Activation Of GABAergic Receptors Research Articles

Effect of coadministration of the GABAB agonist baclofen and the 5-HT2C agonist Ro60-0175 on the expression of amphetamine-induced locomotor sensitization.

GABAB and 5-HT2C agonists are effective in attenuating the behavioral effects of psychostimulants. However, they induce adverse side effects when used in high doses. The previous evidence has suggested that the 5HT2C receptor activation effect could be produced by an increased release of GABA in the ventral tegmental area (VTA) and the consequent activation of GABAergic receptors. Therefore, the objective of this study was to evaluate the effects of joint administration of an intermediate dose of the GABAB agonist baclofen (3.0mg/kg) with different doses of the 5HT2C agonist Ro60-0175 (0.3, 1.0, and 3.0mg/kg) on the locomotor sensitization expression induced by the repeated administration of amphetamine (1.0mg/kg). Our results showed an attenuation of the expression of sensitization in a dose-dependent manner with both agonists. In both cases, we observed a complete blockade at the highest dose. In addition, the intermediate dose of baclofen increased the effects of the three doses of Ro60-0175. These results support the role of the joint action of GABAB and 5-HT2C receptors in the effects of psychostimulants. However, it remains to be explored whether the observed effect can be attributed to receptors located in the VTA or the nucleus accumbens.

Modulation of Puberty Terms and Sexual Behavior of Rats after Prenatal Exposure to Methyldopa, Phenibut, and Stress

Prenatal effects of methyldopa, an inhibitor of noradrenaline synthesis (400 mg/kg/day), GABA agonist phenibut (100 mg/kg/day), or immobilization stress against the background of phenibut action on the timing of puberty and sexual behavior of male and female rats were investigated. The drugs were administered orally to pregnant animals during the last week of pregnancy (from the 15th to the 21st day). In experiments with prenatal stress, pregnant animals were immobilized daily for one hour during the same period of pregnancy. Some of them received phenibut 30 minutes prior to stressing. Application of phenibut to nonstressed pregnant animals led to accelerated maturation, and the use of methyldopa or phenibut resulted in disorders of sexual behavior of male and female offspring. However, phenibut weakened demasculinizing and feminizing effects of prenatal stress on male sexual behavior, as evidenced by the normalization of the latent periods of mountings and intromissions, their number, and a decrease in the number of lordosis reactions. Phenibut partially restored timing of puberty in those animals. The results obtained indicate the involvement of noradrenergic and GABA-ergic mechanisms in the prenatal programming of sexual behavior of animals, as well as the possibility of preventing its disorders in adult prenatally stressed rats by the activation of GABA-ergic receptors. Based on the results of these and previous studies, the concept of dualistic effects of hormonal and pharmacological neurotropic agents that are used during pregnancy has been proposed, according to which these agents may have either harmful or protective effect on the reproductive health and the ability of the offspring to respond to stressor factors.

Sodium and water intake are not affected by GABAC receptor activation in the lateral parabrachial nucleus of sodium-depleted rats

The activation of GABAergic receptors, GABAA and GABAB, in the lateral parabrachial nucleus (LPBN) increases water and sodium intake in satiated and fluid-depleted rats. The present study investigated the presence of the GABAC receptor in the LPBN, its involvement in water and sodium intake, and its effects on cardiovascular parameters during the acute fluid depletion induced by furosemide combined with captopril (Furo/Cap). One group of male Wistar rats (290–300g) with bilateral stainless steel LPBN cannulas was used to test the effects of a GABAC receptor agonist and antagonist on the fluid intake and cardiovascular parameters. We investigated the effects of bilateral LPBN injections of trans-4-aminocrotonic acid (TACA) on the intake of water and 0.3M NaCl induced by acute fluid depletion (subcutaneous injection of Furo/Cap). c-Fos expression increased (P<0.05), suggesting LPBN neuronal activation. The injection of different doses of TACA (0.5, 2.0 and 160 nmol) in the LPBN did not change the sodium or water intake in Furo/Cap-treated rats (P>0.05). Treatment with the GABAC receptor antagonist (Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid sulfate (ZAPA, 10nmol) or with ZAPA (10nmol) plus TACA (160nmol) did not change the sodium or water intake compared with that for vehicle (saline) (P>0.05). Bilateral injections of the GABAC agonist in the LPBN of Furo/Cap-treated rats did not affect the mean arterial pressure (MAP) or heart rate (HR). The GABAC receptor expression in the LPBN was confirmed by the presence of a 50kDa band. Although LPBN neurons might express GABAC receptors, their activation produced no change in water and sodium intake or in the cardiovascular parameters in the acute fluid depletion rats. Therefore, the GABAC receptors in the LPBN might not interfere with fluid and blood pressure regulation.

Synaptic interactions between perifornical lateral hypothalamic area, locus coeruleus nucleus and the oral pontine reticular nucleus are implicated in the stage succession during sleep-wakefulness cycle

The perifornical area in the posterior lateral hypothalamus (PeFLH) has been implicated in several physiological functions including the sleep-wakefulness regulation. The PeFLH area contains several cell types including those expressing orexins (Orx; also known as hypocretins), mainly located in the PeF nucleus. The aim of the present study was to elucidate the synaptic interactions between Orx neurons located in the PeFLH area and different brainstem neurons involved in the generation of wakefulness and sleep stages such as the locus coeruleus (LC) nucleus (contributing to wakefulness) and the oral pontine reticular nucleus (PnO) nucleus (contributing to REM sleep). Anatomical data demonstrated the existence of a neuronal network involving the PeFLH area, LC, and the PnO nuclei that would control the sleep-wake cycle. Electrophysiological experiments indicated that PeFLH area had an excitatory effect on LC neurons. PeFLH stimulation increased the firing rate of LC neurons and induced an activation of the EEG. The excitatory effect evoked by PeFLH stimulation in LC neurons was blocked by the injection of the Orx-1 receptor antagonist SB-334867 into the LC. Similar electrical stimulation of the PeFLH area evoked an inhibition of PnO neurons by activation of GABAergic receptors because the effect was blocked by bicuculline application into the PnO. Our data also revealed that the LC and PnO nuclei exerted a feedback control on neuronal activity of PeFLH area. Electrical stimulation of LC facilitated firing activity of PeFLH neurons by activation of catecholaminergic receptors whereas PnO stimulation inhibited PeFLH neurons by activation of GABAergic receptors. In conclusion, Orx neurons of the PeFLH area seem to be an important organizer of the wakefulness and sleep stages in order to maintain a normal succession of stages during the sleep-wakefulness cycle.

Baclofen inhibits high-threshold calcium currents with two distinct modes in rat hippocampal neurons

In primary cultures of hippocampal neurons, activation of GABA B receptors reversibly inhibits high-voltage activated (HVA) Ca currents. In some neurons the GABA B agonist baclofen produces slow down of Ca current activation. In these cells the inhibitory action of the agonist can be relieved by strong pre-conditioning depolarizations. In other cells, where no significant changes in activation kinetics could be observed during agonist application, conditioning prepulses are nearly ineffective to recover the current from inhibition. Thus, in hippocampal neurons, activation of GABAergic receptors can modulate Ca currents with two different modes: one is voltage-dependent and the other is voltage-independent. In the presence of ω-conotoxin (ω-CgTx), only the second mode is prevented, suggesting that the two modulatory mechanisms (voltage-dependent and voltage-independent) operate in different cells on separate classes of HVA Ca channels.

Influence of Gamma-Aminobutyric Acid on the Changes of Blood Pressure in Rats

This is an attempt to investigate the effect of gamma-aminobutyric acid (GABA), a well-known major inhibitory neurotransmitter in the central nervous system, on the blood pressure response in rats and to elucidate the mechanism of its action. GABA injected into a femoral vein of the rat produced a dose-related fall in blood pressure followed by a secondary pressor response.The depressor response evoked by GABA was clearly blocked by pretreatment with chlorisondamine, diazepam and picrotoxin but was unaffected by atropine, prazosin and debrisoquin. GABA-induced pressor responses were significantly attenuated by pretreatment with prazosin or picrotoxin, while not affected by atropine, diazepam, debrisoquin and chlorisondamine.These experimental data suggest that GABA causes biphasically depressor and pressor responses in rats, and that the hypotensive activity evoked by GABA may be exerted through activation of GABAergic receptors and hypertensive activity due to stimulation of the adrenergic alpha-receptors, which appears to be associated with GABAergic receptors.

Effect of GABAergic transmission in the subpallidal region on the hypermotility response to the administration of excitatory amino acids and picrotoxin into the nucleus accumbens

Excitatory amino acids and picrotoxin have been shown to produce an intense stimulation of co-ordinated locomotor activity after bilateral administration into the nucleus accumbens of rats. The objective of this study was to determine the role of GABAergic neurotransmission in the substantia innominata/lateral preoptic area in the hypermotility responses to excitatory amino acids and picrotoxin. It was found that the bilateral administration of muscimol into the substantia innominata/lateral preoptic area almost completely inhibited the stimulation of locomotor activity induced by the administration of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), kainic acid, N- methyl- d-aspartic acid and picrotoxin into the n. accumbens. In contrast, muscimol did not inhibit locomotor activity or induce catalepsy in control animals injected with saline into the nucleus accumbens. The inhibitory effect of muscimol on the hypermotility responses to excitatory amino acids and picrotoxin was not due to diffusion to the nucleus accumbens and the activation of GABAergic receptors at this site. This conclusion is supported by the finding that the doses of muscimol injected into the substantia innominata/lateral preoptic area, which effectively inhibited the responses to AMPA and picrotoxin, were either much less effective or not effective in inhibiting these responses when injected into the nucleus aecumbens. These observations suggest that the stimulation of locomotor activity produced by the injection of excitatory amino acids or picrotoxin into the nucleus accumbens may be mediated by the inhibition of a GABAergic neuronal pathway projecting from the nucleus accumbens to the substantia innominata/lateral preoptic area.

Medullary effects of nicotine and GABA on tracheal smooth muscle tone

Airway tone can be modulated centrally by the brain as well as by peripheral receptors. In part these changes in airway caliber seem to be secondary to changes in respiratory activity. Since structures near the ventrolateral medullary surface (VMS) can produce profound effects on respiration, it seems reasonable to believe that they might also be capable of modifying tracheal tone. In this study we examined the effects of two agents with respect to their action on tracheal tone; nicotine, a respiratory stimulant when applied to VMS, and gamma aminobutyric acid (GABA), a respiratory depressant when similarly administered. In chloralose anesthetized, paralyzed, artificially ventilated cats, tracheal tone was assessed by measuring pressure changes in a rostral bypassed of the trachea, while phrenic nerve activity was examined simultaneously. Nicotine administered on the intermediate area of the VMS both before and after carotid sinus denervation increased phrenic activity and induced constriction of the rostral tracheal segment. The response to nicotine could be blocked by application of a nicotine antagonist, hexamethonium, or prior local administration of lidocaine to the VMS. Activation of GABAergic receptors by application of GABA on the intermediate area of the VMS markedly reduced respiratory activity and nearly abolished the increased tracheal tone produced by inhalation of 7% CO 2 in O 2. The effects of GABA were eliminated by the prior administration to the VMS of bicuculline, a GABA receptor antagonist. These results indicate that structures located on the ventral surface of the medulla which affect breating may also play a significant role in the regulation of airway smooth muscle tone.

Effect of intrastriatal administration of cholinergic and GABAergic agonists on apomorphine-induced circling.

The objectives of this study were (1) to clarify the effects of muscarinic and GABAergic agonists administered directly into the striatum on the circling behavior produced by dopamine (DA) receptor stimulation and (2) to determine whether the effects produced by these drugs are independent or are mediated through an interaction with GABAergic or cholinergic neuronal systems. Circling behavior was produced by the administration of apomorphine (AP) to rats previously injected into their right substantia nigra with 6-hydroxydopamine (6-OHDA). The circling induced by AP (0.5 mg/kg SC) reached a peak rate 5-10 min after injection. The intrastriatal administration of pilocarpine, a muscarinic receptor agonist, 10 min after AP administration produced a dose-dependent inhibition of the AP-induced circling. Similarly, several GABAmimetic drugs (muscimol, GABA, chlordiazepoxide, sodium valproate) also inhibited AP-induced circling in a dose-dependent manner. The intrastriatal administration of scopolamine, which blocks muscarinic cholinergic receptors, reversed the inhibitory effect of pilocarpine but not that of muscimol. However, picrotoxin, the GABAergic antagonist, reversed the inhibitory effect of both pilocarpine and muscimol. These results suggest that the stimulation of either muscarinic or GABAergic receptors in the striatum inhibits the effects of DA receptor stimulation. The inhibitory effect produced by pilocarpine may involve the activation of GABAergic receptors, presumably through stimulation of GABAergic neurons and subsequent release of GABA.