Central effects of paraoxon on haemodynamics in the cat

Summary Application of paraoxon into the left vertebral artery (8–80 g) or both the left and right vertebral artery (4–8 g) of the anaesthetized cat evoked dose-dependent depressor effects, whereas heart rate was not influenced significantly. Also after systemic administration of paraoxon (150–825 g·kg^–1), while peripheral muscarinic receptors were blocked, depressor effects were still observed. Dose-response curves for the depressor response to paraoxon were established. Infusion of low doses of dexetimide via the vertebral artery prevented the hypotensive action of paraoxon. The distribution of this antimuscarinic drug in the brain was investigated. The depressor effect of paraoxon can be attributed to both a decrease in peripheral resistance and cardiac output. Decerebration and midcollicular transection were carried out in order to elucidate the site and mechanism of action. The depressor effect of paraoxon seems to be mediated by a central mechanism of action located within the lower brain stem.It is concluded that stimulation of muscarinic receptors in the pontomedullary region gives rise to the observed changes in haemodynamic parameters. Muscarinic receptors in the hypothalamus seem to be of minor importance for the hypotensive action of paraoxon.     

Comparison of the cardiovascular effects of intravenously administered GABA,THIP, and isoguvacine in the anesthetized rat

Mean arterial blood pressure and heart rate were monitored in pentobarbital-anesthetized rats after intravenous injections of GABA, THIP, or isoguvacine-HCl (all at 0.1–100 mg/kg). GABA produced dose-dependent hypotension and bradycardia; THIP produced no appreciable effect on either parameter; and isoguvacine produced hypotension, but no marked change in heart rate. The transient hypotension and bradycardia produced by GABA (1 mg/kg) were partially blocked by pretreatment of the animals with bicuculline or bicuculline-methobromide. After pretreatment with bicuculline or bicuculline-methobromide, the hypotensive effect of isoguvacine (1 mg/kg) occurred more rapidly (i.e., during the first 5 min, rather than during 5–15 min after injection of isoguvacine). As THIP penetrates the blood-brain barrier more readily than GABA or isoguvacine, as GABA and isoguvacine exerted more pronounced cardiovascular effects than THIP, and as bicuculline and bicuculline-methobromide affected the cardiovascular actions of GABA and isoguvacine, it is suggested that activation of peripheral GABA receptors might explain part of the cardiovascular effects produced by intravenously injected GABA. Further study of isoguvacine and its derivatives might lead to the development of hypotensive (antihypertensive) agents that act on peripheral GABA-ergic systems.     

Oro-facial dyskinesia and the sub-commissural part of the globus pallidus in the cat: role of acetylcholine and its interaction with GABA

The possible role of cholinergic mechanisms in the sub-commissural part of the globus pallidus (scGP) in the induction of oro-facial dyskinesia (OFD) was studied in cats. Local injections of the cholinergic agonist carbachol into the scGP elicited tongue protrusions in a dose dependent way (100–1000 ng/0.5 l). The effect elicited by 1000 ng carbachol was selectively antagonized by the cholinergic antagonist scopolamine (10 g/0.5 l); this dose of scopolamine was ineffective when injected alone. The tongue protrusions resulted from both normal and abnormal movements: whereas normal movements simply consisted of protruding the flat tongue, abnormal movements implied a variety of movements, especially curling upwards the lateral side(s) or tip of the tongue inside or outside the oral cavity. The abnormal carbachol-induced tongue protrusions formed part of a syndrome marked by dyskinetic movements of the muscles of the eye, ear and cheek, and were identical to those seen previously after local injections of picrotoxin (250–500 ng). Intra-pallidal injections of the abovementioned dose of scopolamine had no effect on the tongue protrusions induced by local injections of 375 ng picrotoxin. However, local injections of 100 ng muscimol, which was previously found to attenuate significantly the effect of 375 ng picrotoxin and which was ineffective when injected alone, significantly attenuated the tongue protrusions induced by local injections of 1000 ng carbachol. These data suggest that the cholinergic effects are mediated via a GABAergic mechanism, but not vice versa. The results are discussed in view of GABAergic and anticholinergic therapies used in oro-facial dyskinesia.     

Pharmacological analysis of the central cardiovascular effects of four GABA analogues

Summary The central cardiovascular effects of 4 structural analogues of GABA were investigated. The drugs were injected intracerebroventricularly (i.c.v.) in cumulative doses into pentobarbital-anaesthetized normotensive rats. Muscimol (0.01–10 g/kg), THIP (0.01–100g/kg), kojic amine (0.1–100 g/kg) and isoguvacine (0.1–100g/kg) produced dose-dependent hypotension and bradycardia. The maximal fall in the mean blood pressure was of about 35% of the initial values. These effects appears to be of central origin since the intravenous (i.v.) injection of the same doses of the drugs did not produce any similar cardiovascular modifications. The hypotensive effects of muscimol and kojic amine were antagonized partly by i.c.v. bicuculline. The combination of bicuculline and kainic acid almost completely prevented the blood pressure lowering effects of muscimol, kojic amine and isoguvacine. THIP however was only slightly antagonized by bicuculline and kainic acid. Atropine i.v. also prevented partly the cardiovascular effects of all these drugs.Thus, the mechanisms of the central cardiovascular actions of GABA analogues appear to be more complex than expected and variable from one drug to another.The involvement of GABA receptors of the A and B types and of cholinergic mechanisms in the hypotensive effect of the drugs is discussed.     

In vivo evidence for GABAergic control of serotonin release in the cat substantia nigra

Push-pull cannulae were used for estimating the release of endogenously synthesized [3H]serotonin in both substantia nigra and caudate nuclei of halothane-anaesthetized cats. The unilateral nigral application of GABA (10-5 M) reduced the local release of [3H]serotonin picrotoxin induced an opposite effect. Both treatments failed to modify [3H]serotonin release in the caudate nuclei or in the contralateral substantia nigra. These results suggest that GABAergic neurons innervating the substantia nigra may regulate nigral serotonin transmission. The possibility that such a regulation could be presynaptic (direct or through other nigral neurotransmitters) or related to a change in the activity of the nigro-raphe projection is discussed.     

Molecular mechanisms regulating the interactions between the benzodazepines and GABA receptors in the central nervous system.

Using radioreceptor assay techniques to measure the kinetics of GABA and diazepam receptors, a relationship between GABA and benzodiazepine receptors has been firmly established in membranes of brain and neuroblastoma NB2a clonal cell lines. Occupancy of benzodiazepine receptors uncovers a new population of GABA receptors (GABA2 receptors) endowed with high affinity for GABA. Moreover, stimulation of GABA receptors increases the affinity of 1,4-benzodiazepine receptors for 1,4-benzodiazepines. This reciprocal interaction appears to be mediated by an endogenous regulatory protein (for details on this protein see [14 and 29]) which allosterically regulates GABA2 receptors while it competitively interacts with benzodiazepines for their specific binding sites. The rank order of potency of the various 1,4-benzodiazepines to block the action of this protein inhibitor on GABA receptors is related to their capacity to displace 3H-diazepam binding. These data suggest that the interaction between the 1,4-benzodiazepine receptors and the endogenous protein modulator of GABA2 receptors might play a role in the pharmacological action of the 1,4-benzodiazepines.     

Inactivation of GABA receptors by phenoxybenzamine: Effects on GABA-stimulated benzodiazepine binding in the central nervous system

Treatment of particulate fractions of rat forebrain with phenoxybenzamine produced dose related inhibition of specific muscimol binding. Scatchard analysis revealed a significant reduction of binding sites but no change in affinity constant. The inhibition was not reversed by washing or incubation at 37°C suggesting that phenoxybenzamine alkylates GABA receptors, i.e. acts as a non-competitive, non-equilibrium inhibitor. Phenoxybenzamine inhibited the GABA-induced increase in specific diazepam binding but had little direct effect on diazepam binding. Preincubation of synaptic membranes with GABA or muscimol, but not diazepam, protected the muscimol binding site from inactivation by phenoxybenzamine.     

The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors.

The pharmacological effects of the enantiomers of cis-3-aminocyclopentanecarboxylic acids ((+)- and (−)-CACP), the enantiomers of trans-3-aminocyclopentanecarboxylic acids ((+)- and (−)-TACP), and the enantiomers of 4-aminocyclopent-1-ene-1-carboxylic acids ((+)- and (−)-4-ACPCA) were studied on human homomeric ρ₁ and ρ₂ GABA_C receptors expressed in Xenopus oocytes using two-electrode voltage clamp methods. These compounds are conformationally restricted analogues of γ-aminobutyric acid (GABA) held in a five-membered ring. (+)-TACP (EC₅₀ (ρ₁)=2.7±0.2 μM; EC₅₀ (ρ₂)=1.45±0.22 μM), (+)-CACP (EC₅₀ (ρ₁)=26.1±1.1 μM; EC₅₀ (ρ₂)=20.1±2.1 μM) and (−)-CACP (EC₅₀ (ρ₁)=78.5±3.5 μM; EC₅₀ (ρ₂)=63.8±23.3 μM) were moderately potent partial agonists at ρ₁ and ρ₂ GABA_C receptors, while (−)-TACP (100 μM inhibited 56% and 62% of the current produced by 1 μM GABA at ρ₁ and ρ₂ receptors, respectively) was a weak partial agonist with low intrinsic activity at these receptors. In contrast, (+)-4-ACPCA (K_i (ρ₁)=6.0±0.1 μM; K_i (ρ₂)=4.7±0.3 μM) did not activate GABA_C ρ₁ and ρ₂ receptors but potently inhibited the action of GABA at these receptors, while (−)-4-ACPCA had little effect as either an agonist or an antagonist. The affinity order at both GABA_C ρ₁ and ρ₂ receptors was (+)-TACP>(+)-4-ACPCA(+)-CACP>(−)-CACP(−)-TACP(−)-4-ACPCA. This study shows that the cyclopentane and cyclopentene analogues of GABA affect GABA_C receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABA_C receptors. This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA.     

Involvement of central GABA receptors in the regulation of blood pressure and heart rate of anesthetized cats

Intracerebroventricular (i.c.c.) injections of muscimol (0.03-3 microgram/kg) and GABA (30-1000 microgram/kg) caused dose-related reductions in blood pressure and heart rate of anesthetized cats whereas glycine (30-3000 microgram/kg) was much less effective. I.v. administration of muscimol or GABA had little or no effect. Renal sympathetic nerve discharge was also reduced by central GABA receptor stimulation. The effects of both muscimol and GABA were reversed by either picrotoxin or bicuculline administered intravenously. The results suggest an important role for GABA receptors in the central regulation of blood pressure and heart rate.     

GABA blockade,dopamine and schizophrenia: Experimental studies in the cat

The effects of blocking putative GABA inhibition on dopamine cells of origin in ventral tegmental area and substantia nigra have been examined in freely moving cats with chronically implanted cannulas and recording electrodes. Instillation of the GABA blocking agent bicuculline in ventral tegmental area induces arousal, searching, slinking, hiding, evidence of fear, catatonic stance, staring and sniffing behaviors which were accompanied by spike activity from nucleus accumbens in several animals. Similar amounts of bicuculline placed in substantia nigra did not induce fear but were followed by ipsilateral grooming, circling and hyperesthesia, with EEG spiking in caudate nucleus and medial and lateral geniculate nuclei in several animals. The relationship of these findings to dopamine induced stereotypies in mesolimbic and nigrostriatal systems and to evidence of dopamine excess or hypersensitivity in limbic striatum in patients with schizophrenic disorders is considered.     

Contribution of presynaptic GABA-B receptors to paired-pulse depression of GABA responses in the hippocampus

The synaptic release of -aminobutyric acid (GABA) is thought to be regulated by presynaptic GABA receptors of the 13-type. It was the goal of this study to validate this concept electrophysiologically using four selective antagonists of GABA-B receptors. Experiments were performed in hippocampal slices exposed to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX 30 M) and d-2-amino-5-phosphonopentanoate (AP5 40 M) in order to block excitatory transmission. Consequently, electrical stimulation of the Schaffer collateral/commissural fibers evoked monosynaptic inhibitory potentials (IPSP) recorded intracellularly from CA 1 pyramidal neurons. In a test called paired-pulse paradigm two identical stimuli were applied at intervals ranging from 350 to 4000 ms. The IPSP evoked by the second stimulation was smaller in its amplitude over the entire interval range. This reduction of the second GABAresponse is thought to result from the activation of presynaptic GABA receptors. The GABA-uptake inhibitor SKF 89976 (100 M) increased the amplitude of the IPSP's and increased the ratio of the first to the second IPSP amplitude. These findings indicate that the drug increases the GABA content in the synaptic cleft leading to a facilitation of paired-pulse depression.The actions of four bath-applied GABAB receptor antagonists were examined in the paired-pulse paradigm. None of these compounds abolished paired-pulse inhibition completely even at concentrations higher than those required to block postsynaptic GABA-B responses. The potent GABA-B antagonists CGP 55845 and CGP 52432 reduced paired-pulse depression by 80% at 10 M (maximal effect). The other two compounds, CGP 46381 and CGP 36742 had no significant or only a subtle effect respectively.The adenosine receptor antagonist, caffeine (100 M) and the metabotropic excitatory amino acid receptor antagonist (1SS, 3 R)-1-aminocyclopentane-t,3-dicarboxylic acid (MCPG, 1 mM) had no effect on paired-pulse depression in the presence of CGP 55845 (10 M)In conclusion since all CGP compounds are GABA-B antagonists at postsynaptic sites these findings suggest that there may be differences between the pre- and postsynaptic GABA-B receptors. Apart from presynaptic GABA-B receptors there appear to exist additional mechanisms involved in paired-pulse depression that remain to be elucidated. Correspondence to: H.-R. Olpe at the above address     

In vivo release of endogenous GABA in the cat hypothalamus

Summary The posterior hypothalamus of anaesthetized cats was superfused with artificial cerebrospinal fluid through a push-pull cannula and the release of endogenous GABA from the hypothalamus into the superfusate was studied. The resting release of GABA varied rhythmically, since phases of high rate of release were separated from each other by phases of low rate of release. The time interval between two adjacent phases of high rate of release was about 70 min. Electrical stimulation of the posterior hypothalamus with the tip of the cannula enhanced the rate of release of GABA in a frequency-dependent way. Superfusion of the hypothalamus with CSF which contained a high concentration of potassium and a low concentration of sodium increased the rate of release of GABA; this effect was dependent on the presence of calcium ions in the superfusing fluid. Pretreatment of the cats with reserpine reduced the levels of GABA in hypothalamus and rest of brain and the concentration of GABA in the superfusate as well. Stimulation of the locus coeruleus with a bipolar electrode elicited an increased release of GABA in the hypothalamus.Part of the results was presented at the Spring Meeting of the German Pharmacological Society, Mainz, March 1978This work was supported by the Deutsche Forschungsgemeinschaft     

Functional evidence for GABA as modulator of the contractility of the longitudinal muscle in mouse duodenum: role of GABA(A) and GABA(C) receptors

We investigated, in vitro, the effects of γ-aminobutyric acid (GABA) on the spontaneous mechanical activity of the longitudinal smooth muscle in mouse duodenum. GABA induced an excitatory effect, consisting in an increase in the basal tone, which was antagonized by the GABA_A-receptor antagonist, bicuculline, potentiated by (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA), a GABA_C-receptor antagonist and it was not affected by phaclofen, a GABA_B-receptor antagonist. Muscimol, GABA_A receptor agonist, induced a contractile effect markedly reduced by bicuculline, tetrodotoxin (TTX), hexamethonium and atropine. Cis-4-aminocrotonic acid (CACA), a specific GABA_C receptor agonist, induced an inhibitory effect, consisting in the reduction of the amplitude of the spontaneous contractions and muscular relaxation, which was antagonised by TPMPA, GABA_C-receptor antagonist, TTX or N^ω-nitro-l-arginine methyl ester (L-NAME), nitric oxide (NO) synthase inhibitor, but not affected by hexamethonium. In conclusion, our study indicates that GABA is a modulator of mechanical activity of longitudinal muscle in mouse duodenum. GABA may act through neuronal presynaptic receptors, namely GABA_A receptors, leading to the release of ACh from excitatory cholinergic neurons, and GABA_C receptors increasing the release of NO from non-adrenergic, non-cholinergic inhibitory neurons.     

Involvement of central GABA receptors in the regulation of the urinary bladder function of anaesthetized rats

Summary Cystometric recordings were performed in pentobaribitone anaesthetized rats and the effects of gammaaminobutyric acid (GABA) mechanisms on urinary bladder function were evaluated as their influence on a bladder hyperactivity induced by 1-dihydroxyphenylalanine (l-DOPA) after peripheral decarboxylase inhibition. The bladder response was inhibited by intracerebroventricular (i.c.v., 4th ventricle) injections of GABA (250 g), muscimol (0.2 g) and glycine (1,000 g) as well as by systemically administered muscimol (4 mg/kg) and diazepam (2 mg/kg). Intravenous (i.v.) bicuculline, but not i.v. strychnine, antagonized the inhibitory actions of intraperitoneal (i.p.) and i.c.v. muscimol and i.v. diazepam while the opposite was true for the inhibitory action of i.c.v. glycine. In rats not pretreated with l-DOPA, i.p. administration of bicuculline (4 mg/kg) after 15 min caused prominent detrusor contractions that were prevented by an infracollicular brain transection.It is suggested that GABA synapses in the pontinemesencephalic brain region may be involved in the modulation of urinary bladder function.     

Interactions of the subthalamic nucleus and the subpallidal area in oro-facial dyskinesia: role of GABA and glutamate

Previous studies have shown that lowering the GABAergic activity in the sub-pallidal area (SP) in the cat results in the display of oro-facial dyskinesia (OFD). There exists an intense, mutual anatomical connection between the SP and the subthalamic nucleus and the adjoining lateral hypothalamic area (STH). The present study investigated whether the STH is also involved in OFD. Once this turned out to be true (see below), it was investigated whether the SP-specific OFD is funneled via the STH, or vice versa. Bilateral injections of low doses (50–250 ng) of picrotoxin, a non-competitive GABA antagonist, into the STH were found to elicit OFD. This effect which was quantified in terms of numbers of tongue protrusions, was dose-dependent: a bell-shaped dose-response was found (50–500 ng). The OFD elicited by the most effective dose of picrotoxin (250 ng) was significantly antagonized by muscimol, a specific GABA_A agonist, in a dose (50 ng) which itself was ineffective, indicating GABA specificity. In addition, it was found that OFD elicited by local injections of picrotoxin (250 ng) into the STH was significantly attenuated by SP injections of the broad spectrum glutamate antagonist kynurenic acid in a dose (1000 ng) which itself was ineffective, but not by muscimol (100 ng), indicating that the STH-elicited OFD needs an intact and functioning glutaminergic, but not GABAergic, transmission process in the SP for its expression. Finally, it was found that OFD elicited by picrotoxin injections (500 ng) into the SP was significantly attenuated by muscimol injections (50 ng) into the STH, indicating that the SP-elicited OFD needs an intact and functioning GABAergic transmission process in the STH for its expression.     

Furosemide modulation of GABA(A) receptors in dopaminergic neurones of the rat substantia nigra

Furosemide is a diuretic which has been shown to decrease recombinant GABA(A) receptor (GABA(A)R)-mediated currents and also to block epileptiform discharges. Here, we show that furosemide actions on GABA(A)Rs of rat substantia nigra dopaminergic neurones depend on both furosemide and GABA(A)R agonist concentrations. The whole-cell currents induced by low concentrations of GABA (5 microM) or by the selective GABA(A)R agonist isoguvacine (7-25 microM) were enhanced by 200 microM furosemide. However, furosemide did not affect GABA(A)R currents induced by 60 microM isoguvacine and even decreased those induced by 200 microM isoguvacine. At the single-channel level, furosemide had comparable effects. It increased the open time proportion with 7 microM isoguvacine but had no significant effect on the open time proportion with 60 microM isoguvacine. These effects resulted from a differential action on the multiple conductance levels activated by GABA(A)R agonists. The concentration-response relationship to isoguvacine in the whole-cell mode revealed the presence of a high and a low apparent affinity GABA(A)R population (EC(50) 4.8 vs 89 microM). These two populations of receptors coexist in the same dopaminergic neurone. They are both furosemide-sensitive and may represent different GABA(A)R subunit assemblies.     

Effect of GABA Analogues on Blood Pressure and Central GABA Metabolism in the Rat

Abstract: Gamma aminobutyric acid (GABA) and different GABA analogues were examined for their cardiovascular actions and their influence on striatal dopamine (DA) levels and GABA accumulation after aminooxyacetic acid (AOAA). Gamma hydroxybutyric acid (GHBA) and baclofen caused hypertension and tachycardia after systemic as well as intracerebroventricular administration, while the opposite was true for GABA and muscimol. The hypertension after GHBA and baclofen was not reduced by picrotoxin or bicuculline and was not influenced by varying GABA levels by 3-mercaptopropionic acid (3-MPA)or AOAA. GHBA and muscimol but not baclofen reduced GABA accumulation induced by AOAA. Picrotoxin in a subconvulsive dose increased GABA accumulation and antagonized the inhibition after GHBA or muscimol. Bicuculline and a moderate dose of picrotoxin tended to decrease GABA accumulation by themselves and if anything augmented the effects of GHBA and muscimol. GHBA and baclofen but not muscimol in combination with AOAA increased DA levels, which was not prevented by picrotoxin or bicuculline. We conclude that the cardiovascular actions of GHBA and baclofen are probably not mediated by mechanisms identical to those of muscimol or exogenous GABA. In view of the biochemical results their actions would however be compatible with a concept of different GABA receptors.     

Weak effects of local and systemic administration of the GABA uptake inhibitor,SK&F 89976, on extracellular GABA in the rat striatum

Summary The effects of local and systemic administration of the potent GABA uptake inhibitor, SK&F 89976, on GABA overflow from the striatum of conscious rats were investigated in brain dialysis experiments. Administration of the compound via the dialysis probe at concentrations of 25 or 100 gmol/l significantly increased basal GABA overflow about 2-fold. Overflow evoked by 104 mmol/l K⁺ remained unaltered at the lower and was almost doubled at the higher concentration; this increase did, however, not reach statistical significance.Given systemically at 50 mg/kg i.p., a dose which is severalfold higher than those which exhibit anticonvulsant effects, SK&F 89976 caused a significant enhancement of K⁺-stimulated GABA overflow by about a factor of 2; the lower dose of 20 mg/kg i.p. was not effective. Basal GABA overflow was not significantly increased by either dose. These results suggest that the marked effects of nipecotic acid on basal GABA overflow reported by several authors seem to be related to GABA displacement rather than uptake inhibition, and that uptake inhibition does not improve the interpretability of measurements of GABA release by brain dialysis. They neither support the idea that the relative insensitivity of extracellular GABA to low Ca²⁺ and tetrodotoxin is indirectly due to very efficient removal of GABA by neuronal and/or glial uptake, leaving only residual amounts to be measured. Send offprint requests to P. Waldmeier at the above address     

Cardiovascular effects of intracerebroventricular GABA,glycine and muscimol in the rat

Summary Intracerebroventricular (i.c.v.) injections of gammaaminobutyric acid (GABA, 125–2,000 g), glycine (250–2,000 g) and muscimol (0.5–4 g) caused dose-dependent reductions of blood pressure and heart rate in conscious rats. Low doses of muscimol (<0.12 g) were hypertensive. The cardiovascular depression induced by GABA was antagonized by bicuculline (3.5 mg/kg i.p.), while that induced by glycine was counteracted more effectively by strychnine (0.7 mg/kg i.v.) than by bicuculline. The cardiovascular response to GABA, but not to glycine, was potentiated by pretreatment with pentobarbitone (50 mg/kg i.p.). It was prolonged by diazepam (5 mg/kg i.p.) and aminooxyacetic acid (AOAA, 25 mg/kg i.p., 4h) but not by AOAA (1 h) or nipecotic acid (1–100 g i.c.v.). Following treatment with d-amphetamine (5 mg/kg i.p.) or reserpine (10 mg/kg i.p., 6h) the cardiovascular depression induced by GABA was attenuated. Propranolol (2.5+2.5 mg/kg i.v. + s.c.) or atropine (2 mg/kg i.v.) alone partially counteracted and in combination completely prevented the negative chronotropic response to GABA. Neither central noradrenaline depletion by means of -MMT (after carbidopa) and -MT nor pretreatment with phenoxybenzamine (20 g i.c.v.) influenced the response to GABA. The arterial hypotension induced by GABA was prolonged after a high dose of atropine (10 mg/kg i.v.) but appeared attenuated by a low dose (2 mg/kg i.v.) or by physostigmine (0.1 mg/kg i.v.). Central serotonergic activation by means of 5-hydroxytryptophan after benzerazid antagonized the cardiovascular actions of GABA. Spiroperidol (0.05 mg/kg i.v.) and apomorphine (1 mg/kg i.v.) did not affect the blood pressure reduction in response to GABA.It is concluded that i.c.v. GABA causes cardiovascular depression by activation of GABA receptors and that the response is mediated by the sympathetic and vagal systems. There were no indications for an involvement of central noradrenergic of dopaminergic mechanisms while a decreased central cholinergic and an increased serotonergic activity possibly contribute to the cardiovascular effects of GABA.     

Unilateral injection of GABA agonists in the superior colliculus: Asymmetry to tactile stimulation

A unilateral microinjection of each one of three different GABA agonists (Muscimol: 1.4 nmoles; Baclofen: 0.8 nmole; THIP: 10.7 nmoles) into the superior colliculus was found to result in a reversible asymmetry in the rat's responsiveness to tactile stimulation. The rat was hyporeactive to stimulations applied contralaterally and hyperreactive to stimulations applied ipsilaterally to the infusion site. Furthermore, the rat showed ipsiversive turning in response to tactile stimulation applied either ipsi- or contralaterally to the infusion site. The results are discussed in relation with motor and sensory asymmetry produced by unilateral manipulations affecting the striato-nigro tectal system.