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Changes in the control of arm position, movement, and thalamic discharge during local inactivation in the globus pallidus of the monkey.

1. To examine the effect of disruption of basal ganglia output on limb stability and movement, muscimol was injected into the internal globus pallidus (GPi) of monkeys trained to make arm movements to visible or remembered targets in a two-dimensional workspace. 2. Injections of as little as 0.25 micrograms muscimol at GPi sites at which pallidal neurons with arm movement activity had been recorded were followed by drift of the contralateral arm within < 10 min. Drift was usually in the flexor direction. Injections at a few sites in or near the external pallidal segment sometimes were followed by extensor drift. 3. Drift was active (accompanied by activation of agonist muscles), but could be overcome by the animal, resulting in an oscillating movement off and on the required position. 4. The pallidal-receiving (PR) area of the thalamus was identified by recording the response of thalamic neurons to stimulation in the globus pallidus. The activity of 15 neurons identified as PR cells (n = 6) or within the PR region was recorded both before and after injection of muscimol into GPi. After the injection, the tonic discharge increased during the hold period in 47% of the cells studied. When postural drift also occurred, there was a close temporal correlation between the postinjection time at which drift occurred and the time at which the tonic discharge rate increased in thalamic neurons that were clearly related to arm movement. 5. The peak velocity of arm movements to visible or remembered visual target locations was decreased after injection of muscimol into GPi, sometimes with an increase in movement time. 6. The firing rate of PR thalamic neurons after injection of muscimol was also increased during the perimovement period. Because of the increase in the tonic discharge rate, however, the phasic movement-related change in activity could stay the same or even decrease. Postinjection changes in this movement-related phasic activity, however, were not necessarily coincident with changes in peak movement velocity. 7. Changes in reaction time were variable after injection of muscimol. In some cases it was increased, and in others decreased. The time of onset of phasic movement-related changes in the activity of PR neurons studied was not altered by the injection. 8. Our data indicate that the tonic inhibitory output of GPi, in particular to the cortical motor areas, is especially important in the maintenance of postural stability. In the absence of normal pallidal output, desired limb position can be achieved on the basis of either current or prior visual cues, but targeted movements are slowed.

Animals↗

Prenatal diazepam exposure functionally alters the GABA(A) receptor that modulates [3H]noradrenaline release from rat hippocampal synaptosomes.

In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the gamma-aminobutyric (GABA)(A) receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABA(A) receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50%) was achieved with a concentration of 30 microM, and the ED(50) was 1.7 microM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3alpha-pregnan-5alpha-ol-20-one (3alpha,5alpha-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 microM), muscimol stimulated the release of [3H]NA with an ED(50) of 0.5 microM; in the presence of 3alpha,5alpha-P (0.1 microM), the ED(50) of muscimol was 0.3 microM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3alpha,5alpha-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABA(A) receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABA(A) receptor complex. Exposure to DZ while the GABA(A) receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3alpha,5alpha-P.

Allosteric Regulation↗

In vivo studies of GABAergic effects in experimental hepatic encephalopathy.

The GABAergic agonist, muscimol, and antagonists, picrotoxin and bicuculline, have been studied in rats with chronic portacaval shunts and in rats developing hepatic encephalopathy after massive ischemic necrosis due to hepatic artery ligation within 48 hr of a portacaval shunt. After the chronic portacaval shunt and to a lesser extent in normal rats intraventricular muscimol resulted in chewing and eating behavior, ataxia and loss of balance that lasted 2 to 3 hr. Lethargy, stupor and coma did not occur. Intraventricular saline had no effect. Bicuculline i.p. lessened the effects of the muscimol. In rats developing hepatic encephalopathy, intraventricular muscimol shortened the time to precoma and coma by approximately 40%. Bicuculline i.p. counteracted this effect of muscimol significantly. However, neither bicuculline nor picrotoxin given alone altered the times to precoma (Stage III), coma (Stage IV) or death. While hepatic encephalopathy in this experimental model is susceptible to GABAergic effects, its natural progression does not appear to be due to GABA.

Animals↗

The effects of compounds related to gamma-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: extinction and successive discrimination.

In a first set of experiments rats were trained to run in a straight alley for food reward on a continuous reinforcement schedule and the running response was then extinguished. On the last 2 days of training and daily throughout extinction different groups of animals were injected IP with saline, 5 mg/kg chlordiazepoxide, 0.75 mg/kg picrotoxin, chlordiazepoxide + picrotoxin, chlordiazepoxide + 1.5 mg/kg bicuculline, 0.00125 or 0.25 mg/kg muscimol, 1 mg/kg baclofen, chlordiazepoxide + baclofen, or 0.00125 mg/kg muscimol + baclofen. Chlordiazepoxide increased resistance to extinction, a well-known anxiolytic effect. This effect was blocked by both picrotoxin and bicuculline. Picrotoxin on its own reduced resistance to extinction (an anxiogenic-like effect). Whether given alone or in combination with other drugs, muscimol and baclofen had no effect. In a second set of experiments rats were trained in a successive operant discrimination (signalled by a flashing or steady light) between components in which sucrose reward was available on a variable-interval schedule for barpressing and components in which no reward was given. Chlordiazepoxide at 10 mg/kg increased responding in both rewarded and nonrewarded components, but more in the latter than could be accounted for by change in the former. This effect is as expected with an anxiolytic drug. It was not altered by administration of bicuculline at 1.5 or 1.75 mg/kg; at 2 mg/kg bicuculline acted synergistically with chlordiazepoxide. Picrotoxin (1 and 1.5 mg/kg) also acted synergistically with chlordiazepoxide, enhancing the latter's rate-increasing effects, but only during rewarded components. Neither muscimol (0.00125 and 0.25 mg/kg) nor baclofen (0.01 mg/kg) affected response rates, whether given alone or in combination. However, baclofen in a dose of 1 mg/kg, provided it was given to rats also injected with muscimol (0.00125 or 0.25 mg/kg) at other times, significantly reduced responding during nonrewarded components (an apparently anxiogenic effect). The results of the two sets of experiments are discussed in relation to the hypothesis that anxiolytic drugs affect behaviour by increasing GABAergic inhibition.

Animals↗

GABA-receptor activation in the globus pallidus and entopeduncular nucleus: opposite effects on reaction time performance in the cat.

The possible role of GABAergic mechanisms in the control of the basal ganglia output structures, the globus pallidus (GP) and the entopeduncular nucleus (EP), was studied in cats performing a conditioned flexion movement triggered by an auditory stimulus. The effects of discrete unilateral microinjections of low doses of the GABAA receptor agonist (muscimol 5-100 ng/0.5 microliter) and antagonist (bicuculline methiodide 25-150 ng/0.5 microliter) in the GP and the EP were tested on the motor performance of eight animals trained to release a lever in a simple reaction time (RT) schedule after an auditory stimulus. Control injections in neighboring structures did not induce any effect except with five- to tenfold higher doses in the closest injection sites. The dose of 20 ng muscimol injected into the ventral and medial part of the GP produced an arrest of the performance after a few unsuccessful trials (over the RT reinforcement limit of 500 ms), while muscimol injected in sites located in the lateral GP resulted in a dose-dependent lengthening in RTs, with a concomitant increase in the force change latency. In most of the subjects, the force exerted on the lever was higher after muscimol than after vehicle injection. Force change velocity was then significantly increased. In contrast, muscimol injected in the ventral and rostral region of the EP produced a decrease in RTs or a complete cessation of responding after a high number of anticipatory responses (release of the lever before the trigger stimulus). No significant changes in the force change latency could be observed while there was a non-significant tendency for the force levels to be lowered. Bicuculline injections in the EP were found to increase RTs with a concomitant increase in force change latency and a slowness of velocity, while no significant effect was observed following injections in the GP. These results suggest that a balance between GABAergic activity in the two output nuclei of the basal ganglia, the GP and the EP, is crucial for the correct initiation and execution of the conditioned motor task.

Animals↗

Bicuculline insensitive effects of baclofen.

The action of bicuculline on the effect of baclofen and muscimol were investigated in behavioural, biochemical and binding studies in rats. Both (+/-)-baclofen (5 mg kg-1 i.p.) and muscimol (1.4 mg kg-1 i.p.) decreased motor activity and aggressiveness. In investigated doses the drugs mentioned raised DOPAC concentration in the rat striatum. (+)-Bicuculline (1.25 mg kg-1 s.c.) potentiated the behavioural effects of baclofen but failed to alter significantly those of muscimol. The DOPAC rise caused by baclofen and muscimol was not substantially affected by bicuculline. 3H-GABA binding to bicuculline insensitive GABA sites was determined in the rat striatal tissue. (+)-Bicuculline was used to suppress bicuculline sensitive GABA binding. Two GABA binding sites were revealed in the presence of calcium ions of which the low affinity site (KD = 447 nM, B max = 109 pmol g-1 protein) was affected by bicuculline whereas the high affinity site (KD = 8 nM, B max = 24 pmol g-1 protein) was not. Muscimol, GABA and (+/-)-baclofen bound in vitro to these GABA sites with IC50, 44, 49 and 431 nM respectively. The involvement of bicuculline insensitive GABA sites in the effects of (+/-)-baclofen on behaviour and dopamine metabolism is suggested.

3,4-Dihydroxyphenylacetic Acid↗

Effects of GABAergic drugs on the GABA turnover in the substantia nigra and the corpus striatum of the rat.

Changes in the endogenous GABA concentration and in GABA turnover following GABA receptor stimulation or blockade were studied in the substantia nigra and the corpus striatum of the rat. The GABA agonists, muscimol, baclofen and THIP decreased the accumulation of GABA following inhibition of GABA-alpha-ketoglutaric acid aminotransferase by gamma-acetylenic GABA (GAG) in both structures investigated. Only the effect of muscimol in the substantia nigra was inhibited by the GABA antagonist, bicuculline. Muscimol, baclofen and progabide reduced the disappearance rate of GABA in the substantia nigra following inhibition of the glutamate decarboxylase by 4-deoxypyridoxine. The endogenous GABA concentration was decreased in the corpus striatum following muscimol, THIP or baclofen, probably due to a decreased synthesis of GABA. Smaller effects were seen on the endogenous GABA concentration in the substantia nigra, since both the synthesis and the utilization of GABA were decreased by muscimol and baclofen. Thus, the turnover of brain GABA might be regulated by changes in receptor activity.

Alkynes↗

Some properties of solubilized GABA receptor.

gamma-Aminobutyric acid (GABA) receptor was solubilized from synaptic membrane of the rat brain by various detergents. Nonidet P-40, a non-ionic detergent, was found to be an effective solubilizing agent, since it caused no interference on the receptor binding assay, yielded a [3H]muscimol binding protein with a high specific activity and no aggregation, and preserved good stability of the solubilized fraction. Ammonium sulfate precipitation of the solubilized supernatant significantly increased the binding of [3H]muscimol to GABA receptor, possibly by removing heat-stable and small molecular inhibitory substances. The specific [3H]muscimol binding to the soluble fraction obtained by Nonidet P-40 treatment and subsequent ammonium sulfate precipitation, was saturable with KD 13 and 64 nM, and Bmax 3.4 and 1.8 pmol/mg protein, respectively. The enhancement of the [3H]muscimol binding by diazepam as found in synaptic membrane was also detected in the soluble fraction. Molecular weight of the [3H]muscimol binding site was determined by gel filtration on Sephadex G-200 and was calculated to be 270,000 daltons. This value was identical with that of the [3H]flunitrazepam binding site which appeared in the same solubilized fraction. These results indicate that the properties of solubilized GABA receptor are identical to those of membrane-bound GABA receptor. Furthermore, the present results suggest that both GABA and benzodiazepine receptors may reside on the same macromolecule in synaptic membrane.

Animals↗

Biochemical and functional alterations of central GABA receptors during chronic estradiol treatment.

The characteristics of GABA and benzodiazepine receptors were examined in the hippocampus, striatum and cerebral cortex of female rats at various times (up to 9 months) after the subcutaneous implantation of an estradiol pellet (10 mg). A significant decrease in the Bmax of the high-affinity binding of [3H]muscimol to membranes from these 3 regions was detected as soon as one week after the implantation. Although the characteristics of the high-affinity binding of [3H]flunitrazepam remained unaffected during the whole treatment, the stimulatory effect of GABA (and muscimol) on this binding was significantly reduced by estrogenization. The changes in GABA receptor binding appeared functionally relevant since the elevation of striatal acetylcholine levels normally induced by the peripheral administration of muscimol (5 mg/kg) was significantly lower in estradiol-treated than in control female rats. In contrast to that observed in intact female rats, the implantation of estradiol in hypophysectomized animals did not affect the characteristics of [3H]muscimol binding to hippocampal, striatal and cortical membranes. [3H]muscimol binding was also unchanged in female rats implanted with estradiol and treated chronically with bromocriptine for 3 weeks. Since both hypophysectomy and the chronic administration of bromocriptine suppressed the hyperprolactinemia normally induced by estrogenization, the down-regulation of central GABA receptors very likely involved prolactin in intact animals implanted with 17-beta-estradiol.

Acetylcholine↗

Modulation of the GABA receptor complex by a steroid anaesthetic.

The interactions of a steroid anaesthetic, alphaxalone, with the GABA receptor-ionophore complex were investigated by two different experimental approaches. In the rat cuneate nucleus slice, alphaxalone (0.1-10 microM) potentiated depolarizing responses to superfused GABA and muscimol, but not those to glycine. The potentiating effect of alphaxalone was unaltered by the benzodiazepine antagonist Ro 15-1788. Alphaxalone (0.1-30 microM) also enhanced [3H]muscimol binding to rat brain membranes in the presence of Cl-ions; the enhancing effect on [3H]muscimol binding was abolished by Triton X-100. Analysis of binding curves for [3H]muscimol indicated that the steroid anaesthetic increases the affinity for [3H]muscimol of low affinity binding sites; this property is shared by pentobarbitone. The physiologically inactive beta-hydroxy isomer of the steroid was without activity in either of the experimental situations at 30 microM. It is suggested that alphaxalone and pentobarbitone share a common mode of action on the GABA system, which may be relevant to the mechanisms by which these drugs produce anaesthesia.

Anesthetics↗

GABAergic mechanisms in nucleus tractus solitarius alter blood pressure and vasopressin release.

GABAergic agents microinjected into the nucleus tractus solitarius (NTS) influence blood pressure (BP) and plasma vasopressin (VP) levels. The direct-acting GABAergic agonist muscimol (3.75-160 pmol) microinjected bilaterally into the NTS of chloralose-anesthetized, paralyzed, ventilated rats increased BP without significantly altering heart rate. Similar results were obtained using the indirect GABA agonist nipecotic acid (10 nmol), a GABA uptake blocker. In contrast, blocking the action of GABA with bicuculline (5 pmol) elicited a small but consistent decrease in BP. Injections of the vehicle (artificial cerebrospinal fluid) into the NTS or GABAergic agents in an area lateral to the NTS did not alter BP. Unilateral injection of muscimol into the NTS did not elicit immediate pressor responses as did bilateral injections; unilateral muscimol injections following destruction of the contralateral NTS produced a pressor response similar to that seen following bilateral muscimol administration. Stimulation of GABA receptors within the NTS by either muscimol or nipecotic acid resulted in an increase in plasma VP levels. The elevated levels of plasma VP contributed to the pressor response elicited by stimulation of GABAergic receptors as evidenced by the decrease in BP observed following the intravenous administration of a VP pressor antagonist during the pressor response. These studies indicate that tonically active GABAergic mechanisms within the NTS influence BP and VP release, and provide further evidence that VP can be involved in cardiovascular responses elicited from the NTS.

Animals↗

Substance P and GABAergic effects on adrenal and autonomic function evoked by microinjections into trigeminal subnucleus caudalis in the cat.

To assess the contribution of putative neurotransmitters in mediating changes in adrenal and autonomic function evoked by activation of medullary dorsal horn neurons, microinjections of substance P, bicuculline methiodide, or muscimol were directed at various laminac of trigeminal subnucleus caudalis in the anesthetized cat. Injections of substance P (35.6 pmol) into the superficial layers (lamina I-II) of subnucleus caudalis increased the adrenal secretion of epinephrine (+8.3 +/- 2.3 ng/min, P less than 0.01), arterial pressure (+11 +/- 5.3 mm Hg, P less than 0.01), and heart rate (+19.4 +/- 4.9 beats/min, P less than 0.01) by 1 min, and increased the plasma concentration of adrenocorticotropin (+26 +/- 10 pg/ml, P less than 0.01) by 3 min. Substance P injections into the magnocellular layers (lamina III-IV) or deep magnocellular layers (lamina V-VI) had no significant effects. Microinjections of the GABAA antagonist, bicuculline methiodide (62.4 pmol), into the superficial layers of subnucleus caudalis increased the adrenal secretion of epinephrine (+4.5 +/- 3.2 ng/min, P less than 0.01) by 1 min, whereas injections of the GABAA agonist, muscimol (280 pmol), decreased the secretion (-5.8 +/- 2.8 ng/min, P less than 0.05) by 6 min. Arterial pressure increased after bicuculline (+17.8 +/- 8.2 mm Hg, P less than 0.01) and decreased after muscimol (-6.3 +/- 2.9 mm Hg, P less than 0.01) injections into the superficial layers. Injections of bicuculline or muscimol into the magnocellular layers or into the deep magnocellular layers had no effect on adrenal secretion of catecholamines or on systemic cardiovascular function. Peripheral venous concentrations of adrenocorticotropin were not affected significantly by microinjections of GABAergic agents regardless of the laminar site of injection within subnucleus caudalis. Equivalent volume injections of artificial cerebrospinal fluid into the superficial laminae of subnucleus caudalis had no significant influence on any measured variable. Substance P-evoked changes in the adrenal secretion of epinephrine were not correlated with changes in adrenal venous blood flow, whereas bicuculline- and muscimol-evoked changes in adrenal secretion of catecholamines were positively correlated with changes in adrenal blood flow (P less than 0.01). The results indicate that substance P and GABA contribute significantly to the trigeminal control of adrenal and autonomic function by acting on neurons in the superficial layers of subnucleus caudalis, a brainstem region that processes nociceptive sensory information.

Adrenal Glands↗

Changes in gamma-aminobutyric acid, mu-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens.

Discrete quinolinic acid lesions in the nucleus accumbens altered [3H]muscimol binding to gamma-aminobutyric acid receptors, [125I]neurotensin binding to neurotensin receptors, [125I]Tyr-D-Ala-Gly-NMePHe-Gly-OH binding to mu-opioid receptors, and [3H]quinuclidinyl benzilate binding to muscarinic receptors. Within lesions of the lateral accumbens core, [3H]muscimol binding increased and [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH, [125I]neurotensin and [3H]quinuclidinyl benzilate binding decreased. Lesions of the medial nucleus accumbens resulted in decreased [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH and [3H]quinuclidinyl benzilate binding while no alterations were observed for [3H]muscimol or [125I]neurotensin binding. These data support anatomical distinctions between medial and lateral nucleus accumbens. Destruction of intrinsic neurons in the dorsomedial nucleus accumbens core increased [3H]muscimol binding in the dorsal rim of the ventral pallidum and the rostral globus pallidus without altering [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH binding. Destruction of neurons in the lateral nucleus accumbens core or medial shell did not alter [3H]muscimol binding in the ventral pallidum. The lack of upregulation in gamma-aminobutyric acid receptors suggests that the gamma-aminobutyric acid-containing projection from the dorsomedial core to the dorsal rim of the ventral pallidum differs from the projection from the lateral accumbens core and medial shell to the more ventral regions of the pallidum. Fluoro-gold retrograde tracer histochemistry confirmed the specific projection from the dorsomedial core to the dorsal ventral pallidum; and from the shell of the nucleus accumbens to more ventral regions of the ventral pallidum.

Animals↗

Analgesic properties of the GABA-mimetic THIP.

The analgesic properties of the muscimol analogue THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in laboratory animals were compared with those of baclofen, morphine and muscimol. THIP was active orally and parenterally and resembled muscimol qualitatively in its actions. Quantitatively, THIP and baclofen were 2--3 times less potent than morphine and 5--15 times less potent than muscimol. The analgesic effects of THIP, baclofen and muscimol were not reversed by naloxone or bicuculline.

Analgesics↗

Gabaergic stimulation inhibits central actions of angiotensin II: pressor responses, drinking and release of vasopressin.

In conscious rats, intracerebroventricular (i.c.v.) treatment with the GABA agonist muscimol (1-100 ng) suppressed the pressor responses to ANG II (100 ng i.c.v.) in a dose-dependent and reversible fashion. Treatment i.c.v. with GABA (1-500 micrograms) produced a similar but shorter inhibition. Inhibition of endogenous GABA degradation with amino-oxyacetic acid (AOAA, 30 mg/kg i.p.) markedly reduced the pressor responses to ANG II (10-1000 ng i.c.v.) with a recovery period of 24 h. This inhibition was reversed by the GABA antagonist bicuculline (1 microgram i.c.v.). Muscimol (100 ng i.c.v.) did not significantly attenuate the pressor responses to i.c.v. histamine (10 micrograms). Pretreatment with muscimol (100 ng i.c.v.) drastically reduced the drinking responses to i.c.v. ANG II (500 ng) and increased the latency to drink. Muscimol also suppressed drinking induced by carbachol (50 ng i.c.v.). Muscimol (10-1000 ng i.c.v.) inhibited the ANG II (100 ng i.c.v.)-induced release of AVP from the pituitary gland with complete suppression of the response at the highest dose. Our results demonstrate that the GABAergic system exerts an inhibitory control on pathways mediating the various central actions of ANG II, which appears to be most specific for the ANG II-induced pressor responses.

Aminooxyacetic Acid↗

Antagonism of flurazepam and other effects of Ro15-1788, PK8165 and Ro5-4864 on the GABA-A receptor complex in rat cuneate nucleus.

In slices of rat cuneate nucleus, responses to the GABA-A receptor agonist muscimol were potentiated by flurazepam. The maximal potentiation by 1 microM flurazepam was antagonized by the neuronal benzodiazepine receptor ligand Ro15-1788 3 microM, by the quinoline derivative PK8165 0.1 microM and by the peripheral-type benzodiazepine receptor ligand Ro5-4864 0.1 microM. Another ligand for the peripheral-type benzodiazepine receptor, PK11195 10 microM, enhanced the potentiating effect of a submaximal concentration of flurazepam 0.1 microM and prevented the antagonism of flurazepam by Ro5-4864. At much higher concentrations of these drugs, additional effects were seen. Ro15-1788 30 microM and PK11195 30 microM each caused small potentiations of muscimol while Ro5-4864 30 microM caused a small antagonism. Ro15-1788 30 microM, PK8165 100 microM and Ro5-4864 30 microM all antagonized the potentiation of muscimol by pentobarbitone 10 microM; also, PK8165 and Ro5-4864 enhanced the potency of picrotoxin as an antagonist of muscimol. It is concluded that both Ro5-4864 and PK8165 have several distinct effects on the GABA-A receptor complex, all of which could result in reduced responses to muscimol.

Animals↗

The central pressor actions of substance P are inhibited by GABA.

The influence of GABA-ergic stimulation on the centrally evoked pressor and tachycardic responses to substance P (SP) was investigated in conscious rats. Intracerebroventricular (i.c.v.) pretreatment with the potent GABA agonist muscimol attenuated the pressor responses to i.c.v. administered SP in a dose-dependent and reversible fashion. Inhibition was maximal 5-60 min after muscimol injection and lasted up to 3 h. In contrast, the increases in heart rate in response to i.c.v. administered SP were not consistently inhibited by muscimol. Central pretreatment with muscimol prevented the increase of plasma adrenaline but not of plasma noradrenaline in response to i.c.v. administered SP. Our results demonstrate that the GABA-ergic system can exert an inhibitory control on pathways mediating the central pressor actions of SP. The selective inhibition of adrenaline secretion by muscimol implies that suppression of sympathetic outflow to the adrenal gland may be involved as an important mechanism. In addition, our findings point to a dissociation between pathways mediating the pressor and tachycardic effects of SP.

Animals↗

On the mechanism by which dopamine inhibits prolactin release in the anterior pituitary.

An in vitro perfusion system was used to assess the effects of chloride channel blockers, dopamine (DA) receptor agonists and antagonists, and GABA receptor agonists and antagonists on prolactin release from the mouse anterior pituitary. Dopamine and muscimol inhibited prolactin release (IC50 = 6 X 10(-8)M and 10(-5)M respectively). The GABA receptor antagonist bicuculline blocked the inhibition of prolactin release by muscimol but not dopamine. The dopamine receptor antagonist chlorpromazine blocked the dopamine- but not muscimol-induced inhibition of prolactin release. Haloperidol, however, reversed both the muscimol and dopamine induced inhibition of prolactin release. Furthermore, the chloride channel blocker picrotoxinin blocked the inhibition of prolactin release elicited by both dopamine and muscimol. These later results suggest that the anterior pituitary dopamine receptor which mediates the inhibition of prolactin release may be coupled to a picrotoxinin sensitive chloride ionophore and that haloperidol may affect the function of both DA and GABA receptors in the anterior pituitary.

Animals↗