Midazolam cue in rats: Effects of Ro 15-1788 and picrotoxin

The discriminative stimulus effect of midazolam, a short-acting benzodiazepine, was used for testing the effects of drugs thought to act as antagonists at different sites in the proposed benzodiazepine receptor complex. Rats were trained in a standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. The benzodiazepine receptor antagonist Ro 15-1788 blocked the discriminative effect of midazolam but did not influence generalization to pentobarbitone (7.5 mg/kg). The indirect GABA antagonist picrotoxin attenuated both generalization to pentobarbitone and its response rate-reducing effect. Picrotoxin had no effect on the discriminative effect of midazolam at 0.4 mg/kg but it blocked the effect of 01 mg/kg. Even in doses which reduced overall response rates, nicotine did not block discrimination of midazolam (0.4 mg/kg). The results are consistent with models which postulate a GABA-linked ion channel which is a site of action for barbiturates and which is downstream of the benzodiazepine receptor itself.     

Convulsant properties of GABA antagonists and anticonvulsant properties of ethanol in selectively bred Long- and Short-Sleep mice

The convulsant potency of bicuculline, a GABA antagonist, was shown to be greater in Short-Sleep (SS) mice than in Long-Sleep (LS) mice. LS mice, selectively bred for lengthy ethanol-induced narcosis, had longer latencies to myoclonus and clonus following administration of bicuculline and picrotoxin than did ethanol-resistant SS mice. SS mice were also more susceptible to pentylenetetrazol-induced myoclonus, but not clonus. F₁ hybrids showed bicuculline seizure sensitivity intermediate to the two parent lines. Ethanol weakly inhibited bicuculline-induced myoclonus in both LS and SS mice. Clonus was clearly antagonized by ethanol in both lines, but to a similar degree. These data provide evidence for a GABAergic role in geno-type-dependent sensitivity to ethanol.     

Intermediate cerebellum and conditioned eyeblinks

The intermediate cerebellum (the intermediate cerebellar cortex and interposed nuclei) and associated brainstem circuits are essential for the acquisition and expression of classically conditioned eyeblinks in the rabbit. The purpose of the present experiment was to determine whether these circuits are also involved in adaptive eyelid closure learned in an instrumental paradigm. For that purpose, rabbits with unrestrained eyelids were trained in two tasks: (1) classical conditioning of the eyeblink; and (2) a new instrumental task in which they avoided delivery of an aversive stimulus by maintaining tonic eyelid closure. To examine the involvement of the intermediate cerebellum in these two types of learned behavior, the cerebellar interposed nuclei were injected with the GABAA agonist muscimol and with the GABAA antagonist picrotoxin. Inactivating the interposed nuclei with muscimol abolished classically conditioned eyeblinks and severely affected the rabbit's capacity to maintain tonic eyelid closure. On the other hand, reducing inhibition with picrotoxin failed to interrupt the learned responses and increased the amplitude of eyelid closure. These data indicate that the cerebellar interposed nuclei control both phasic classically conditioned eyeblinks and tonic instrumental eyelid closure. To account for this new finding, a "hybrid" hypothesis combining the cerebellar learning hypothesis and the performance hypothesis is proposed.     

The puzzle of drug-induced conditioned taste aversion: Comparative studies with cathinone and amphetamine

Two methods were used to test rats' responses to novelty in the T-maze: (1) a test of spontaneous alternation allowing separate measurement of place and body turn alternation; and (2) a test of entry into an arm of changed brightness (response to stimulus change). Chlordiazepoxide reduced spontaneous alternation by specifically weakening body turn alternation and eliminated the response to stimulus change. These findings are similar to those previously reported for the barbiturate sodium amylobarbitone. The same pattern of change in the two tests was seen after a low dose of the GABA_A agonist muscimol (0.00125 mg/kg); when the dose of muscimol was raised (0.01 and 0.25 mg/kg), place alternation was also reduced. Picrotoxin but not bicuculline (both GABA_A blockers) reversed the effects of muscimol and partially those of chlordiazepoxide on the response to stimulus change; in the spontaneous alternation test picrotoxin only marginally affected the response to 0.25 mg/kg muscimol and actually enhanced the effect of 0.000125 mg/kg. The GABA_B agonist baclofen (1 mg/kg) acted in the test of response to stimulus change like chlordiazepoxide and muscimol; however, when baclofen was combined with muscimol, the two drugs tended to show mutual blocking. These results are generally consistent with the hypothesis that GABAergic mechanisms play a role in anxiolytic behavioural activity, but many details are difficult to explain.     

Can drug effects on anxiety and convulsions be separated?

The effects of benzodiazepines, barbiturates, a series of novel putative anxiolytic compounds and anxiogenic compounds are reviewed in animal tests of anxiety and on experimentally-induced seizures. It is clear from the data that drug effects on anxiety and convulsions are not always in the same direction; certain compounds are apparently both anxiolytic and proconvulsant, others are anxiogenic and anticonvulsant, others have varied effects depending on the test situation. It is suggested that this work necessitates considerable revision of our traditional concepts of an "anticonvulsant." The extent to which drug-induced anxiety is correlated with weak epileptiform activity in the brain is discussed. Finally, the Discussion considers a number of possible mechanisms that could underlie the separation of drug effects on anxiety and convulsions that is observed.     

化学点燃癫痫大鼠在水迷宫中学习记忆能力的测定

目的 观察印防己毒（Picrotoxin,PTX)化学点燃癫痫大鼠在水迷宫中学习记忆能力与发作频率及类型的关系。为进一步研究癫痫患者记忆损害的治疗提供线索。方法 34只雄性SD大鼠随机分为点燃组和对照组。分别用PTX和生理盐水腹腔注射，根据点燃情况点燃组再分为全面发作（A），频繁发作（B）和部分发作（C）组，对照组即为迷宫训练（D）组。然后进行水迷宫行为测试，评价其学习记忆能力。结果 癫痫大鼠在水迷宫测定中，除B组第1天的成绩较对照组差外，其余各组及B组在第2，3，4、5天中寻找平台的潜伏期时间与对照组相比没有显著性差异。点燃各组对平台空间位置的记忆能力较对照组要差。差异有显著性。结论 首次用化学点燃模型研究癫痫大鼠在水迷宫中的学习记忆能力后发现。PTX化学点燃癫痫大鼠在水迷宫中学习记忆能力下降。发作频繁者学习记忆受损明显，但与发作的严重程度无关。     

Glycine-activated chloride currents of neurons freshly isolated from the ventral tegmental area of rats

Properties of whole-cell glycine currents (I_Gly) of ventral tegmental area (VTA) neurons from 3- to 7-day old Sprague–Dawley rats were investigated with the patch-clamp technique. Ninety-three percent of the 126 neurons examined produced I_Gly in response to glycine. For 70% of these neurons, I_Gly did not decay in response to a threshold concentration of glycine (1–5 μM). At elevated glycine concentrations, I_Gly consistently decayed from a peak to a steady state (SS). I_Gly increased in amplitude sigmoidally as a function of the concentration of agonist with an EC₅₀ of 32 μM. Strychnine (STR), when co-applied with glycine after a prepulse of STR, suppressed both the peak and SS I_Gly noncompetitively. In the absence of a prepulse, STR had a smaller effect on peak I_Gly while increasing its decay rate; the SS amplitude decreased. These STR effects were concentration dependent with an IC₅₀ of 31 nM and 184 nM STR for the peak and SS I_Gly, with prepulse, respectively, and 732 nM and 193 nM for the peak and SS I_Gly, respectively, without prepulse. Picrotoxin (PTX) co-applied with glycine suppressed both the peak and the SS I_Gly with an IC₅₀ of 25 μM. In contrast to STR, 1 min preincubation with PTX had no effect on I_Gly. Thus, PTX acts on the open channel. The inhibitory effects of both STR and PTX on I_Gly did not depend on the membrane potential.     

Evaluation of anticonvulsant activity of hydroalcoholic extract of Mussaenda philippica on animals

ObjectiveTo evaluate the anticonvulsant activity of hydroalcoholic extracts of leaves and sepals of Mussaenda philippica (M. Philippica) and its fractions (methanol, dioxin and aqueous) against pentylene tetrazole (PTZ), maximal electroshock (MES), Strychnine (STR), Picrotoxin induced convulsions at different dose levels.MethodsThe anticonvulsant effect of extracts was studied by the MES, PTZ, STR and Picrotoxin-induced seizure.ResultsThe extract at 100 and 200 mg/kg, produced a significant (P <0.01) dose dependent increase in onset of convulsion compared to the control in MES, PTZ, strychnine and picrotoxin-induced seizures.ConclustionsThe data obtained indicates that Hydroalcoholic extracts of M. philippica leaves and sepals may help to control grandmal and petitmal epilepsy.