7-OHDPAT and alcohol consumption, withdrawal and discriminative stimulus properties in rats.

A series of experiments was performed, which indicated that 7-OHDPAT is only active in rats that are still in the dynamic phase of the development of a high and stable level of alcohol preference and in a drug discrimination test procedure, but not in rats with a matured preference for 3% alcohol. These data may point to a limited use of 7-OHDPAT in conditions of alcohol misuse and dependence.

Quantification of tremor sensitivity and inhibition of exploratory behaviour during alcohol withdrawal in rats.

Rats given a 10% (v/v) alcohol liquid diet over two weeks reached high blood alcohol levels of around 200mg/dl. Discontinuation of the alcohol intake resulted within 6h in several withdrawal reactions including a tremorogenic activity and a reduction in exploratory behaviour in novel environments. The tremorogenic activity of the alcohol withdrawal could be quantified, using a piezo-film technique, in terms of a supersensitivity to both an inactive and a moderately active dose of the tremorogenic compound harmine. As compared to controls, the rats in alcohol withdrawal revealed more frequent tremor after both 5 and 10mg/kg harmine. The supersensitivity to harmine-induced tremor started within 6h after alcohol withdrawal and remained present with 10mg/kg harmine for up to 48h. The supersensitivity was independent of the length of the tremor bursts used to quantify harmine-induced tremor. Alcohol withdrawal also resulted in an inhibition of exploratory behaviour in a neutral two-chamber box. Both in terms of the number of transits into the open field as well as the time spent in the open area, rats in alcohol withdrawal were significantly less active than control animals. The reduced exploration started within 6h after withdrawal and remained present for up to 24h after the last alcohol intake. These results indicate that both alcohol withdrawal-induced sensitivity to tremorogenic agents and inhibition of exploratory behaviour can be quantified over time, allowing the pharmacological mechanisms involved to be studied.

In vivo studies on the mechanism of action of the broad spectrum anticonvulsant loreclezole.

In animal models of epilepsy the anticonvulsant profile of loreclezole resembles that of barbiturates and benzodiazepines. We examined whether the increase in seizure threshold to pentylenetetrazole infusion produced by 10 mg/kg of loreclezole, pentobarbital or diazepam could be reversed by a spectrum of benzodiazepine partial inverse to full inverse agonists (FG-7142 beta-carboline carboxylate, CGS-8216, Ro-15-4513 and DMCM) or by a benzodiazepine neutral antagonist (Ro-15-1788). The doses of the benzodiazepine inverse agonists were chosen to produce a 20-40% decrease in seizure threshold. The seizure threshold increase produced by loreclezole and pentobarbital was reduced by all the benzodiazepine inverse agonists and potentiated by Ro-15-1788. Diazepam was antagonized by the benzodiazepine inverse agonists and by the neutral antagonist. The generality of this finding was examined in amygdala-kindled rats. The decrease in the duration of forepaw clonus and the reduction in behavioural stage34 produced by loreclezole, pentobarbital and diazepam was reversed by CGS-8216. Ro-15-1788, which itself showed anticonvulsant effects in this model, antagonized the effects of diazepam, but not loreclezole or pentobarbital. Thus loreclezole behaves more like a barbiturate than a benzodiazepine in these two in vivo models. This suggests a possible mechanism of action of loreclezole at a neuromodulatory site within the GABAA receptor complex, which is unlikely to be a benzodiazepine receptor.

Effects of ritanserin and chlordiazepoxide on sleep-wakefulness alterations in rats following chronic cocaine treatment.

The effects of ritanserin, a 5-hydroxytryptamine-2 (5-HT2) receptor antagonist, and chlordiazepoxide, a benzodiazepine agonist, on sleep-wakefulness disturbances in rats after acute administration of cocaine and after discontinuation of chronic cocaine treatment were examined. Intraperitoneal (IP) injection of chlordiazepoxide (10 mg/kg) but not ritanserin (0.63 mg/kg) prevented the increase of wakefulness (W) and the reduction of light slow wave sleep (SWS1) and deep slow wave sleep (SWS2) induced by an acute injection of cocaine (20 mg/kg IP). Daily injection of cocaine (20 mg/kg for 5 days, then 30 mg/kg for 5 days IP) at the onset of the light phase elicited an increase of W and a concomitant decrease of SWS1, SWS2 and paradoxical sleep (PS) in the light phase, followed by a rebound in SWS2 and PS in the subsequent dark phase. Following cocaine discontinuation, the circadian distribution of sleep-wakefulness states remained disturbed in saline-treated rats for at least 5 days. Both ritanserin (0.63 mg/kg IP/day) and chlordiazepoxide (10 mg/kg IP/day) reduced the alteration in the distribution of W and SWS2 throughout the light-dark cycle from the first day of administration on, but failed to prevent PS alterations. The mechanisms by which both compounds exert their effect are probably quite different. For chlordiazepoxide sedative and sleep-inducing properties probably play a major role. In contrast, for ritanserin SWS2-increasing properties and its ability to reverse preference for drugs of abuse without inducing aversion might be key factors.

Sabeluzole (R58 735) increases consistent retrieval during serial learning and relearning of nonsense syllables.

Consistent retrieval during serial learning of nonsense syllables was investigated under sabeluzole (10 mg b.i.d. for 7 days) and placebo. The same material was relearned 1 week after withdrawal of the drug. During learning a twofold improvement in retrieval efficiency was seen when volunteers learned new material under steady-state levels of sabeluzole. During relearning, material originally learned under sabeluzole was significantly better retrieved than material learned under placebo. The results suggest that sabeluzole influences basic mechanisms involved in storage and retrieval of new information.

The effect of R 58 735 (Sabeluzole) on memory functions in healthy elderly volunteers.

The effects of chronic treatment (5 mg b.i.d. for 2 days followed by 10 mg b.i.d. for 5 days) with R 58 735 on human memory functions were studied in healthy elderly (age greater than or equal to 50 years) volunteers in a double-blind placebo-controlled study. Serial learning of nonsense syllables was better under R 58 735, and relearning 1 week after termination of the treatment was superior to relearning of similar material initially learned under placebo. Free recall of nonsense syllables was significantly better when these were learned under active compound. Proactive inhibition induced by consecutive presentation of word lists was attenuated by R 58 735. Short-term memory functions, retrieval accuracy from semantic memory and unprepared reaction times were unchanged. R 58 735 ameliorated both learning and recall in conditions of age-related mild hypofunction in healthy volunteers. The compound seems to have had positive effects on encoding and consolidation of new material.

Cerebral resuscitation: pathophysiology and therapy.

The interest in the possibility of cerebral resuscitation has been growing exponentially during the last decade. It became clear that pharmacotherapeutic interaction can possibly alter the outcome of cerebral hypoxia/ischemia. The present review is an attempt to provide an organizational framework for a systematic integration of studies specifically dealing with pharmacological treatment post-insult.

The effect of hypoxia on the acquisition of a two-way avoidance task in the guinea-pig.

Male guinea-pigs learned conditioned two-way shuttle behaviour to acoustic stimuli. Training was given during 5 consecutive days. Two daily training sessions were held with intersession intervals of 120 (Experiment 1) and 60 (Experiment 2) min. In each experiment one group was given post-session hypoxia (H) and another group received no hypoxia (NH). In the NH group the performance during the second session was higher than during the first session on the same day. In the H group this gain was abolished but the course of acquisition was unchanged. The induced amnesia confirmed the selective effect of hypoxia on medium-term memory (MTM) formation previously observed in rats. The results are discussed with reference to the validity of the multistage model of memory formation.

Pharmacological protection against hypoxia-induced effects on medium-term memory in a two-way avoidance paradigm.

Male guinea-pigs were trained in a two-way avoidance task. They were exposed for 1 min to 100% nitrogen after each of the two daily sessions on 5 consecutive days. Eight groups of 10 animals were pretreated with a single dose of either flunarizine (0.16 or 0.63 mg/kg), nimodipine (0.16 or 0.63 mg/kg), nifedipine (0.16 or 0.63 mg/kg) or verapamil (0.63 or 2.5 mg/kg) 1 h before the first daily session. Only flunarizine protected against the hypoxia-induced amnesia. The results are discussed with reference to protective effects in other paradigms and the utility of the paradigm for pharmacological research purposes.