Effects of NMDA and GABA-A Receptor Antagonism on Auditory Steady-State Synchronization in Awake Behaving Rats.

BACKGROUND: The auditory steady-state response, which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human electroencephalogram studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia show a deficit in auditory steady-state response at 40 Hz, and therefore this may be a useful biomarker to study this disorder. METHODS: We used auditory steady-state response recordings from the primary auditory cortex, hippocampus, and vertex electroencephalogram sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimics auditory steady-state response abnormalities in schizophrenia. RESULTS: We found the most robust response to auditory stimuli in the primary auditory cortex, in line with previous studies suggesting this region is the primary generator of the auditory steady-state response in humans. Acute MK-801 (0.1mg/kg i.p.) increased primary auditory cortex intertrial coherence during auditory steady-state response at 20 and 40 Hz. Chronic MK-801 (21-day exposure at this daily dose) had no significant effect on 40-Hz auditory steady-state response. Furthermore, we found no effect of acute or chronic picrotoxin (a GABA-A antagonist) on intertrial coherence. CONCLUSIONS: Our data indicate that acute N-methyl-d-aspartate receptor antagonism increases synchronous activity in the primary auditory cortex in a frequency-specific manner, supporting the widely held view that acute N-methyl-d-aspartate antagonism augments gamma oscillations. Thus, rodent auditory steady-state response could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies.

[Effects of Tianbingtiaodu capsule on improvement of learning and memory abilities and expression of NMDAR1 of epileptic rats in the hippocampus].

OBJECTIVE: To study effects of Tianbingtiaodu capsule on changement of learning and memory abilities and expression of NMDAR1 in epileptic rats. METHODS: Picrotoxin (1.5 mg/kg) was injected intraperitonrally in SD rats for thirty days. After the repeated attacks epilepsy model had been established successfully, model rats were randomly divided into model group, Tianbingtiaodu capsule low dosage (0.4 g/kg) group, Tianbingtiaodu capsules high dosage(0. 8 g/kg) group, Piracetam group and Piracetam and Valproate group. All groups were fed everyday. Sixty days later, the learning and memory abilities were tested with Morris water maze method. Expression of NMDAR1 in hippocampus was observed with western-blot and immunohistochemical method. The expression of NMDAR1 mRNA in hippocampus was determined by RT-PCR. RESULTS: Compared to the control group, the learning and memory abilities were significantly lower (P < 0.01), immune positive remarks of expression of NMDAR1 in hippocampus AC3 significantly increased in model group (P < 0.05); Compared with model group,the learning and memory abilities and expression of NMDAR1 in hippocampus was improved significantly in Tianbingtiaodu group (P < 0.05 or P < 0.01). CONCLUSION: Tianbingtiaodu capsule could improve the impairment of learning and memory in rats after repeated attacks of epilepsy through adjusting the NMDAR1 expression.

Acute effects of melatonin on spontaneous and picrotoxin-evoked sleep-wake behaviour in the rat.

Various studies indicate that exogenous melatonin has hypnotic properties in humans, which may be mediated by its influence on the circadian timing system or direct sleep-promoting actions, e.g. through a modulation of GABAergic transmission. The aim of the present placebo-controlled study was to examine the effects of melatonin on sleep in rats and the contribution of gamma-aminobutyric acid (GABA)A receptors. Sleep-wake behaviour was assessed in nine rats after intraperitoneal (i.p.) administration of pharmacological doses of melatonin (5 and 10 mg kg(-1)) and after combined administration of the GABAA receptor antagonist picrotoxin (1.5 mg kg(-1)) and melatonin (10 mg kg(-1)). To prevent chronobiotic effects, melatonin was delivered in the middle of the light period. Neither doses of melatonin exerted significant effects on brain temperature, sleep architecture or sleep electroencephalogram (EEG). Moreover, melatonin failed to attenuate the picrotoxin-induced promotion of wakefulness. These observations indicate that melatonin hardly influences sleep-wake behaviour in rats.

Latent acquisition of timed responses in cerebellar cortex.

Evidence indicates that rabbit eyelid conditioning is mediated by plasticity in the interpositus cerebellar nucleus and in cerebellar cortex. Although the relative contributions of these sites are not fully characterized, evidence suggests that plasticity in the cerebellar cortex influences conditioned response amplitude and timing, whereas plasticity in the interpositus nucleus is necessary or permissive for conditioned response expression. Recent empirical and computational analyses suggest that, during training, plasticity is initially established in the cerebellar cortex, whereas conditioned response expression begins later as plasticity is induced in the interpositus nucleus. We used the dependence of response timing on the interstimulus interval (ISI) to test this latent learning hypothesis. Rabbits were initially trained using a tone conditioned stimulus (CS) with a relatively long ISI to a low-criterion threshold. The relative absence of plasticity in the interpositus nucleus was then examined via reversible disconnection of the cerebellar cortex. Later, to induce plasticity in the interpositus nucleus, subjects were trained to robust levels of conditioned response expression using a shorter ISI. Reversible disconnection of the cerebellar cortex at this time confirmed the presence of robust interpositus nucleus plasticity after the second phase. Subsequent probe trials with the long CS alone then revealed double-peaked responses whose peaks were appropriately timed to the two ISIs. The results are consistent with the hypothesis that temporally specific learning occurs first in the cerebellar cortex before the appearance of conditioned responses. This latent learning is expressed only after plasticity is induced in the interpositus nucleus.

Local release of GABAergic inhibition in the motor cortex induces immediate-early gene expression in indirect pathway neurons of the striatum.

The neocortex is thought to exert a powerful influence over the functions of the basal ganglia via its projection to the striatum. It is not known, however, whether corticostriatal effects are similar across different types of striatal projection neurons and interneurons or are unique for cells having different functions within striatal networks. To examine this question, we developed a method for focal synchronous activation of the primary motor cortex (MI) of freely moving rats by local release of GABAergic inhibition. With this method, we monitored cortically evoked activation of two immediate-early gene protein products, c-Fos and JunB, in phenotypically identified striatal neurons. We further studied the influence of glutamate receptor antagonists on the stimulated expression of c-Fos, JunB, FosB, and NGFI-A. Local disinhibition of MI elicited remarkably selective induction of c-Fos and JunB in enkephalinergic projection neurons. These indirect pathway neurons, through their projections to the globus pallidus, can inhibit thalamocortical motor circuits. The dynorphin-containing projection neurons of the direct pathway, with opposite effects on the thalamocortical circuits, showed very little induction of c-Fos or JunB. The gene response of striatal interneurons was also highly selective, affecting principally parvalbumin- and NADPH diaphorase-expressing interneurons. The glutamate NMDA receptor antagonist MK-801 strongly reduced the cortically evoked striatal gene expression in all cell types for each gene examined. Because the gene induction that we found followed known corticostriatal somatotopy, was dose-dependent, and was selectively sensitive to glutamate receptor antagonists, we suggest that the differential activation patterns reflect functional specialization of cortical inputs to the direct and indirect pathways of the basal ganglia and functional plasticity within these circuits.

Optokinetic and vestibulo-ocular reflex adjustment by GABA antagonists.

We determined if high and low doses of anti-GABAergic drugs have opposite effects on the visuo-vestibular activity in pigmented rats and examined a possible correlation with the level of GABA in the related structures. First, the horizontal optokinetic and vestibulo-ocular reflexes of most animals were depressed by high doses of anti-GABAergic drugs (10(-3) M purified picrotoxin or 10(-6) M picrotoxin in unpurified vegetal extract). Simultaneously, a drop in GABA level in the cerebellum and posterior brainstem was detected. Second, after a subsequent injection (1 ml) of the diluted extract (10(-13) M picrotoxin), the reflexes returned to normal despite the fact that no correlation with the GABA level was found. These results demonstrate that small doses of anti-GABAergic drugs reverse the depressive effect created by large doses of these drugs on the oculomotor system, and even adjust the reflexes to the stimulation. This adjustment, without correlation with the GABA level, suggest a powerful effect of very low dose of the drug to modulate either the activity of the cerebellar inhibiting input or of the vestibular nuclei neurons or to trigger the adaptation by other neurotransmitter systems involved in the performances of the reflexes.

Inhibitory effect of 5 beta-pregnan-3 alpha-o1-20-one on gonadotropin-releasing hormone gene expression in the male rat.

Neuroanatomical data have documented the existence of synaptic contacts between gamma-aminobutyric acid (GABA) terminals and preoptic gonadotropin-releasing hormone (GnRH) neurons in the rat anterior hypothalamus. In addition, pharmacological studies have suggested that the GABAergic system may be involved in the control of gonadotropin release. Moreover, it has been shown that some progesterone metabolites such as 5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha P) are able to interact with the GABAA receptor complex. In the present study, we have investigated the effects of chronic (5 days) treatment with the GABAA-positive ligand 5 beta 3 alpha P (20 mg/kg body weight i.p., twice a day) or with the GABAA agonist muscimol (1 mg/kg body weight i.p., twice a day) alone or in combination on GnRH mRNA levels in the preoptic area of the male anterior hypothalamus as measured by in situ hybridization. Treatment with 5 beta 3 alpha P produced a 30% decrease in the number of grains overlying labelled cells, while muscimol treatment decreased the hybridization signal by 36%. The concomitant administration of 5 beta 3 alpha P and muscimol resulted in a 46% decrease in the GnRH mRNA levels. This inhibitory effect was completely antagonized by the concomitant administration of picrotoxin (4 mg/kg body weight i.p., twice a day). These data suggest that the GABAA receptor complex and steroids that interact positively with this GABAA receptor complex may play an important role in the regulation of GnRH biosynthesis by hypothalamic neurons.

GABA-related feeding control in genetically obese rats.

Feeding in response to glucoprivation induced by 2-deoxy-D-glucose (2-DG) is impaired in genetically obese (Zucker) rats. Muscimol, a GABAA-agonist (0.5 nmol/0.5 microliter in each area) increased food intake in lean rats over 3 h but in fatty rats only at 30 min after infusion into the VMH. Injection of muscimol into the DMH and PVN increased feeding of both phenotypes. Picrotoxin, a non-competitive GABAA-antagonist (0.1 nmol/0.5 microliter) increased food intake after infusion into the LH of both phenotypes and decreased food intake over a 3 h period when infused into the VMH. DMH and PVN of fatty rats. In the lean littermates, picrotoxin was only effective in reducing food intake at 30 min after infusion into the VMH and PVN but not the DMH. The present results suggest that the fatty Zucker rat has a disturbance in the GABA-related regulatory mechanism of feeding behavior in the ventromedial hypothalamus, which may be responsible for the impaired response to glucoprivation found in these rats.

Butyrylcholinesterase fluctuation in male albino rats with intracerebroventricular injection of gamma aminobutyric acid, muscimol, and picrotoxin.

The effects of intracerebroventricular injection of gamma-Aminobutyric acid, muscimol, or picrotoxin have been studied on butyrylcholinesterase (BuChE) activities in the serum and several hypothalamic nuclei using biochemical, histochemical, and cytophotometric techniques, respectively. The blood samples were withdrawn from indwelling catheters in jugular vein 1, 15, 30, 45, 60, 90, and 120 min after injection of the drugs. Biochemical estimations demonstrated a significant inhibition of BuChE after GABA and muscimol injections, whereas a pronounced stimulation of BuChE was observed after injection of picrotoxin. The peak changes were observed within 30 min of drug injection. Cytophotometric studies have appeared to dovetail the biochemical findings. Only a marginal decrease was observed after injection of GABA in all nuclei, while muscimol induced a very conspicuous decrease of BuChE. On the contrary, intracerebroventricularly administered picrotoxin markedly increased the levels of BuChE activity. Thus it could be concluded that probably GABA and muscimol along with picrotoxin appear to alter BuChE.

Centrally administered GABA and GABA-selective agonist and antagonist in rats: histoenzymological cytophotometric study.

In the present study, the effect of intracerebroventricular (icv) injection of GABA, its agonist--muscimol, and antagonist--picrotoxin, has been studied on histoenzymological alterations of acetylcholinesterase (AChE). butyrylcholinesterase (BuChE), monoamine oxidase (MAO), and succinic dehydrogenase (SDH) by cytophotometric technique. This study was conducted on medial preoptic area (mPOA), nucleus paraventricularis hypothalami (PVH), area lateralis hypothalami (LHA), nucleus dorsomedialis hypothalami (DMH), and nucleus ventromedialis hypothalami (VMH). Results showed that GABA and muscimol inhibited AChE, BuChE, MAO, and SDH in all the areas while picrotoxin stimulated these enzymes. These changes in enzyme activity by GABA, muscimol, and picrotoxin and their possible mode of action are discussed.