A causal role for the pulvinar in coordinating task-independent cortico-cortical interactions.

The pulvinar is the largest nucleus in the primate thalamus and has topographically organized connections with multiple cortical areas, thereby forming extensive cortico-pulvino-cortical input-output loops. Neurophysiological studies have suggested a role for these transthalamic pathways in regulating information transmission between cortical areas. However, evidence for a causal role of the pulvinar in regulating cortico-cortical interactions is sparse and it is not known whether pulvinar's influences on cortical networks are task-dependent or, alternatively, reflect more basic large-scale network properties that maintain functional connectivity across networks regardless of active task demands. In the current study, under passive viewing conditions, we conducted simultaneous electrophysiological recordings from ventral (area V4) and dorsal (lateral intraparietal area [LIP]) nodes of macaque visual system, while reversibly inactivating the dorsal part of the lateral pulvinar (dPL), which shares common anatomical connectivity with V4 and LIP, to probe a causal role of the pulvinar. Our results show a significant reduction in local field potential phase coherence between LIP and V4 in low frequencies (4-15 Hz) following muscimol injection into dPL. At the local level, no significant changes in firing rates or LFP power were observed in LIP or in V4 following dPL inactivation. Synchronization between pulvinar spikes and cortical LFP phase decreased in low frequencies (4-15 Hz) both in LIP and V4, while the low frequency synchronization between LIP spikes and pulvinar phase increased. These results indicate a causal role for pulvinar in synchronizing neural activity between interconnected cortical nodes of a large-scale network, even in the absence of an active task state.

Modulation of tonic immobility by GABAA and GABAB receptors of the medial amygdala.

Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.

GABA(A) receptors in the central amygdala are involved in memory retention deficits induced by cannabinoids in rats.

The central nucleus of the amygdala (CeA) as the main output of amygdala plays an important role in memory processes. In this study we first evaluated the effects of intra-CeA administrations of different doses of a cannabinoid CB1 agonist, WIN55, 212-2, GABA(A) receptor agonist and antagonist, muscimol and bicuculline, alone on memory retention using passive avoidance learning (PAL) test in rats. Then we examined the effects of GABA(A) receptor agents on the responses induced by intra-CeA microinjection of different doses of WIN55, 212-2. We found that administration of WIN55, 212-2 (0.05, 0.1, 0.2 and 0.4µg/rat) immediately after training impaired memory retrieval in a dose-dependent fashion. Although pre-test intra-CeA administration of muscimol (125, 250 and 500ng/rat) alone had no effect on the step-through latency, its co-administration (125ng/rat) with different doses of WIN55, 212-2 potentiated the amnesic effects of any doses of WIN55, 212-2. The results also showed that pre-test intra-CeA administration of bicuculline (200, 400 and 800ng/rat) alone had no significant effect, but at dose of 200ng/rat disrupted post-training WIN55, 212-2-induced amnesia in the retention test. Furthermore, the additional effect of muscimol (125ng/rat) on memory impairment induced by WIN55, 212-2 (0.1µg/rat) was prevented by intra-CeA co-injection of bicuculline (200ng/rat). We indicated that stimulating or blocking GAGA(A) receptors in the CeA by muscimol and bicuculline interfere with WIN55, 212-2-induced deficits in memory retention in a PAL task and therefore suggests an interaction between cannabinergic and GABAergic systems of the CeA in memory process.

Muscimol-induced long-term depression in the hippocampus: lack of dependence on extracellular calcium.

We have recently reported a new protocol for inducing long-term depression through activation of GABAA receptors in the hippocampal site. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one. It was also shown that glutamate receptor activity is not involved in the induction of this type of long-term depression. The present study investigates the role of calcium in the induction of this novel form of long-term depression and attempts to determine the mechanism of reversal of muscimol-induced long-term depression. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that the muscimol-induced long-term depression can be obtained in the absence of calcium in the bathing medium. In addition to this, the long-term depression was reversed by N-methyl-D-aspartate, kainic acid, high potassium medium, veratrine and the calcium ionophore A23187 but not high calcium (10 mM) medium. High potassium medium in the absence of calcium reversed the long-term depression induced by muscimol 10 microM. The results suggest that this type of glutamate-independent long-term depression can be induced in the absence of extracellular calcium. Extracellular calcium is not necessary for reversal of the long-term depression, although when intracellular calcium levels are raised, as by A23187, this is capable of inducing reversal.

Distinction between the effects of barbiturates, benzodiazepines and phenytoin on responses to gamma-aminobutyric acid receptor activation and antagonism by bicuculline and picrotoxin.

1 Interactions of depressant and anticonvulsant drugs with the neuronal gamma-aminobutyric acid (GABA) receptor + effector system have been examined on afferent fibres to the rat cuneate nucleus in vitro. Three types of interaction have been measured: (a) potentiation of depolarizing responses to the GABA analogue, muscimol: (b) reduction in the potency of bicuculline as an antagonist of muscimol at the GABA receptor: (c) reduction in the potency of picrotoxin as an antagonist of muscimol acting on the effector mechanism. 2 Phenobarbitone reduced the potency of picrotoxin in doses which did not affect the potency of bicuculline and which caused only a small potentiation of muscimol. Pentobarbitone did not show such selectivity, a reduction in potency of picrotoxin always being accompanied by a reduction in potency of bicuculline and a substantial potentiation of muscimol. 3 Flurazepam and lorazepam both reduced the potency of picrotoxin without affecting that of bicuculline and with very little potentiation of muscimol. Phenytoin had no effect on the potency of picrotoxin whilst potentiating muscimol to the same extent as phenobarbitone. 4 The spectrum of drug activity in reducing the potency of picrotoxin correlates well with the reported anticonvulsant effects of these drugs against kindled amygdaloid seizures. Potentiation of muscimol and reduction of bicuculline potency appear more closely related to hypnotic properties.

Antagonism of inhibitory amino acids by the steroid derivative RU5135.

The steroid derivative RU5135 has been tested for its ability to antagonize glycine and the gamma-aminobutyric acid (GABA) analogue muscimol on isolated preparations of rat optic nerve and cuneate nucleus, respectively. On the cuneate nucleus, RU5135 antagonized muscimol in a competitive manner with a pA2 value of 8.31. RU5135 shared a common site of action with bicuculline that was separate from the picrotoxin site. On the optic nerve, RU5135 antagonized glycine with a pA2 of 7.67. It shared a common site of action with strychnine.

Depolarizing responses to glycine, beta-alanine and muscimol in isolated optic nerve and cuneate nucleus.

Concentration-dependent depolarizations were evoked by glycine and beta-alanine 5 X 10(-4)-10(-2)M and by the gamma-aminobutyric acid (GABA) analogue, muscimol 10(-6)-10(-4)M. The maximal response to glycine was several-fold higher than that to muscimol on optic nerve but the reverse was found on the dorsal funiculus fibres in the cuneate nucleus. beta-Alanine evoked a similar maximal response to glycine on optic nerve but a considerably higher maximum than glycine in the cuneate nucleus. Strychnine was 19.5 times more potent as a glycine antagonist (pA2 = 6.58) than as a muscimol antagonist. Bicuculline was 156 times more potent as a muscimol antagonist than as a glycine antagonist. Other antagonists of muscimol, i.e. tubocurarine, picrotoxin and leptazol, and potentiators of muscimol, i.e. pentobarbitone and flurazepam, had little or no effect on responses to glycine. Responses to beta-alanine had pharmacological properties compatible with a mixed action on both GABA and glycine receptors. The rat isolated optic nerve appears to be a useful preparation for studying the pharmacology of the neuronal glycine receptor plus chloride ionophore complex.

A new method for the evaluation of benzodiazepines based on their ability to block muscimol-induced myoclonic jerks in mice.

A number of clinically used benzodiazepines were tested for their effectiveness in blocking muscimol-induced myoclonic jerks in mice. Their ED50 values were determined from their dose-response curves. These data gave the following relative potencies with respect to diazepam: diazepam = 1, medazepam = 0.24, oxazepam = 1.27, flurazepam = 1.90, lorazepam = 3.01, nitrazepam = 3.93, clonazepam = 33.14, and flunitrazepam = 116.00. Because our earlier studies indicated that muscimol-induced myoclonic jerks probably originate from the spinal cord, the present method may prove to be suitable for quantitatively evaluating the effect of benzodiazepines on the spinal cord. The present results also indicate the possible value of flunitrazepam in the management of neurologic disorders in which preferential action on the spinal cord is desired.

Effect of typical and atypical neuroleptics on the behavioural consequences of activation by muscimol of mesolimbic and nigro-striatal dopaminergic pathways in the rat.

Direct injections of muscimol into the ventral tegmental area (VTA) or substantia nigra zona reticulata (SNR) have been used to selectively stimulate the mesolimbic and nigro-striatal dopamine pathways respectively. Such injections induced locomotor activity, rearing, sniffing and in some animals an intermittent grooming response. These responses were rapid in onset, dose-related and relatively short lasting (less than 40 min). Selective increases in dopamine turnover were seen in the nucleus accumbens and in the striatum following VTA and SNR injections of muscimol (100 ng) respectively. Haloperidol inhibited the behavioural consequences of VTA and SNR injections of muscimol with similar potency (ED50S 0.01-0.03 mg/kg IP), and fluphenazine did likewise (ED50S 0.05-0.16 mg/kg IP). However, thioridazine (ED50S VTA: 1.45-2.04 mg/kg IP, SNR 8.50-9.20 mg/kg IP) and in particular clozapine (ED50S VTA: 0.24-0.58 mg/kg IP, SNR: 6.10-9.70 mg/kg IP) were more potent at inhibiting the locomotor activity and sniffing responses due to VTA rather than SNR administered muscimol. Since dopamine D2 antagonists are believed to exert their anti-psychotic effects via an action on mesolimbic dopaminergic systems, and their ability to induce extrapyramidal side effects (EPS) is thought to be due to an action on nigro-striatal dopamine systems, these results suggest that the behavioural models described can be used to predict efficacy and side-effect liability of potential neuroleptic drugs.

Muscimol induces state-dependent learning in Morris water maze task in rats.

Effects of muscimol on the place learning in Morris water maze task were investigated in rats. Rats were given 4 training trials per day with the submerged platform at a fixed location in the maze for 4 days. On day 4, rats were required to swim in the pool without the platform after 4 training trials (probe test). Compared to the saline-treated rats, the rats treated with muscimol on day 1-4 showed no modifications of place learning in the training trials and the probe test. However, in the rats treated with muscimol on day 1-3 and treated with saline on day 4, there was increased latency to reach the platform and reduced duration in the quadrant where the platform had been located on day 4. The increased latency in the training trials and reduced duration in the probe test on day 4 was blocked by bicuculline, when bicuculline and muscimol were co-administered on day 1-3, and saline was injected on day 4. Moreover, in the rats treated with muscimol on day 1-3, co-administration of bicuculline and muscimol on day 4 blocked place learning: increased latency in the training trials and reduced duration in the probe test was observed. These results suggest that muscimol induces state-dependent learning (SDL) in Morris water maze task, and that muscimol-induced SDL is mediated by GABAA receptors.

Muscimol injections into the nucleus basalis magnocellularis of rats: selective impairment of working memory in the double Y-maze.

Anatomical and neurochemical results suggest that the cortico- and amygdalopetal cholinergic neurons of the nucleus basalis magnocellularis (NBM) may receive GABAergic inputs. The present experiments were undertaken to evaluate the possible influence of intra-NBM injections of the GABAA agonist, muscimol, on memory. In two experiments, rats were chronically implanted with guide cannulae placed bilaterally into the NBM. Rats were trained to a criterion of at least 83% correct on each component in a double Y-maze task that allowed a dissociation of working and reference memory. The task began with placement into one of the two end arms of the first Y-maze and the reference memory task was to go to the stem for food. Access to the second Y was then given and the working memory task was to go to the goal arm opposite the arm in the first maze from which that trial began. In experiment 1, pre-trained rats (n = 7) received muscimol (0.5 microliter) in doses of 0, 0.01, 0.1 and 1.0 microgram in a counterbalanced order with re-training to criterion between injections. In experiment 2, pre-trained rats (n = 8) received saline, muscimol (0.1 microgram), the GABAA antagonist, bicuculline (0.01 microgram), and muscimol + bicuculline. Results of experiment 1 revealed that intra-NBM muscimol produced a dose-dependent and differential impairment of working and reference memory. A dose of 0.1 microgram impaired working memory without significantly affecting reference memory; doses of 0.01 microgram and 1.0 microgram affected neither and both types of memory, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentration-dependent effects of muscimol to enhance pulsatile GnRH release from GT1-7 neurons in vitro.

Immortalized GT1-7 neurons were used to characterize the effect of muscimol, a GABAA receptor agonist, to enhance pulsatile gonadotropin-releasing hormone (GnRH) release. GT1-7 neurons were grown on Cytodex-3 beads and placed in special superfusion microchambers. The cells were superfused at a rate of 6.2 ml x h-1 with Media 199 (pH 7.35) using a commercially available perfusion system. After a pre-muscimol period of 120 min, the cells were exposed for 5 min to 0.35, 1, 5 or 10 microM muscimol or 5 microM muscimol+20 microM of the GABAA receptor antagonist, bicuculline. Following removal of the muscimol (and bicuculline, in the case of the latter experiment), the superfusion was continued for another 115 min. Sample fractions were collected at 5 min intervals throughout the perfusion. Basal GnRH release from the GT1-7 neurons was pulsatile with an average interpulse interval of 45.4+/-0.5 min and an average pulse amplitude of 191.5+/-22.6 pg x min x ml-1. Our results also demonstrated that the GABAA receptor agonist, muscimol, enhances pulsatile GnRH release from GT1-7 neurons in culture. The response to muscimol was saturable and concentration-dependent with an EC50 of 0.47 microM. The effects of 5 microM muscimol to increase GnRH pulsatility were blocked by co-exposure to the GABAA receptor antagonist, bicuculline. The average GnRH interpulse intervals were 41.7+/-1.8 min, 32.5+/-2.9 min, 30.6+/-0.7 min and 25.5+/-0.4 min in the period following exposure to 0.35, 1, 5 and 10 microM of muscimol, respectively (post-muscimol period). GnRH pulse amplitude (mean-area for each pulse) was increased during exposure to muscimol but not during the pre- or post-muscimol periods. The GABAA receptor antagonist, bicuculline, itself had no effect on pulsatile GnRH release. These results are consistent with previously published reports suggesting that activation of the GABAA receptor stimulates hypothalamic GnRH release in embryonic and neonatal animals.

GABAA receptors in the amygdala: role in feeding in fasted and satiated rats.

The purpose of this study was to clarify further the site of action in the amygdala as well as functional characteristics of feeding in response to two GABA receptor agonists. Guide cannulae for microinjection were implanted stereotaxically in the rat just above the central nucleus of the amygdala (CNA). Microinjections of 0.05, 0.25, 0.5 or 1.0 nmol muscimol, a GABAA-selective receptor agonist, produced a dose- and time-dependent decrease of food intake in both the satiated and fasted rat. The bilateral injection of muscimol into the amygdala was more effective than a unilateral injection during the first 2 h, although the overall effects were similar. Microinjection of 0.1 nmol bicuculline methiodide, a GABAA receptor antagonist, into the CNA significantly blocked this inhibitory effect of 0.05 and 0.5 nmol muscimol again in both the satiated and fasted rat. Doses of 0.05, 0.5, 5.0 and 10.0 nmol of the selective GABAB agonist, baclofen, injected into homologous sites in the CNA did not alter food intake. These findings support the viewpoint that the amygdala and its central nucleus comprise a pivotal region involved in the mechanisms underlying the control of feeding behavior. Further, it is envisaged that hypophagic or anorexic responses are induced through the activation of GABAA receptors by the presynaptic release of GABA from neurons which form a component of the anatomical system for hunger and satiety.

Pregnenolone-sulfate: an endogenous antagonist of the gamma-aminobutyric acid receptor complex in brain?

The interaction of the 'neurosteroid', pregnenolone-sulfate (PS), with the GABA/benzodiazepine/chloride ionophore receptor complex was investigated in rat brain subcellular preparations. At low micromolar concentrations PS competitively inhibited the binding of the convulsant [35S]t-butylbicyclophosphorothionate (TBPS) and antagonized pentobarbital-stimulated [3H]flunitrazepam binding to synaptosomes. In addition, PS inhibited muscimol-stimulated 36Cl-uptake in brain synaptoneurosomes, including that PS has characteristics of a relatively potent antagonist of the chloride channel coupled to the GABA receptor. Together with our previous finding that A-ring reduced metabolites of progesterone and deoxycorticosterone also interact with the GABA receptor complex but as hypnotic barbiturates, these data suggest that the regulation of GABAergic neurotransmission by various neurosteroids may be an important mechanism for controlling neuronal excitability.

Zinc modulation of GABAA receptor-mediated chloride flux in rat hippocampal slices.

We studied the effect of ZnCl2 application on GABAA receptor-mediated 36CI- flux in microsacs prepared from whole rat hippocampus and in region-specific hippocampal slices. Slices were obtained from the dentate gyrus (DG), which contains the zinc-enriched hilar region, and from the CA1 region which contains lower levels of endogenous zinc. Muscimol (10 microM)-evoked 36Cl- flux was significantly reduced by ZnCl2 (100 microM) in hippocampal microsacs. In hippocampal slices, muscimol (50 microM)-evoked 36Cl- efflux was higher in CA1 (112.5 +/- 27.9% above basal efflux rate) than in DG slices (29.7 +/- 5.6%). In the presence of ZnCl2, the muscimol effect on efflux rate in CA1 and DG regions was decreased to 10.6 +/- 5.4% and 6.9 +/- 4.9%, respectively. Preincubation with the zinc chelator, tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, 20 microM), caused a significant increase in muscimol-evoked 36Cl- efflux only in DG slices (57.2 +/- 7.0%), suggesting that GABAA receptors in the DG of rat hippocampus under physiological conditions may function under the inhibitory influence of endogenous chelatable zinc. In intracellular recordings, ZnCl2 (100 microM) application had no effect on the responses to GABA applied perisomatically or in the dendritic region of CA1 neurons. The lack of Zn2+ effect on the postsynaptic GABAA receptor-mediated responses suggests that the decreases of the 36Cl- efflux observed in the biochemical assays may be due to zinc action on neurons other than the principal pyramidal CA1 cells, and possibly the non-neuronal cell populations.

Involvement of GABA(B) receptor systems in action of antidepressants: baclofen but not bicuculline attenuates the effects of antidepressants on the forced swim test in rats.

Involvement of GABAergic systems in action of antidepressants was examined in the forced swim test in rats. Rats were forced to swim in a cylinder for 15 min on day 1 and for 5 min on day 2. Desipramine, mianserin and buspirone, administered after the 15-min swim session on day 1 and before the 5-min swim test on day 2, dose-dependently decreased the duration of immobility in the swim test on day 2. Baclofen attenuated the decreased duration of immobility induced by desipramine, mianserin and buspirone in the swim test, although baclofen did not affect the duration of immobility when it was injected alone. Muscimol dose-dependently decreased the duration of immobility in the swim test on day 2. Bicuculline antagonized the decreased duration of immobility induced by muscimol. However, bicuculline failed to antagonize the decreased duration of immobility induced by desipramine, mianserin and buspirone. These results suggest that GABA(B) but not GABA(A) receptor systems may be involved in action of antidepressants.

Infusions of physostigmine into the hippocampus or the entorhinal cortex attenuate avoidance retention deficits produced by intra-septal infusions of the GABA agonist muscimol.

Septal gamma-aminobutyric acid (GABA) receptor activation is known to disrupt memory formation, although the mechanisms underlying this impairment remain unclear. The present study explored the possibility that high levels of septal GABA receptor activity might impair memory by down-regulating acetylcholine (ACh) function in archicortex and entorhinal cortex. To test this possibility, rats were trained on an avoidance task 15 min after receiving intra-septal infusions of vehicle or muscimol (5 nmol/0.5 microl) combined with unilateral intra-hippocampal (10 microl/1 microl) or intra-entorhinal cortex (1.875 microg/0.25 microl) infusions of vehicle or the acetylcholinesterase inhibitor physostigmine. We demonstrate that these infusions do not alter acquisition performance on a continuous multiple trial inhibitory avoidance task. However, intra-septal infusions of muscimol dramatically impair retention performance 48 h later. More importantly, infusions of physostigmine into the hippocampus or the entorhinal cortex, at doses that do not influence acquisition or retention performance when infused alone, attenuate the impairing effects of the muscimol infusions on retention. We suggest that high levels of septal GABA receptor activity might impair memory by down-regulating ACh levels in the hippocampal region, and that such memory impairments can be ameliorated by increasing ACh levels in the hippocampus or entorhinal cortex.

A midline area in the nucleus commissuralis of NTS mediates the phrenic nerve responses to carotid chemoreceptor stimulation.

The carotid body chemoreceptor afferents have been reported to project to a discrete area located in the nucleus commissuralis of nucleus tractus solitarius [A. Vardhan et al., Am. J. Physiol., 264 (1993) R41-R50]. The afore-mentioned study was done in spontaneously breathing rats and the afferents and efferents located in the chest wall and the respiratory tract of these animals were intact. In order to exclude the role, if any, of these afferents and efferents, in the present experiments respiratory changes were monitored by recording the phrenic nerve activity instead of tracheal airflow. Experiments were carried out in pentobarbital-anesthetized, bilaterally vagotomized, paralyzed and artificially ventilated rats with a pneumothorax. The carotid body chemoreceptors were stimulated with tracheal administration of nitrogen for 7-10 s. The chemoreceptor stimulation induced an increase in the frequency and amplitude of phrenic nerve bursts. A decrease in the duration of inspiratory (T1), expiratory (TE) and total cycles (TTOT) was observed in the phrenic nerve activity. Inhibition of neuronal cell bodies by microinjections of muscimol (140 pmol/20 nl) into a discrete area in the commissural subnucleus of the nucleus tractus solitarius (coordinates in mm: 0.3 rostral to 0.5 caudal, 0 to 0.5 lateral and 0.3 to 0.5 deep with respect to the calamus scriptorius), attenuated the phrenic nerve responses to the carotid body stimulation. On the other hand, control injections of saline (0.9%) into this site did not alter the phrenic nerve response to the carotid body stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Medullary ventral surface GABA receptors affect respiratory and cardiovascular function.

We previously demonstrated that GABA and muscimol administered either into the cisterna magna or the fourth ventricle to chloralose-anesthetized cats cause respiratory depression, hypotension, and bradycardia. Injection of these substances into the lateral and third ventricles had no effect. In order to localize the site of action, muscimol and GABA were applied by Perspex rings to the ventral surface of the medulla. Application of muscimol (0.25-2.66 micrograms) to Schlaefke's area in 6 cats reduced minute ventilation from 443 +/- 38 to 291 +/- 52 ml/min by reducing tidal volume from 31.8 +/- 2.3 to 17.6 +/- 1.4 ml, without changing respiratory rate and duration of inspiration. Hypotension and bradycardia were also observed. Application of GABA (0.14-4.86 mg) produced similar effects on respiratory activity and arterial blood pressure. No significant effects occurred when high doses of these agents were applied to Loeschcke's and Mitchell's areas. Application of bicuculline (5-25 micrograms) to Schlaefke's area had the opposite effect of muscimol and GABA on respiratory activity and blood pressure, and reversed the respiratory and cardiovascular depressant effects of both agents. We conclude that GABA receptors are present at Schlaefke's area, and that activation of these receptors results in respiratory depression, hypotension, and bradycardia. Our results suggest that GABA may be an important inhibitory neurotransmitter in the modulation of respiratory and cardiovascular control.

Contralateral turning evoked by the intranigral microinjection of muscimol and other GABA agonists.

Contraversive turning was evoked by the microinjection of GABAergic agents into the substantia nigra (SN) of the rat. Muscimol, the most potent GABA agonist, evoked contralateral turning when injected into the SN in doses of 0.005, 0.05, 0.5 and 5 microgram, whereas 0.5 microgram of muscimol applied at extranigral sites produced no turning. A shorter lived contraversive turning response was evoked by the intranigral micro-injection of imidazole acetic acid (10 or 50 microgram), ethanolamine-O-sulphate (25 or 50 microgram), or GABA (50 microgram). No increase in GABA-induced turning was produced by local pretreatment with pipecolic acid (5 microgram). When injected into the SN, neither picrotoxin, in doses of 0.1, 0.5, 1.0 or 2.0 microgram, nor bicuculline methiodide (Bm), in doses of 0.1 or 0.2 microgram, elicited a significant amount of turning. Picrotoxin, however, partially blocked the turning evoked by the intranigral injection of muscimol, both via the i.p. and intranigral routes of administration whereas Bm did not. In addition, haloperidol (1 mg/kg i.p.) antagonized the muscimol-induced turning. Hence, we feel GABA mimetic substances injected within the SN might evoke contralateral turning via activation of a heretofore undescribed neural system arising from the SN or by activating the ipsilateral dopaminergic neurons projecting from the SN.