate-independent mechanism, baclofen has a different pattern of active sites from morphine, shows no shift in its dose-response curve in morphine-dependent animals, and shows no cross-tolerance with morphine 122,247,255.These findings, therefore, suggest that the analgesic actions of baclofen do not depend on inhibiting opiate or cholinergic systems. This does not mean, however, that the actions of baclofen are independent of all other transmitter systems in pain control pathways. For example, blockade of catecholamines with systemic injections of reserpine, a-methyltyrosine, phentolamine, chlorpromazine and haloperidol enhances baclofen analgesia 202. Blockade of spinal catecholamines with intrathecal ti-hydroxydopamine or phentolamine, however, attenuates baclofen analgesia2”s. Thus, it appears that baclofen interacts with catecholamine systems in both ascending and descending pain pathways. The precise nature and sites of interaction however are as yet unknown. Baclofen is also capable of interacting with substance P, a transmitter that is released from small diameter primary afferent terminals that are involved in nociception’07~‘h”. Again, however, the interactions between baclofen and substance P appear to be complex. Capsaicin-induced degeneration of neurons suggests that 40-50% of GABA, receptors in the spinal cord are on neurons that carry studies indicate substance Pt*‘. Electrophysiological further that i.t. or i.v. baclofen decreases the activity of dorsal horn C fiber units through presynaptic mechanisms49,5s,96,*~2. These effects are insensitive to bicuculline, naloxone and strychnine, suggesting that GABA,, opiate and glycine systems are not mediating the responses58Y96. Furthermore, the inhibitory effects of baclofen cannot be mimicked or influenced by the GABA, agonist, muscimo196; and the responses of u/? (non-nociceptive) fibers are not

211

affected activity5’.

by doses of baclofen These

findings

taken

that inhibit together

C fiber

baclofen

strongly

through GABA, receptors. THIP has also been reported to be cross-tolerant with morphine, although this has never been reported with bac-

suggest that the interactions of GABA, with substance P involve presynaptic mechanisms. However, baclofen does not inhibit substance P release as would be expected from a presynaptic mechanism”‘, 206; and other investigators have reported strong inhibitory effects of baclofen on postsynaptic actions of substance P45,49,74,97.169,199. Therefore, GABAnsubstance

P interactions

postsynaptic mechanisms. The multiple actions

may involve of baclofen

both pre- and that

are un-

masked when one looks at interactions with other transmitter systems may reflect the varied actions that baclofen can have through GABA, receptors. Specifically, GABA may be involved in some sort of modulation or gating mechanism in pain transmission. Under some conditions, GABA may be involved in pain transmission (e.g. when catecholamines are blocked in the spinal cord) while under others, GABA may be involved in inhibition of pain (e.g. by inhibiting the excitatory actions of substance P). The presence of GABA in both ascending and descending pain pathways also suggests that this is possible. Further studies, however, are necessary to assess the validity of this hypothesis. Although GABA, agonists (muscimol and THIP) can produce analgesia88,100*247, these effects do not seem to be mediated by GABA receptors. Analgesia produced by muscimol and THIP are not blocked by the GABA, antagonist, bicuculline or the chloride channel blocker, picrotoxin887’003247. Therefore, the effects of THIP and muscimol are probably not mediated by GABA, receptors. Since baclofen shows some cross-tolerance with THIP247, it is possible that the analgesic effects of THIP are mediated through GABA, receptors. This possibility is supported by binding studies which show THIP and muscimol to have low affinities for GABA, receptors24. Although possible, it is unlikely, however, that THIP and muscimol act through GABA, receptors. If these compounds were producing their actions through GABA, receptors, one would expect these agonists, at high doses, to exhibit a GABAn-like profile. This is not observed; THIP, muscimol and baclofen are often about equipotent in analgesia tests”‘. One would expect THIP and muscimol to be much weaker than

if they

lofen247. Again, lofen

were

all producing

this suggests

are not working

through

their

that THIP

effects

and bac-

the same types of

receptors. Finally, ha!operidol can enhance baclofen analgesia on the hot plate test in mice, but has no effect on THIP-induced

analgesia247.

These

obser-

vations strongly suggest that THIP and muscimol

act

independently of GABA, receptors. THIP, muscimol and baclofen appear to be working through different mechanisms to produce similar outcomes. Analgesia produced by THIP and muscimol is not antagonized by naloxone (opiate antagonist), phentolamine (adrenergic antagonist), or methysergide (serotonin antagonist)88,‘00. Therefore, in addition to producing non-GABAergic effects, the actions of THIP and muscimol do not seem to be mediated by opiate, adrenergic or serotonergic systems. Atropine, an acetylcholine antagonist, on the other hand, attenuates THIP-induced analgesia247. Therefore,

PAG

ROSTRAL MEDULLA

e SP

Fig. 5. Putative involvement of GABA in ascending and descending pain control pathways. Solid, square butons form inhibitory synapses while open circle butons have excitatory connections. 5HT, serotonin; OP, opioid peptide; NE, norepinephrine; NT, neurotensin; SP, substance P (Basbaum and Fields”).

212 some interaction with cholinergic systems may be involved in the analgesia produced by THIP and muscimol. The anatomical act are unclear systemically site-specific

sites at which THIP and muscimol since the drugs were administered

or parenterally in most studies. No microinjections have been reported with

THIP and muscimol although intracerebroventricular and intrathecal injections suggest that they are active in the brain but not in the spinal cord9’,“‘. Although THIP and muscimol do not act by inhibiting opiates, it appears that opiates may act in part through inhibition of GABA. Changes in activity at the GABA, receptor complex have been shown to modulate opiate analgesia’49~‘7’. These effects are varied and may involve GABA, receptors on interneurons that are part of local circuit149

. In summary, the GABAergic mechanisms involved in antinociception appear to be complex. Both GABA, and GABA, receptors can influence the analgesia produced through other neurotransmitter systems. In addition, GABA itself produces analgesia through pre- and postsynaptic mechanisms at many levels of the brain and spinal cord. These latter effects appear to be mediated primarily through GABA, receptors. ry

3.3. Cardiovascular regulation GABA affects blood pressure and heart rate through peripheral and central mechanisms. Very low doses of systemically or i.v. administered GABAergic ligands tend not to cross the bloodbrain barrier15*129. Therefore, low systemic doses of GABAergic ligands are presumed to act peripherally. High doses of parenterally administered compounds, on the other hand, cross the blood-brain barrier and thus can act through both peripheral and central mechanisms. Although this review will concentrate on the central effects of GABA, it should be noted that many of the studies described below used systemic or i.v. injections. Therefore, one cannot totally ignore the possibility that some of the described effects involve peripheral as well as central mechanisms. In general, GABA, muscimol and THIP decrease blood pressure and heart rate12,177,178*194.These effects are blocked by bicuculline and picrotoxin’7z,

lx9, suggesting

a GABA,

effect.

Intravenous

bicu-

culline alone produces a transient increase in blood pressure’78~200. Therefore, these data suggest that the depressor actions of muscimol and GABA are mediated by GABA, receptors. The mechanisms through which these cardiovascular effects occur vary at different levels in the brain. In the forebrain, for instance, GABA, antagonists activate sympathetic pressor actions and decrease vagal (parasympathetic) depressor effects”y~h’~21”~253.GABA, agonists, however, are inactive in the forebrain, although they can reverse the effects of GABA antagonists2’)“0,222~253. This suggests that GABA is tonically active in the forebrain. Adding an agonist therefore, has no effect because the system is already functionally inhibited. Antagonists, however, act under these circumstances by releasing inhibition. The depressor actions of GABA, agonists in the midbrain are best characterized in the area of the dorsal raphe. GABA and muscimol decrease blood pressure and heart rate when microinjected into the dorsal raphe’94. These effects are blocked by picrotoxin, suggesting a GABA, effect’94. In the dorsal raphe, GABAergic neurons appear to inhibit serotonergic neurons76,24x; and stimulation of serotonergic neurons in the dorsal raphe appears to increase blood pressure’17.‘y4. Therefore, the depressor effects of GABA may be mediated through an inhibition of serotonergic pressor effects. An extensive investigation of the interactions of GABA with central adrenergic, dopaminergic, serotonergic and

T

5-HT

increase

blood pressure Fig. 6. Role of GABA in the mediation of cardiovascular regulation in the dorsal raphe. The depressor effects of GABA result from inhibition of serotonin pressor actions. The depressor actions of GABA can be attenuated with acetylcholine antagonists or by increasing serotonin activity. ACh, acetylcholine; S-HT, serotonin.

213 cholinergic systems supports this. The depressor effects of GABA can be attenuated by increasing serotonin activity with benserazid + 5-hydroxytryptophan’77. In addition, cholinergic blockers (atro-

GABA, mechanism was involved, bicuculline should have no effect since by definition GABA, receptors are insensitive to bicuculline98. These pressor responses may involve the sympathetic ner-

pine and physostigmine) antagonize the depressor effects of GABA17’, suggesting a cholinergic input

vous system since cervical

onto GABAergic neurons. Fig. 6 schematizes the interactions between GABA, serotonin and acetylcholine in this area of the brain. In contrast to forebrain and

transection

of the spinal

cord abolishes the effects5’. Further evidence for sympathetic involvement comes from the ability of adrenergic

blockers

(hexamethonium,

reserpine,

Q-

mecha-

MMT, phenoxybenzamine + propranolol) to antagonize the depressor actions of baclofen38,51.

nisms, GABA appears to exert its depressor actions in the brainstem by decreasing noradrenergic sym-

A pressor response specific to the nucleus tractus solitarii (NTS) that may or may not be related to the

pathetic

midbrain

outflow l6 . Drugs that increase

noradrener-

gic activity (D-amphetamine, propranolol and reserpine) block the hypotensive effects of GABA. Since atropine also prevents GABA receptor-mediated inhibition of heart rate60,‘77, an interaction with parasympathetic systems also appears to exist. Taken together, these observations suggest that GABA, receptors mediate depressor actions at different levels of the brain through different mechanisms. Although many studies have investigated the effects of baclofen on cardiovascular regulation, its actions are not well understood. Baclofen appears to have biphasic effects. At low doses (less than 5 x 10-a mol), baclofen causes a transient decrease in blood pressure and heart rate38. These effects are not antagonized by bicuculline or picrotoxin5’, suggesting a GABA, mechanism. Furthermore, the hypotension produced by baclofen is not antagonized by atropine, mepyramine or methysergide38, suggesting that cholinergic, histaminergic and serotonergic systems are not involved in the effect. In contrast, however, baclofen interacts with the adrenergic system since /3-adrenergic blockers (propranolol, pindolol, isoprenaline) can sometimes attenuate the depressor actions of baclofen3s. The specific sites at which these actions occur are as yet unknown since all studies to date have used i.p., i.v. or i.c.v. injections. At high doses (greater than 5 x lo-’ mol), baclofen increases blood pressure and heart rate3s. This effect does not appear to involve GABA receptors since bicuculline enhances and prolongs the response3*. If this response was mediated by GABA, receptors, one would expect bicuculline to antagonize rather than enhance the drug-induced increase in blood pressure and heart rate. If a

one just described, appears to be mediated GABA receptors. The NTS pressor response

by is

produced by microinjections of baclofen, GABA, and muscimol into the nucleus tractus solitarii’76. The effects of muscimol are reversed by bicuculline**, suggesting a GABA, mechanism. This response appears to be extremely site-specific since the effect cannot be mimicked by injections into the hypothalamus and dorsal raphe176, and systemic and intracerebroventricular injections of GABA and muscimol usually cause a decrease in blood pressure and heart rate rather than an increase. In summary, GABA is involved in cardiovascular regulation. Decreases in heart rate and blood pressure appear to be mediated primarily by GABA, receptors, although some involvement of GABA, receptors is also suggested. GABA, receptors in the NTS appear to be involved in a pressor response. A more global pressor response can be elicited by baclofen and appears to involve adrenergic input to the sympathetic nervous system. 3.4. Depression Changes in norepinephrine and serotonin levels have been the favored hypotheses in explaining the neuropathology of depression. Although ample evidence implies the involvement of these transmitter systems in depression, much evidence is inconsistent with a monoamine theory of depression’*‘. In addition to norepinephrine and serotonin, acetylcholine, dopamine and histamine have also been implicated in the neuropathology of depression44@. None of these transmitter systems individually can account for the data in the literature. It seems likely, therefore, that norepinephrine, serotonin and the other transmitters share a common mechanism in the

neuropathology

of depression.

That link appears

be an interaction with the GABA, receptor. Changes in GABA activity are associated

to

with

depression in humans and animal models of the disease. Lower levels of GABA in the cerebrospinal fluid and plasma are found in, depressed patients more often than in normal adu1ts”~79~N4~‘X’.Animal models of depression also reveal changes in GABA levels”25~“s0~2’7.Although alterations in GABA leveis were known to be associated

with depression,

the

bihty time of rats in the behavioral

pressant

actions.

However,

the

‘despair’

:est

in-

volves a locomotor component and movement studies have shown baclofen, but not GABA, agonists, to have locomotor reducing effects’. Therefore, the lack of effect of baclofen in the ‘despair’ test may reflect a locomotor reducing effect rather than a lack

possibility of a direct GABAergic mechanism was rejected until very recently. Most antidepressant

of antidepressant activity. Due to such problems

drugs were reported

available

to have minimal affinities for some GAGABA receptors’“; and therapeutically, BA agonists were effective in treating depression while others were ineffective. These discrepancies, however, can be resolved by taking into account the two GABA receptor subtypes. Until very recently, competitive binding studies had used ~~H~muscimol, a GABA, ligand, to indicate activity at GABA receptors. Therefore, the possibility of a GABA, mechanism had gone untested in biochemical assays. The therapeutic effectiveness of GABAergic compounds can also be predicted when taking into account activity at GABA, and GABA, receptors. For instance, many cases of depression can be successfully treated clinically by increasing activity at GABA, receptors’25.2”“, but GABA, agonists are ineffective”. The antidepressant effects of GABA, agonists such as progabide appear to be most effective in treating primary. unipolar depression although they also relieve symptoms in some patients with bipolar and reactive episodes’S’,‘“5.2”“. Findings such as these imply that changes in GABA, receptors somehow contribute to decreased GABA activity in depressed people and that antidepressant drugs act by countering this effect. A rigorous investigation of the neuropathology underlying depression is problematic due to ethical considerations when dealing with human subjects and the lack of convincing animal models for the human equivalent of the disease. Although animal models can be useful, interpretation of the data can be confounded by the actions of GABAergic compounds on other physiological systems. For example, GABA, agonists, but not baclofen (a GABA, agonist), have been reported to reduce the immo-

‘despair’ test’s.

A reduction of immobility time is taken as an index of antidepressant efficacy in humans. This would therefore imply that GABA, agonists have antide-

behavioral

data,

of interpretation the

remainder

of the of this

section will address the plausibility of a GABA, mechanism in depression from a pharmacological viewpoint. Several lines of evidence suggest the involvement of a GABA, mechanism in mediating the effects of antidepressant drugs. First of all, chronic, but not acute, administration of different classes of antidepressant drugs and etectroshock up-regulates GABA, receptors12h*‘27. 233. Up-regulation tends to be associated with the activity of antagonists and contributes to increased binding of agonists and behavioral supersensitivity 19x.238.24”.264. Since antidepressant drugs with biochemical actions at norepinephrine, dopamine, serotonin and GABA receptors all up-regulate GABA, receptors, it seems likely that antidepressant drugs act through a common mechanism involving GABA, receptors. Antidepressant drugs further appear to share a common primary mechanism at GABA, receptors since they often regulate these receptors with lower doses of treatment than required to produce changes in norepinephrine and serotonin receptors127. This action of antidepressant drugs could also account for the delay in therapeutic efficacy associated with antidepressant therapy. The delay may be associated with the time needed for the up-regulation of GABA, receptors. Once these changes in GABA, receptors have occurred, the therapeutic effects of the drugs become evident. It is notable that the effects of antidepressant drugs are specific to GABA, receptors and localized primarily in the cerebral cortex, an area rich in GABA, receptors. Chronic administration of antidepressant drugs have no effect on GABA, receptors’*‘; and although regulation of serotonin and

215 norepinephrine administration

receptors

has been reported,

of all classes of antidepressant

chronic drugs

and electroshock do not produce similar effects44,127. The fact that these changes occur first in the cortex is consistent with other reports of active sites involved in depression57.‘97. The

exact

mechanism

through

which

diverse

classes of antidepressant therapies produce upregulation of GABA, receptors is unknown, but may involve a common ion channel or second messenger system 67*233 . It is apparent,

however,

that decreased

GABA levels are associated with many cases of depression and that these effects can be overcome by increasing

activity

at GABA,

receptors.

3.5. Epilepsy Animal and human studies suggest that alterations in the GABA, system may underlie some of forms of epilepsy. Epilepsy is associated with excessive neuronal discharge which leads to seizures and convulsions; many studies show that deficiencies in brain GABA systems also produce similar effects. Until recently, studies which assessed GABA levels in epileptic patients reported conflicting results due to problems in measuring GABA levels in postmortem tissue or to the lack of adequate control groups124.21’. Recent studies, however, support a relationship between lowered GABA levels and epilepsy. GABA levels in the CSF of epileptic patients and children with febrile convulsions have been reported to be significantly lower than in controls without neurological disorders’“6~21’*25”~259. GAD levels in the epileptic foci from patients with intractible epilepsy have also been reported to be much reduced as compared to normal tissue from the same patient in 60-70% of casesL24. Such deficiencies in GABA level are consistent with the reports of Tower2j4 that epileptic portions of brain tissue are unable to maintain the synthesis of GABA although normal tissue from the same patient can. These studies suggest that in at least some people, deficiencies in GABA levels are associated with epilepsy. The relationship between GABA levels and seizures and convulsions has been more rigorously studied in animals. Generally, seizures and convulsions, symptoms of epilepsy, are induced in experimental animals to model epilepsy in humans, If

release

from GABAergic

inhibition

is responsible

for seizures and convulsions, experimentally blocking GABAergic activity should induce seizures in animals while activating GABAergic synapses should protect against them. Such relationships between GABA levels and seizure activity have been demonstrated. ity by blocking

Inhibition either

the

of GABAergic synthesis

activ-

of GABA,

GABA, receptors, or Cl- ionophores elicits seizures in mice and rats124*146,257,2M). Activation of GABAergic activity on the other hand, many types of seizures in animals.

protects

against

Biochemical studies in animals also demonstrate a relationship between endogenous levels of GABA and seizure activity. The onset of seizures following the inhibition of GAD is related to a decreased availability of newly synthesized GABA2’7 and the postictal rise in seizure threshold following electroconvulsive shock is accompanied by an increase in GABA levels in the cortex, hippocampus and h~othalamus - . These findings thus suggest that ~2’ changes in brain GABA levels affect susceptibility to seizures. The pharmacology of these effects suggests a role for GABA,, but not GABA,, receptors. Barbiturates, benzodiazepines and GABA, agonists (GABA, THIP, muscimol) protect against pentylenetetrazol-, isoniazid-, bicuculline-, and picrotoxin-induced seizures, generalized absence seizures and maximal electroshock seizures’““.‘33’141.14f,‘88*260. Thus, ligands that increase GABA, activity protect against many types of seizures in animal models of epilepsy. In contrast, the anticonvulsive responses mediated through GABA, receptors appear primarily in vitro9.236. In vivo, GABA, receptors facilitate some of the effects of other anticonvulsants, although alone, they either lack anticonvulsive activity ‘4s,246or exhibit anticonvulsive properties against seizures elicited through non-GABAergic mechanisms (e.g. strychnine-induced seizures)260. These studies, taken together, suggest a relationship between the loss of neuronal inhibition via suppressed activity at GABA, receptors and the onset of seizures. It is important to realize the GABAergic mechanisms may be one way through which seizure activity is elicited, but similar effects may be produced through other mechanisms as well. Seizures in

216 TABLE III

GABA in anxiety suggest that the anxiolytic effects of GABA are probably indirect. Anatomical studies

involvement of GABA receptor types in variousphysiological effects ____..-.___ ._~_.. __ -. GABA, GABA, _.~____. .-.I-_______..X Analgesia Anticonvulsive activity X Anxiety X Cardiovascular effects X X Depression X Feeding X __.-... ~--

If benzodiazepines and barbiturates produce anxiolytic effects by facilitating the actions of GABA,

animals through

one would expect GABA, agonists to produce similar effects and antagonists to block these actions. The data in this regard are conflicting2”, suggesting

may be a number

induced and protected against of non-GABAergic mechanisms

(e.g. glycine, norepinephrine, serotonin, dopamine, adenosine)4”,72,‘33~‘45. The literature on humans also suggests the involvement of non-GABAergic mechanisms in the etiology of epilepsy. The pharmacological treatment of epilepsy with GABAergic drugs has been Iimited in success: effective in treating some people 13’ but not others (e.g. those with intractible epilepsy). In addition, deficiencies in GABA levels are not found in many patients afflicted with epilepsy and alterations in other neurochemical systems may existz”.37~191. Thus, although GABA appears to be associated with some forms of epilepsy, it appears unlikely that changes in the GABA system alone explain the etiology of epilepsy. Deficiencies in the GABA, system are likely to be one cause or component of epilepsy with abnormal Ievels in other transmitter systems also contributing to the disorder. It is also likely that various transmitter systems underlie different types or components of seizures”. 3.6. Anxiety It has been suggested that GABA may be involved in anxiety. Changes in GABAergic neurotransmission can influence some types of anxiety in animal models. In addition, human forms of acute anxiety can be successfully treated with benzodiazepines, such as chiordiazepoxide and diazepam. Both benzodiazepines and barbiturates are effective anxiolytics and they facilitate the actions of GABA in electrophysiological studies4.L04,134.‘“‘,22*. These anxiolytic effects are thought to occur primarily at the GABA, receptor since the GABA, agonist, baclofen, has weak and inconsistent anxiolytic actionss6. Studies which have investigated the role of

have shown that GABAergic neurons terminate on noradrenergic cells in the locus coeruleus and serotonergic neurons in the dorsal raphe’89v245. Activation of both noradrenergic and serotonergic systems results in anxiogenic effects2*(j and inhibition of these systems by GABA has anxiolytic actions105.

that benzodiazepines

and barbiturates

may not act

purely by influencing GABAergic neurotransmission. It is possible that anxiety may be associated with the benzodiazepine-binding domain of the GABA, macromolecule through a mechanism that is independent of GABA itself. Benzodiazepine receptors are found in some areas of the brain that lack binding for GABA, ligands’43. Furthermore, most antibodies raised against the GABA, receptor recognize either the GABA-binding or benzodiazepine-binding subunit of the receptor, but not both*l’. A number of endogenous ligands for the benzodiazepine site have also been identified, some of which lack affinity for the GABA, site2”. It is thus possible that the benzodiazepine subunit of the GABA, receptor may mediate some of its anxiolytic activity through non-GABAergic mechanisms. Anxiety appears to be a complex state which is as yet, pooriy understood. Changes in GABAergic activity may be one factor which influences this state. However, other transmitter systems may also play a role. 3.7. Other behaviors In addition to the behaviors already discussed, there are many other physiological and behavioral processes which involve GABA, but the nature of the involvement (e.g. GABA, or GABA, effect) is unclear. Although they will not be discussed in detail here, behavioral and physiological responses that fall into this category are: sexual behavio?,69.70*7*.139, thermal regulation 1,215,216, locomotion2~106~‘12,16”,237, muscle relaxation1745’84, sleep144, behavioral effects of alCohol”‘2,2”‘,,~““, and streSS14,93,167,213,220,223.

217 level, but that they also have different

4. SUMMARY

the mammalian The putative involvement of GABA, and GABA, receptors in various behavioral and physiological effects is summarized in Table III. A division of function among the two types of GABA receptors

central

nervous

functions

in

system.

The association of different subtypes of a receptor with different functions and mechanisms of action is not unique to the GABA system. D, and D, receptors in the dopamine system, for example, also exhibit some separation of function33,73,214 as do the

appears to exist. GABA, receptors mediate feeding, cardiovascular regulation, anxiolytic effects, and anticonvulsive activity. GABA, receptors, on the

p, 6 and IC types of opiate receptors’03~11s~‘38~ 140~152~158~173~195. Different subtypes of neurotran-

other hand, are involved

smitter receptors,

in analgesia,

cardiovascular

regulation, and depression. Although there is some overlap and shared functions among the receptor types, it is evident that GABA, and GABA, receptors have different behavioral and physiological profiles. Feeding, anticonvulsive activity and anxiety, for example, primarily involve GABA, receptors. Analgesia and depression, on the other hand, are GABA, effects. In those cases where GABA, and GABA, receptors mediate similar functions (e.g. cardiovascular regulation), they do so by affecting different transmitter systems and cellular mechanisms. It is proposed, therefore, that GABA, and GABA, receptors differ not only at the cellular

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