GABA and the regulation of serotonin N-acetyltransferase activity in amphibian retina—I. Effects of GABA agonists and antagonists

Retinal melatonin biosynthesis is regulated in part by changes in the activity of serotonin N-acetyltransferase (NAT), which increases at night in dark-adapted retinas, but not in light-exposed retinas. Using an in vitro preparation of Xenopus laevis (African clawed frog) eye cups, we have obtained evidence supporting the involvement of gamma-aminobutyric acid (GABA) in the regulation of NAT activity. GABA, the GABA-A receptor agonists muscimol and isoguvacine, and the GABA-B receptor agonist (−)baclofen, in the presence of 3-isobutyl-1-methylxanthine, mimicked dark adaptation by increasing the activity of NAT in light-exposed retinas. The response to GABA agonists was not additive to that observed in darkness. Diazepam increased NAT activity of light-exposed retinas when added in the presence of muscimol, but had no significant effect when added alone. Picrotoxin, an antagonist of the GABA-A receptor-linked Cl⁻ channel, blocked both the stimulation caused by dark adaptation and that caused by GABA-A agonists. The increase of NAT activity elicited by muscimol, but not that by baclofen, was blocked by bicuculline methobromide and picrotoxin. The results implicate GABA, acting through GABA-A and possibly GABA-B receptors, in the regulation of NAT activity in retina.     

GABA-A and GABA-B receptors in the cuneate nucleus of the rat in vivo

Electric stimulation of the rat forepaw evokes a negative potential (N-wave) at the ipsilateral cuneate nucleus. The responses of the N-wave to microiontophoretically applied GABA agonists and antagonists have been studied. Applications of GABA-A agonists (3-amino-propanesulfonic acid and muscimol) reduce the amplitude of the N-wave. This effect decreases during prolonged application, suggesting a desensitization of GABA-A receptors. In addition the effect of muscimol is reduced by (-)-bicuculline methiodide. Baclofen (a GABA-B agonist) also depresses the N-wave but its action lasts longer, is less reversible, shows no desensitization and is not blocked by (-)-bicuculline methiodide. The different responses of the N-wave to GABA-A and GABA-B agonists are compatible with the existence of different types of functional receptors for them in the cuneate nucleus of the rat. The receptors activated by muscimol (GABA-A) are clearly not the same as the ones activated by baclofen (conceivably GABA-B).     

Effects of muscimol and baclofen on levels of monoamines and their metabolites in the El mouse brain

We compared the changes in monoamines and their metabolites in the El mouse brain induced by GABA-A and GABA-B receptor agonists. Muscimol was used as a GABA-A receptor agonist, and baclofen as a GABA-B receptor agonist. Muscimol (3 mg/kg) significantly increased the DOPAC level in all parts of the mouse brain and the HVA level in the cortex, striatum, and midbrain. No significant change was observed in the dopamine (DA) level. These findings suggest that muscimol may accelerate both the synthesis and catabolism of DA. Baclofen (20 mg/kg) increased the DA level in the hippocampus and midbrain, and the DOPAC level in the hippocampus. Muscimol increased 5-HIAA levels and decreased 5-HT levels. This result suggests that 5-HT metabolism is accelerated by muscimol. No change in 5-HT or 5-HIAA levels was induced by baclofen. The GABA-A receptor system seems to have a potent effect not only on DA neurons, but on 5-HT neurons. However, the GABA-B receptor system appears to have almost no effect on 5-HT neurons, though it appears to have some effect on DA neurons.     

The role of GABA-A and GABA-B receptors in the development of amnesia

The paper deals with analysis of the influence of blockade of separate components of benzodiazepine-GABA-ionophore complex on the recovery of memory trace amnesia under GABA-A and GABA-B receptors activation in the experiments with conditioned reaction of passive avoidance of mice. Activation of GABA-A receptors did not change the behavioural amnesia manifestation at all terms of testing. Activation of GABA-B receptors before learning and amnestic influence caused spontaneous recovery of avoidance reaction. Blockade of chloride channel by picrotoxin and of benzodiazepine receptor by flumazepil restored the reproduction of the memory trace disturbed against the background of GABA-B receptors activation. Systemic flumazepil administration contributed to the memory trace reproduction against the background of GABA-A receptors activation by muscimol in the dose of 0.5 mg/kg. In conditions of amnesia development against the background of muscimol in the dose of 1 mg/kg the blockade of any component of benzodiazepine-GABA-ionophore complex was not effective. The obtained data testify that activation of GABA-A and GABA-B receptors changes the amnesia development and correction of amnesia memory trace by the blockade of separate components of benzodiazepine-GABA-ionophore complex.     

GABA receptors ameliorate Hcy-mediated integrin shedding and constrictive collagen remodeling in microvascular endothelial cells

Mammalian endothelial cells are deficient in cystathionine β synthetase (CBS) activity, which is responsible for homocysteine (Hcy) clearance. This deficiency makes the endothelium theprime target for Hcy toxicity. Hcy induces integrin shedding in microvascular endothelial cells (MVEC) by increasing matrix metalloproteinase (MMP). Hcy competes with inhibitory neurotransmitter γ aminobutyric acid (GABA)-A receptor. We hypothesized that Hcy transduces MVEC remodeling by increasing metalloproteinase activity and shedding β-1 integrin by inactivating the GABA-A/B receptors, thus behaving as an excitatory neurotransmitter. MVEC were isolated from mouse brain. The presence of GABA-A receptor was determined by immunolabeling. It was induced by muscimol, an agonist of GABA-A receptors as measured by Western blot analysis. Hcy induced MMP-2 activity in a dose- and time-dependent maner, measured by zymography. GABA-A/B receptors ameliorated the Hcy-mediated MMP-2 activation. Hcy selectively increased the levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 but decreased the levels of TIMP-4. Treatment with muscimol decreased the levels of TIMP-1 and TIMP-3 and increased the levels of TIMP-4 to control. Hcy caused a robust increae in the levels of a disintegrin and metalloproteinase (ADAM)-12. In the medium of MVEC reated with Hcy, the levels of β-1 integrin were significantly increased. Treatment with muscimol or baclofen (GABA-B receptor agonist) ameliorated the levels significantly increased. Treatment with muscimol or baclofen (GABA-B receptor agonist) ameliorated the levels of β-1 integrin in the medium. These results suggested that Hcy induced DAM-12. Significantly, Hcy facilitated the β-1 integrin shedding. Treatment of MVEC with muscimole or baclofen during Hcy administration ameliorated the expression of metalloproteinase, integrin-shedding, and constrictive collagen remodeling, suggesting a role of Hcy in GABA receptor-mediated cerebrovascular remodeling.     

GABA-B receptor activation and conflict behaviour

Baclofen and oxazepam enhance extinction of conflict behaviour in the Geller-Seifter test while baclofen and diazepam release punished behaviour in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on [3H]-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increased Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render it unlikely that the effect of baclofen on extinction of conflict behaviour and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex.     

Depression of the vestibulo-ocular and optokinetic responses by intrafloccular microinjection of GABA-A and GABA-B agonists in the rabbit

The functional implication of the cerebellar flocculus in regulation of the VOR and OKR gain has mostly been studied by lesion experiments, and the hypotheses derived from these experiments are not always in line with one another. In the present study, a reversible method was used to inhibit floccular Purkinje cells. The GABA-A agonist muscimol or the GABA-B agonist baclofen were bilaterally injected into the flocculus of rabbits, and the effects of these injections on the gain of the VOR and OKR were studied. Both drugs induced a reduction by at least 50% of the gain of the VOR in light and darkness, and of the OKR. Although GABA-A and GABA-B receptors are known to have different cerebellar localizations, muscimol and baclofen injections resulted in quantitatively similar effects. It is suggested that these GABA-agonists cause either direct or indirect inhibition of floccular Purkinje cells, thus reducing modulation of the firing rate of these neurons by afferent mossy and climbing fibers. Because the flocular Purkinje cells act out of phase with the vestibular neurons which drive the oculomotor neurons, a reduced output of floccular Purkinje cells would result in a reduction of the VOR and OKR gain. These experiments provide strong evidence that the cerebellar flocculus has a positive influence on the basic VOR and OKR gain.     

GABA receptors and nitric oxide ameliorate constrictive collagen remodeling in hyperhomocysteinemia

Elevated plasma levels of homocysteine (Hcy) are associated with vascular dementias and Alzheimer's disease. The role of Hcy in brain microvascular endothelial cell (MVEC) remodeling is unclear. Hcy competes with muscimol, an gamma-amino butyric acid (GABA)-A receptor agonist. GABA is the primary inhibitory neurotransmitter in the brain. Our hypothesis is that Hcy induces constrictive microvascular remodeling by altering GABA-A/B receptors. MVEC from wild type, matrix metalloproteinase-9 (MMP-9) knockout (-/-), heterozygote cystathionine beta synthase (CBS-/+), and endothelial nitric oxide synthase knockout (eNOS-/-) mouse brains were isolated. The MVEC were incorporated into collagen (3.2 mg/ml) gels and the decrease in collagen gel diameter at 24 h was used as an index of constrictive MVEC remodeling. Gels in the absence or presence of Hcy were incubated with muscimol or baclofen, a GABA-B receptor agonist. The results suggested that Hcy-mediated MVEC collagen gel constriction was ameliorated by muscimol, baclofen, MMP-9, and eNOS gene ablations. There was no effect of anti-alpha 3 integrin. However, Hcy-mediated brain MVEC collagen constriction was abrogated with anti-beta-1 integrin. The co-incubation of Hcy with L-arginine ameliorated the Hcy-mediated collagen gel constriction. The results of this study indicated amelioration of Hcy-induced MVEC collagen gel constriction by induction of nitric oxide through GABA-A and -B receptors.     

Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

Background

Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug''s consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit.

Methodology/Principal Findings

We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine.

Conclusions/Significance

Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus–nearly perfectly correlated with the infusion–likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse.     

Sensitivities of Achatina giant neurones to putative amino acid neurotransmitters

1. GABA receptors in Achatina identifiable giant neurones were classified into the muscimol I, muscimol II and baclofen types. Muscimol I and II type GABA receptors were sensitive to GABA and muscimol but insensitive to baclofen, whereas baclofen type receptors were sensitive to GABA and baclofen but insensitive to muscimol. Muscimol I and baclofen types were associated with the inhibition caused by GABA, while muscimol II type with the GABA excitation.2. GABA, muscimol and TACA produced a transient outward current (I_out) with an increase in membrane conductance (g) of an Achatina neurone, TAN, having the muscimol I type GABA receptors. Their relative potency values (RPV) at GABA ed₅₀ (approximately 10⁻⁴ M) were: GABA: muscimol: TACA = 1:0.6:0.3. The GABA effects were potentiated by pentobarbitone, antagonized competitively by pitrazepin and non-competitively by picrotoxin and diazepam, and unaffected by bicuculline. The ionic mechanism of effects of GABA and its two analogues was the increase in membrane Cl⁻ conductance (g_Cl).3. GABA and (±)-baclofen produced a slow I_out with a g increase of another Achatina neurone, RPeNLN, having the baclofen type GABA receptors. The two compounds were almost equipotent (ed₅₀: approximately 3 × 10⁻⁴ M). The ionic mechanism of their effects was the increase in g_k. The two compounds hardly affected the voltage-gated and slowly inactivating calcium current. I_out produced by GABA and (±)-baclofen were reduced by TEA, but unaffected by 4-AP, bicuculline, pitrazepin and picrotoxin.4. β-hydroxy-l-glutamic acid (l-BHGA) showed the marked effects on the Achatina giant neurones; the two neurones were excited by the compound, whereas the three inhibited. D-BHGA, l-Glu, d-Glu and NMDA were less effective than l-BHGA or almost ineffective. Erythro-l-BHGA was more or less effective than threo-l-BHGA according to the neurones tested.5. α-Kainic acid and domoic acid excited the two neurones, which were excited by l-BHGA. l-Quisqualic acid showed the similar effects to l-BHGA, which were mostly much stronger than l-BHGA. Erythro-l-tricholomic acid and dl-ibotenic acid showed the effects similar to l-BHGA selectively on some neurones.6. It was pointed out that the pharmacological features of GABA on the Achatina neurones are simpler than those of l-BHGA, due to the simpler structure of the former compound having less binding sites than the latter.     

Intracellular effectors and modulators of GABA-A and GABA-B receptors: a commentary

The inhibitory neurotransmitter GABA activates two receptor subtypes that can be distinguished by their pharmacology. The GABA-A site is competitively antagonized by bicuculline and exclusively coupled to a chloride channel. The GABA-B receptor, for which baclofen is the only specific agonist, is resistant to bicuculline inhibition and, depending upon its localization, will activate K currents and/or inhibit Ca currents. Both electrophysiological and biochemical approaches have been applied to the study of each receptor. The membrane and intracellular components that to date have been implicated in GABA-B activation are discussed: G proteins, adenylate cyclase and intracellular calcium levels. This latter factor is also discussed with respect to GABA-A receptor action.     

Classification of inhibitory amino acid receptors in the mammalian nervous system

Electrophysiological and pharmacological evidence is summarized for the existence of an inhibitory receptor system operated by glycine and another two separate systems operated by gamma-aminobutyric acid (GABA) through GABA-A and GABA-B receptors, respectively. Claims for subclasses of GABA-A receptor are critically reviewed and found not-proven. A quantitative pharmacological profile of the GABA-A receptor and associated regulatory sites for picrotoxin, barbiturates and benzodiazepines on the dorsal funiculus of the rat cuneate nucleus is described. When compared with this profile and the pharmacological properties of the glycine receptor complex, the effects of taurine cannot be entirely explained by actions on these two receptor systems.     

Enhancement by Baclofen of the Gs-Coupled Receptor-Mediated cAMP Production inXenopusOocytes Expressing Rat Brain Cortex Poly (A)+RNA: A Role of G-Protein βγ Subunits

We investigated the mechanism by which GABA-B receptors enhance the Gs-coupled receptor-mediated cAMP production inXenopusoocytes expressing poly (A)⁺RNA derived from rat brain cortex. We expressed the cystic fibrosis transmembrane conductance regulator gene (CFTR) as a reporter for cAMP changes in oocytes. The GABA-B agonist (-)baclofen enhanced the adrenergic β₂agonist isoproterenol- or vasoactive intestinal peptide (VIP)-induced CFTR currents, whereas (-)baclofen alone did not cause any currents. The (-)baclofen-enhanced currents were inhibited by the GABA-B antagonist 2-OH saclofen. The enhancement by (-)baclofen was further augmented by coexpressing adenylyl cyclase (AC) type II, an isotype activated by Gβγ and Gαs, but not by coexpressing AC type III, an isotype insensitive to Gβγ. Moreover, pretreatment of the oocytes with pertussis toxin (PTX) abolished the enhanced effect of (-)baclofen. These results indicate that upon GABA-B activation, the Gβγ released from PTX-sensitive G-proteins activates the AC type II (or IV), and this process requires the Gαs activation by Gs-coupled receptors.     

GABA-B receptor activation in the rat globus pallidus potently suppresses pentylenetetrazol-induced tonic seizures

To determine the involvement of the globus pallidus in mediating epilepsy, the effects of microinjection of a GABA uptake blocker (tiagabine), a benzodiazepine agonist (zolpidem) and a GABA-B receptor agonist (baclofen) on pentylenetetrazol (PTZ)-induced tonic seizure were examined in adult rats. Administration of PTZ induced tonic seizures in all control animals, accompanied with a 100% mortality rate. Pretreatment with bilateral intrapallidal microinjection of tiagabine (1 mM) suppressed the incidence of tonic seizures to 67.7% and reduced the mortality rate to 16.7%. Furthermore, the latency to tonic seizures was 1,275 ± 277 s, which was significantly longer than that of the corresponding control animals (319 ± 225 s). On the other hand, administration of zolpidem (1 mM) was without significant effects on the mortality rate, the incidence and latency of the tonic seizure. In sharp contrast, microinjection of baclofen (1mM) completely suppressed PTZ-induced tonic seizures and reduced the mortality rate to 0%. This effect was largely abolished by co-injection of the GABA-B receptor antagonist CGP55845. To elucidate the direct cellular action of baclofen, the excitability and membrane potential of globus pallidus neurons were studied by cell-attached and whole-cell patch-clamp recordings in the brain slice. Bath application of baclofen (50 µM) significantly reduced the firing of these neurons, and was often accompanied by a clear membrane hyperpolarization, in a CGP55845-sensitive manner. These data suggest that activation of GABA-B receptors in globus pallidus could significantly modulate PTZ-induced tonic seizures.     

The Development of a Preference for Cocaine over Food Identifies Individual Rats with Addiction-Like Behaviors

Rationale

Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards.

Objectives

To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this “addicted” phenotype.

Methods

Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward.

Results

Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic.

Conclusions

The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.     

GABA receptors in Deiters nucleus modulate posturokinetic responses to cortical stimulation in the cat.

The early component of the postural responses which accompany the limb flexion during unilateral stimulation of the motor cortex in the cat is not of reflex origin, but results from a central command. These postural adjustments are characterized by a decreased force under the limb diagonally opposite to the moving one and an increased force under the other two. Since the lateral vestibular nucleus (LVN) exerts an excitatory influence on ipsilateral limb extensor motoneurons, experiments were performed in cats to establish whether the cortical-induced postural changes were mediated through the LVN. This structure is tonically inhibited by GABAergic synapses originating from Purkinje cells of the cerebellar vermis, so that local microinjection into the LVN of GABA agonists or antagonists should either decrease or increase the spontaneous discharge of their neurons. Unilateral microinjection of 0.25 microliters of the GABA-A agonist muscimol or the GABA-B agonist baclofen (at 2-4 micrograms/microliters saline) into the LVN produced a short-lasting episode of ipsilateral postural hypotonia and contralateral hypertonia, during which the cats were unable to stand on the measurement platform. When, shortly after, some recovery of the postural activity appeared, no changes in threshold, latency or amplitude of the cortical-induced flexion movement were observed; however, the early component of the postural responses decreased in the other three limbs. Moreover, the slope of the response curve of the moving limb remained unmodified, while that of the early component of the postural responses, which involved the remaining limbs, decreased following stimulation of the motor cortex at different stimulus intensities. These effects started a few min after the injection and lasted for about 2-3 h. The effects described above were dose-dependent. Moreover, histological controls indicated that the structure responsible for these postural changes corresponded to the middle part of the LVN. The specificity of the results was shown by the fact that unilateral microinjection of 0.25 microliters of the GABA-A antagonist bicuculline or the GABA-B antagonist phaclofen (at 5-8 micrograms/microliter saline) into the LVN produced a postural asymmetry opposite in sign to that elicited in the same experiments by the corresponding agonists. These injections did not modify the amplitude of the cortical-induced limb flexion, but rather enhanced the amplitude of the early component of the postural responses in the other three limbs.(ABSTRACT TRUNCATED AT 400 WORDS)     

A Novel Procedure for Evaluating the Reinforcing Properties of Tastants in Laboratory Rats: Operant Intraoral Self-administration

This paper describes a novel method for studying the bio-behavioral basis of addiction to food. This method combines the surgical component of taste reactivity with the behavioral aspects of operant self-administration of drugs. Under very brief general anaesthesia, rats are implanted with an intraoral (IO) cannula that allows delivery of test solutions directly in the oral cavity. Animals are then tested in operant self-administration chambers whereby they can press a lever to receive IO infusions of test solutions. IO self-administration has several advantages over experimental procedures that involve drinking a solution from a spout or operant responding for solid pellets or solutions delivered in a receptacle. Here, we show that IO self-administration can be employed to study self-administration of high fructose corn syrup (HFCS). Rats were first tested for self-administration on a progressive ratio (PR) schedule, which assesses the maximum amount of operant behavior that will be emitted for different concentrations of HFCS (i.e. 8%, 25%, and 50%). Following this test, rats self-administered these concentrations on a continuous schedule of reinforcement (i.e. one infusion for each lever press) for 10 consecutive days (1 session/day; each lasting 3 hr), and then they were retested on the PR schedule. On the continuous reinforcement schedule, rats took fewer infusions of higher concentrations, although the lowest concentration of HFCS (8%) maintained more variable self-administration. Furthermore, the PR tests revealed that 8% had lower reinforcing value than 25% and 50%. These results indicate that IO self-administration can be employed to study acquisition and maintenance of responding for sweet solutions. The sensitivity of the operant response to differences in concentration and schedule of reinforcement makes IO self-administration an ideal procedure to investigate the neurobiology of voluntary intake of sweets.     

Sensitivity of hippocampal interneurons and pyramidal cells to GABA and some of its agonists:in vitro experiments

Effects of GABA and its agonists baclofen and muscimol on the background spike activity of single hippocampal neurons were studied in rat brain slices using an intracellular recording technique. Interneurons localized in thestratum alveus-oriens and pyramidal neurons of thestratum pyramidale showed high sensitivity to GABA (mean ID₅₀=65 µM and 40 µM, ranges 10–140 µM and 3–200 µM), baclofen (ID₅₀=2.6 µM and 3.5 µM, ranges 0.6–20.0 µM and 0.4–30.0 µM), and muscimol (ID₅₀=0.85 µM and 0.21 µM, ranges 0.11–4.0 µM and 0.05–0.45 µM, respectively). Responses of hippocampal neurons to application of GABA or either of its agonists were predominantly inhibitory. A part of interneurons (30%) differed from pyramidal neurons in their irresponsivity or low sensitivity to baclofen applications. GABA- or muscimol-induced inhibition of spike activity in many pyramidal cells was preceded by a short-lasting excitation. Our findings indicate that a part of hippocampal interneurons are very poorly supplied with GABAb receptors. Inhibition of pyramidal cells evoked by activation of GABAa receptors probably develops against the background of accompanying depolarization, which in some cases can result in a provisional excitation of these neurons. The excitatory effects of GABA on the pyramidal cells are mediated by GABAa receptors.Neirofiziologiya/Neurophysiology, Vol. 27, No. 1, pp. 36–44, January–February, 1995.     

Evidence that GABA in the nucleus dorsalis raphé induces stimulation of locomotor activity and eating behavior

Recent electrophysiological studies have provided evidence that GABA controls inhibitorily the activity of the serotonin containing cell bodies in nucleus dorsalis raphé (NDR). The present investigation shows that local injection of baclofen or the GABA agonist muscimol (25–100 ng) into the NDR strongly increased locomotor activity and stimulated eating in satiated rats. These effects are antagonized by the GABA antagonists bicuculline or picrotoxin given systemically or locally. Muscimol injected in NDR also decreased serotonin and 5-hydroxyindole acetic acid in hypothalamus but not in striatum. These findings support a transmitter role of GABA in NDR and may be interpreted related to a decreased activity of serotonin.