Central GABAergic System Research Articles

Effect of pentobarbital and chlordiazepoxide on the central pressor action of angiotensins in normo- and hypertensive rats

Pentobarbital and chlordiazepoxide administered intracerebroventricularly (i.c.v) attenuated dose dependently the pressor action of i.c.v. angiotensin II and angiotensin III in the conscious spontaneously hypertensive rat (SHR) and the normotensive control Wistar Kyoto rat (WKY). Attenuation of the pressor action by the two drugs was more marked in the WKY than in the SHR. Based on the fact that both drugs act via the γ-aminobutyric acid (GABA) receptors, the data support the suggestions (i) that a central GABAergic system regulates blood pressure, (ii) that there is probable dysfunction of the GABA receptors in SHR.

Melatonin as an anxiolytic in rats: time dependence and interaction with the central GABAergic system

Anxiolytic and pro-exploratory melatonin properties were assessed in rats using a plus-maze procedure. Both melatonin (1 mg/kg) and diazepam (0.5 mg/kg) showed a significant diurnal variation to decrease anxiety and to promote exploratory behavior. Melatonin displayed anxiolytic activity at night, with absence of effects at noon and a weak activity at the beginning of the light phase. Melatonin pro-exploratory activity was found only at night. Diazepam exerted significant anxiolysis during the night, with less activity during the day. Diazepam pro-exploratory activity was found during the night only. A dose-response study carried out by injecting 1–20 mg/kg melatonin at 12:00 or 18:00 h indicated that melatonin activity was greatest at 18:00 h. Diazepam was anxiolytic at both times, and pro-exploratory at 18:00 h only. Melatonin activity was blunted by administration of the benzodiazepine antagonist, flumazenil.

Effects of central and peripheral type benzodiazepine ligands on growth hormone and gonadotropin secretion in male rats.

The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.

Lack of effects of handling habituation and swimming stress on ethanol-induced motor impairment and GABAA receptor function.

The effects of handling habituation and swimming stress on ethanol-induced motor impairment and the GABAA receptor function were studied in adult male Wistar rats. Daily handling for 3 to 5 weeks had no significant effect on ethanol-induced motor impairment in the tilting plane test or on the activity of the rats in the elevated plus-maze test of anxiety. Plasma corticosterone concentrations were greatly elevated by the tilting plane test procedure, irrespective of handling habituation. Acute, 10-min swimming stress at +25 degrees C produced an elevated plasma corticosterone concentration comparable to that produced by the tilting plane test, again irrespective of handling habituation. In cerebrocortical homogenates, short-term swimming stress had no statistically significant effect on the muscimol stimulation of the GABAA receptor-mediated 36Cl- flux in handled and non-handled animals. Thus, handling habituation and stress had only minor effects on the activity of the central GABAergic systems in acute tests at behavioural and biochemical levels.

O-068 - Pregnanolone, a metabolite of progesterone, increases gastric acid secretion via central GABAergic system in rats.

O-068 - Pregnanolone, a metabolite of progesterone, increases gastric acid secretion via central GABAergic system in rats.

Effects of ceruletide and CCK-8 on the central cholinergic and gabaergic systems in mice

Effects of ceruletide and CCK-8 on the central cholinergic and gabaergic systems in mice

Chronic Central GABAergic Stimulation Attenuates Hypothalamic Hyperactivity and Development of Spontaneous Hypertension in Rats

To determine whether chronic central gamma-aminobutyric acid (GABA) stimulation would attenuate development of hypertension, tail-cuff systolic pressures were measured in male spontaneously hypertensive rats (SHR) treated with either an inhibitor of GABA breakdown (valproate, VPA), or a GABA-receptor agonist (muscimol). When VPA was injected intraperitoneally (i.p.) daily for 4 weeks, tail-cuff systolic pressures were decreased during the last 2 weeks. On the other hand, continuous infusion of muscimol into the lateral cerebral ventricle for 14 days using an osmotic minipump decreased systolic pressures throughout the 10-day observation period. During terminal experiments under urethane anesthesia, pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were reduced in VPA- or muscimol-treated SHR. Pressor responses to intravenously (i.v.) injected norepinephrine (NE) were unaltered by either treatment, indicating that diminished pressor responsiveness to hypothalamic stimulation was not due to diminished cardiovascular reactivity. Regardless of either VPA acid or muscimol treatment, basal blood pressure (BP), heart rate (HR), and responses to hypothalamic stimulation were lower in normotensive Wistar-Kyoto controls (WKY) than in SHR. In addition, chronic treatment with either drug had weaker hypotensive and hypothalamic depressant effects in WKY than in SHR. Our results suggest that in SHR the central GABAergic system is impaired and that chronic treatment with GABAergic stimulants can attenuate development of spontaneous hypertension by reducing hypothalamic overactivity.

On the Relationship between Noradrenergic Stimulatory and GABAergic Inhibitory Systems in the Control of Luteinizing Hormone Secretion in Female Rats

The relationship between noradrenergic (NA) stimulatory and gamma-aminobutyric acid (GABA)-mediated inhibitory systems in the control of luteinizing hormone (LH) secretion was examined in ovariectomized rats. Stimulation of the GABAA receptor by an intraventricular (i.c.v.) administration of a GABAA agonist, muscimol, significantly attenuated the LH secretory response to the subsequent i.c.v. injection of NA in estrogen-primed rats. On the other hand, blockade of alpha-adrenergic receptors by phenoxybenzamine did not interfere with the stimulatory effect of an i.c.v. injection of a GABAA antagonist bicuculline. In a different series of experiments, ovariectomized animals had been treated with i.c.v. injections of 6-hydroxydopamine (6-OHDA) or its vehicle. An i.c.v. injection of muscimol or phentolamine significantly inhibited the estrogen-induced surge of LH secretion in vehicle-treated rats. Muscimol also inhibited the existing pulsatile LH secretion in vehicle-treated, estrogen-unprimed animals. In animals in which hypothalamic NA terminals were presumed to be destroyed by 6-OHDA, the inhibitory effect of phentolamine was significantly diminished while that of muscimol was unaltered. These results permit the following conclusions: (1) the central GABAergic system inhibits LH secretion via GABAA receptors; (2) this inhibitory GABA system operates without mediation by the NA system, and (3) the GABAergic non-NA-mediated system can affect physiological patterns of pituitary LH secretion in female rats.

Acute and long-lasting effects of peripheral injection of caerulein and CCK-8 on the central GABAergic system in mice

Acute and long-lasting effects of peripheral injection of caerulein (CLN) and cholecystokinin octapeptide (CCK-8) on the gamma-aminobutylic acid (GABA) content and the GABA accumulation by aminooxyacetic acid (AOAA) in the discrete brain regions of mice were examined. The content and accumulation of GABA in the striatum, hypothalamus, and frontal cortex was measured with high performance liquid chromatography with electrochemical detection (HPLC-ECD). The GABA content slightly decreased in the striatum 60 min after CLN and CCK-8 were administered, whereas it slightly increased in the hypothalamus and frontal cortex. Moreover, with CLN and CCK-8, the GABA accumulation after AOAA treatment decreased in the striatum and hypothalamus 30 min after injection. Meanwhile, when administering CLN, the GABA content as well as the GABA accumulation after AOAA treatment increased in the striatum and frontal cortex 1 day after injection, and continued to increase the second and third day in the striatum. These results showed that peripheral injection of CLN and CCK-8 had effects on the central GABAergic system with local specific actions, and also the long-lasting and time-dependent biphasic effects of CLN.

Changes in the central GABAergic system after acute treatment with corticosterone.

The acute effects of corticosterone (0.5 and 1 mg/kg, i.p.) upon the GABAergic system have been investigated. While no changes were detected after treatment with corticosterone 0.5 mg/kg, the administration of 1 mg/kg lowered the levels of gamma-aminobutyric acid (GABA) (29%) in the mediobasal hypothalamus either 30 or 60 min after injection in both young (3-4 weeks old) and adult (7-8 weeks old) rats. No changes were found in the frontal cerebral cortex. Only in young rats did the administration of corticosterone (1 mg/kg, 30 min) reduced GABA levels in the corpus striatum (34%). In young rats this dose of corticosterone: 1. did not affect the activity of the enzymes of the metabolism of GABA (GAD and GABA-T); 2. reduced neuronal 3H-GABA uptake in the corpus striatum (30%) and in the mediobasal hypothalamus (46%), and increased it in the frontal cortex (2-fold); 3. enhanced the turnover of GABA (2-fold) in the corpus striatum. These values were unaffected by 0.5 mg/kg. Corticosterone 0.5 and 1 mg/kg did not alter non-neuronal 3H-GABA uptake. These findings show an area-related and age- and dose-dependent response of the GABAergic pathways to acute corticosterone treatment. This is discussed in relation to the age-related sensitivity to the environmental stimuli which cause this release of corticosteroids. The stimulation of GABAergic function which occurs mainly in the corpus striatum as estimated from the increase in its turnover may be related to the postulated anticonvulsant role of corticosteroids.

Possible involvement of the central GABAergic system in pentobarbital-stimulated gastric acid secretion in the perfused rat stomach preparation

The effects of several convultants and diazepam on pentobarbital-stimulated gastric acid secretion were studied in the perfused stomach of rats under urethane anesthesia. Picrotoxin and pentylenetetrazol, GABA antagonists, and 3-mercaptopropionic acid, an inhibitor of GABA biosynthesis, strongly inhibited the pentobarbital-stimulated gastric acid secretion. The secretory action of pentobarbital was transiently depressed by strychnine, a glycine antagonist, and by bicuculline, a GABA antagonist; vigorous convulsions were observed in these rats. Diazepam had no effect on the pentobarbital-stimulated gastric acid secretion. These findings suggest that the potentiation of central GABAergic mediation by pentobarbital could be a main mechanism involved in pentobarbital-stimulated gastric acid secretion.

Effect of nicotine on central GABAergic system

1. 1. The acute and chronic effects of nicotine (1.5 mg/kg/day) on the striatal and mesolimbic GABAergic systems were examined in the rat. 2. 2. Despite altering the striatal DAergic activity, neither acute nor chronic administration of nicotine significantly affected the GABAergic system. 3. 3. The nicotine treatment did not alter the ability of muscimol to inhibit the hyperactivity elicited by apomorphine. 4. 4. Similarly, the levels of GABA in striata and nucleus accumbens remained unchanged.

Operant behavior and reactivity to the anticonflict effect of diazepam in perinatally undernourished rats

Adult female rats perinatally submitted to a protein deprivation schedule and then recovered with balanced chow, were tested under two different operant schedules of reinforcement, variable ratio-20 (VR-20) and differential reinforcement of low rate-5 sec (DRLR-5″). Undernourished animals showed higher response rates in the VR-20 schedule and a lower efficiency in the DRLR-5 as compared to controls, effects that could be attributed to the hyperreactivity to aversive or stressful situations characteristic of these animals. As the behavioral responses to anxiogenic stimuli are sensitive to drugs acting on the GABAergic system, the functionalism of the central GABAergic system in the undernourished group was evaluated by studying the reactivity to the anticonflict effect of diazepam in two conflict tests. Undernourished animals had a lower response to the anticonflict effect of diazepam when compared to control rats. The altered reactivity to the anticonflict effect of diazepam between both groups suggest that some aspects of the GABAergic neurotransmission may be involved in the behavioral abnormalities present in adult rats that were undernourished at perinatal age.

Inhibition of carrageenin-induced pedal oedema in rats by immobilisation stress.

The effect of immobilisation stress on acute pedal inflammation induced by carrageenin, and the mechanism of stress-induced anti-inflammatory effect, were investigated in male Wistar strain albino rats. Carrageenin-induced pedal inflammation oedema was attenuated by immobilisation stress in a time-dependent manner, when the rats were restrained for 30 min, 1 h, and 2 h immediately after the induction of the inflammation. Pentobarbitone exhibited significant anti-inflammatory effect of its own in an anaesthetic dose and also inhibited stress (1 h)-induced attenuation of the inflammation. Likewise, lignocaine, injected behind the knee joint of the inflamed limb, attenuated the inflammation and also inhibited the stress-induced anti-inflammatory effect. These findings indicate the importance of the central nervous system (CNS) and the afferent/efferent neural pathways from and to the inflammatory site, in inflammation and in stress-induced anti-inflammatory effect. Earlier studies from this laboratory have shown that the central noradrenergic, histaminergic, serotonergic and GABA-ergic neurotransmitter systems have a modulatory anti-inflammatory effect on carrageenin-induced pedal oedema. Since all these neurotransmitter systems have been reported to be activated by stress, their role was assessed in the inflammation-attenuation effect of immobilisation stress. The present studies indicate that, of these neurotransmitters, only the central noradrenergic system is involved in the anti-oedema effect of stress. Endogenous opioid peptides may also be involved in the stress-inflammation interaction, since naloxone inhibited the stress effect. Bilateral adrenalectomy and peripheral chemical sympathectomy, induced by i.p. administration of 6-hydroxydopamine, augmented carrageenin oedema and antagonised the stress-induced anti-inflammatory effect. However, metyrapone, an inhibitor of endogenous corticoid synthesis, failed to inhibit the stress effect. These findings indicate that the sympatho-medullary system, which is known to be activated during stress, is responsible for the observed anti-inflammatory effect of immobilisation stress, rather than augmented release of adrenal corticoids. It is suggested that the observed inflammation reducing effect of immobilisation stress is a consequence of increased central noradrenergic and peripheral sympatho-medullary activity.

Does pipecolic acid interact with the central GABA-ergic system?

Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neurones in situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones. Furthermore, L-PA proved to have no affinity for any of the three components of the GABA-benzodiazepine-chloride channel receptor complex. However, using a modification of published methods a weak affinity for the GABA-B receptor site was demonstrated (IC50 = 1.8 X 10(-3) M). L-PA showed no anticonvulsive activity in several tests; in particular, it did not protect mice from seizures induced by inhibition of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). L-PA had a very weak action on brain GABA levels of mice, and did not modify the rate of GABA synthesis. In conclusion, these results are not compatible with a strong in vivo interaction between L-PA and GABA-mediated inhibitory transmission.

GABAergic influences on barbital withdrawal induced convulsions.

Animals which had been long-term treated with increasing concentrations of sodium barbital in the drinking water were killed 30 min or 72 hr after the last day of treatment, to determine striatal GABA levels and turnover rate. The effects of pentobarbital administration on GABA metabolism of rats withdrawn or not withdrawn from barbital were also studied. Barbital withdrawal induced a significant decrease in striatal GABA levels and also in the turnover rate after pentobarbital treatment. The latter effect was greater in rats killed 72 hr after drug removal. In control animals, pentobarbital treatment increased striatal GABA levels but did not affect the turnover rate. Barbital removal also made the rats less responsive to the effects of pentobarbital on striatal GABA levels. These results suggest the participation of a central GABAergic system in barbital withdrawal convulsions.

Enhanced depressor effect of muscimol in the DOCA/NaCl hypertensive rat: evidence for altered GABAergic activity in brain.

To elucidate the role of the central gamma-aminobutyric acid (GABA) system in the maintenance of deoxycorticosterone (DOCA)NaCl hypertension, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), and epinephrine (EP) to intracerebroventricular (ICV) administration of muscimol, a GABA agonist, and the responses of MAP to bicuculline, a GABA antagonist, and to clonidine, an alpha 2-adrenoceptor agonist known to lower blood pressure by inhibiting sympathetic tone, were examined in conscious, unrestrained 4 week DOCA/NaCl hypertensive rats and age-matched uninephrectomized control rats. Muscimol (50-1000 ng/300 g, ICV) caused dose-dependent decreases in MAP which were greater in DOCA/NaCl rats than in controls. Basal plasma NE and EP were significantly higher in DOCA/NaCl rats than in controls. Muscimol (1000 ng/300 g, ICV) induced decreases in plasma EP which were greater in DOCA/NaCl rats than in controls without changing NE levels in either group. Bicuculline (3 micrograms/300 g, ICV) caused increases in MAP which were the same in both groups. The depressor response to clonidine (5 micrograms/300 g) was greater in DOCA/NaCl rats than in controls. These results suggest that the activity of the central GABAergic system is altered in the rat with established DOCA/NaCl hypertension and that the alteration in central GABAergic function may be related to the increased sympathoadrenal activity and the maintenance of hypertension in this model.

Effects of naloxone on methamphetamine and apomorphine stereotypy and on haloperidol catalepsy in rats.

Pretreatment with the opiate antagonist naloxone, at 1.25-5 mg/kg, increased the intensity of methamphetamine stereotypy, had no effect (over a range of 0.3125-5 mg/kg) on apomorphine stereotypy, and antagonized haloperidol catalepsy in rats at 1.25-5 mg/kg. It is suggested that naloxone, by blocking the opiate receptors located on the nigro-striatal and mesolimbic dopamine (DA) nerve terminals, releases the DA systems from endogenous inhibition, presumably caused by endogenous opiate systems, and thereby potentiates methamphetamine stereotypy and antagonizes haloperidol catalepsy. However, the possibility that naloxone might have affected methamphetamine stereotypy and haloperidol catalepsy by modulating the activity of the central noradrenergic and GABAergic systems, which are reported to influence dopaminergically mediated behaviours, also needs to be considered.

THIP inhibits feeding behavior in fasted rats.

The effects of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP) were compared with those of d-amphetamine and GABA in fasted rats. Intravenously-administered THIP produced a dose-dependent decrease in food consumption (ED50 congruent to 1.5 mg/kg) by an action that was not reversed by prior subcutaneous or simultaneous intravenous (IV) injection of bicuculline. d-Amphetamine-SO4 also produced a decrease in food consumption in this model (ED50 congruent to 0.2 mg/kg, IV). Unlike THIP, GABA (in doses up to 100 mg/kg, IV) did not produce a marked anorexigenic effect. These results provide further evidence that THIP can penetrate the "blood-brain barrier", and that central GABA-ergic systems are involved in controlling food intake.

Studies on GABA and cardiovascular function using in vivo and in vitro technics

AbstractRecent in vivo and in vitro studies regarding the involvement of GABAergic systems in cardiovascular function have been reviewed and analyzed. It seems evident, from studies conducted with various GABA agonists and GABA antagonists, that activation of central GABAergic systems reduces sympathetic outflow from the hindbrain area of mammals, thereby producing bradycardia and hypotension. As GABA agonists can relax cerebral arteries, blood‐borne GABA might also play a role in cerebrovascular regulation. Further research concerning the mechanisms involved in GABA agonist‐induced cardiovascular responses could lead to the development of agents that might be effective in treating certain cardiovascular disorders of man, such as hypertension, cerebral atherosclerosis, migraine, and stroke.