A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic.

This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.

Effects of methylphenidate on responding under extinction in the presence and absence of conditioned reinforcement.

Pigeons pecked a key during sessions that began with a variable number of reinforcers under a second-order schedule of food presentation. Every 30sec, on the average, a key peck was followed immediately by one of two consequences: (a) food presentation, accompanied by a stimulus complex that consisted of houselight off, key color change, tone presentation, and hopper-light illumination, or (b) the stimulus complex alone. Following the last food presentation, 20min of one of two types of extinction began. The two types of extinction were: (a) standard extinction (key pecks had no consequence) and (b) key pecks produced, on a variable-interval schedule, the stimulus complex previously paired with food. Consequently, it was possible to study performance under extinction during which responses either did or did not result in occasional presentation of a food-paired stimulus complex. Methylphenidate (5, 10 and 20mg/kg) occasionally was administered before sessions containing each type of extinction. At moderate doses methylphenidate produced higher response rates during extinction when the stimulus complex was presented than when it was not. These results support previous findings with rats that stimulant drugs can enhance responding during extinction when responding produces conditioned reinforcers, and illustrate this effect in a novel, within-subject design.

Low doses of cis-flupentixol attenuate motor performance.

We evaluated the effects of cis-flupentixol on reinforced responding. The experimental subjects were rats and the reinforced response was a lever press. The procedure was a five-component multiple schedule that provided five different reinforcement rates. Cis-flupentixol produced dose-dependent decreases in reinforced responding. An equation, the matching law, was fitted to the results. One parameter of this equation represents the estimated response rate asymptote. Cis-flupentixol produced dose-dependent decreases in the asymptotes. A second parameter of the equation represents the rate of reinforcement that maintains a one-half asymptotic response rate. Cis-flupentixol did not appear to affect this measure. There is evidence that the response rate asymptote measures motor components of response rate and that the reinforcement parameter measures the efficacy of the reinforcement maintaining the response. According to these results, cis-flupentixol systematically affected the motor-component of reinforced responding-it slowed down lever pressing-without affecting the subject's sensitivity to the reinforcer maintaining the response. In contrast, other neuroleptics have decreased the subjects' sensitivity to reinforcement, according to the matching law measures.

Effect of chronic desmethylimipramine or electroconvulsive shock on selected brain and platelet neurotransmitter recognition sites.

Rats were treated with electroconvulsive shock (ECS), desmethylimipramine (DMI), ECS plus DMI, or diazepam. In vitro analyses showed that chronic ECS produced an elevated density of recognition sites for [3H]imipramine (IMI) in platelet membranes, but had no effect on membrane preparations derived from cortical tissue. A similar elevation in receptor binding was seen exclusively in platelets after chronic ECS plus DMI, whereas no effect was observed with DMI alone. Equilibrium dissociation constant (KD) values for [3H]IMI were also increased in platelet membranes from rats given chronic ECS or ECS plus DMI treatment. Chronic ECS or DMI administration produced a decreased density of beta-adrenergic recognition sites in frontal cortex and cerebellum as assessed by [3H]dihydroalprenolol (DHA) binding. The combination of ECS plus DMI produced a similar decrease. In addition, chronic diazepam administration produced a down-regulation of the beta-adrenergic receptor only in the cerebellum. These data provide evidence for the differential regulation of brain and peripheral neurotransmitter recognition sites.

Hippocampal muscarinic receptor loss following trimethyl tin administration.

The effects of trimethyl tin on passive and active avoidance behavior, hippocampal muscarinic receptors and hippocampal cell destruction were examined in male rats. The animals were intubated with 18 mumoles/kg (3.5 mg/kg) of TMT hydrochloride or vehicle. When tested two weeks later treated animals exhibited marked deficits in retention of passive avoidance and extinction of active avoidance tasks. Receptor binding analysis, using 3H-QNB, revealed a significant decrease (21%) in muscarinic receptor density in the hippocampus. Histological examination of the hippocampus revealed a concomitant loss in pyramidal cells in these animals. These results suggest that muscarinic receptors reside on the hippocampal pyramidal cells and that these cells and receptors may be involved in retention of passive avoidance behavior.

Antagonism of the anxiolytic action of diazepam and chlordiazepoxide by the novel imidazopyridines, EMD 39593 and EMD 41717.

The imidazopyridines EMD 35993 and EMD 41717 antagonized the anticonflict actions of diazepam and chlordiazepoxide in rodent models which are predictive for anxiolytic action in man. In contrast to other described benzodiazepine antagonists, these compounds did not antagonize either the anticonvulsant or muscle relaxant properties of either benzodiazepine. Both EMD 39593 and EMD 41717 competitively inhibit the binding of [3H]diazepam to brain membranes, but do not exhibit regional differences in potency. These observations suggest that both EMD 39593 and EMD 41717 display some selectivity in antagonizing the anxiolytic properties of benzodiazepines, and as such may be useful tools in identifying neuronal substrates of anxiety.

Psychomotor performance in the senescent rodent: reduction of deficits via striatal dopamine receptor up-regulation.

In order to determine the relationship between striatal dopamine (DA) receptor density and psychomotor performance in senescent animals, two experiments were carried out. In the first, the age-related motor deficits were characterized using a battery of four psychomotor tests (rod walking, wire hanging, inclined screen, plank walking). These tests were administered to three groups of male Fischer rats (mature, 6-8 months; middle aged, 12-18 months; and senescent, 25 months) and performance measured. Age-related differences were observed on all the tasks, with the oldest animals showing the poorest performance. These animals were then used in a second experiment in which one-half of the group of animals from each age was administered 1.86 mg/kg/day of haloperidol for 14 days (via surgically implanted Alza Minipumps. Control groups of animals from each age were given pumps which contained only the vehicle (HCl diluted with distilled water, pH = 2.9). Following the 14 day drug administration, the pumps were surgically removed and 3 days later all the groups were retested on the psychomotor tests. Stereotypy (to 0.5 mg/kg of apomorphine, sniffing, licking, grooming and cage crossings) was also re-examined. Results show that haloperidol-treated animals from all three age groups display greater response times (i.e., better performance) than vehicle-treated animals on the battery of four motor tests and, the haloperidol-treated old animals exhibit more sniffing and grooming than the vehicle-treated old animals. Parallel increases in [3H]spiperone binding seen in all haloperidol-treated groups suggest a relationship between increases in the density of striatal DA receptors and improvement in motor performance.

Role of serotonin in the blockade of muricidal behavior by tricyclic antidepressants.

Dose-response curves for the ability of three tricyclic antidepressants, imipramine, desmethylimipramine and amitriptyline to inhibit muricidal behavior were measured after treatment with a tryptophan-free diet and after administration of p-chloroamphetamine. Both treatments, which have been reported to specifically reduce central levels of serotonin, decreased the ability of the drugs to inhibit muricide. The results suggest that all three antidepressants block muricide in part through their effects on serotonin.

Stimulus efficacy, chlorpromazine, and schizophrenia.

Stimulus efficacy can be defined in terms of rat least two variables: Proximity of a stimulus to reinforcement and the association of a stimulus with reinforcements of different magnitudes. The behavioral effects of chlorpromazine were found to be significantly modulated by stimulus efficacy and increases in efficacy attenuated drug effect. The relevance of this finding to various conjectures about the deficits seen in schizophrenia is discussed.

Effects of dibutyryl cyclic AMP on restoration of function of damaged sciatic nerve in rats.

In two experiments, the sciatic nerve of rats was either crushed or hemisected, and N(6),O(2)-dibutyryl adenosine 3',5'-monophosphate or saline was injected intramuscularly near the site of the lesion. In both types of nerve damage, the sensorimotor functions of animals treated with N(6),O(2)-dibutyryl adenosine 3',5'-monophosphate returned earlier than did those of saline-treated control animals.

Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety.

Drugs that reduce anxiety may be mediated by cyclic adenosine monophosphate in the brain because (i) potent anxiety-reducing drugs are also potent inhibitors of brain phosphodiesterase activity; (ii) dibutyryl cyclic adenosine monophosphate has the ability to reduce anxiety; (iii) the methylxanthines show significant anxiety-reducing effects; (iv) theophylline and chlordiazepoxide produce additive anxiety-reducing activity; and (v) there is a significant correlation between the anxiety-reducing property of drugs and their ability to inhibit phosphodiesterase activity in the brain.