Nonspecific Sedation Research Articles

The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity.

It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.

L-fenfluramine in tests of dominance and anxiety in the rat.

l-Fenfluramine (1.25 and 2.5 mg/kg) significantly reduced the success of dominant rats competing with untreated middle rank rats for chocolate. In resident rats, l-fenfluramine (2.5 mg/kg) significantly increased the number of submissions, and the time spent submitting, to untreated rats intruding into their home-cage territory; it also significantly reduced the number of kicks directed at, and the time spent kicking, the intruder; and the incidence of, and time spent in, aggressively grooming the intruder. When the intruder rats were treated with l-fenfluramine the only significantly change was a decrease in the number of wrestling bouts and the time spent wrestling. Since l-fenfluramine did not change other behaviours in this test (e.g. sniffing the opponent) the decrease in dominance behaviours was probably not secondary to nonspecific sedation. In the social interaction test of anxiety, l-fenfluramine (2.5 and 5 mg/kg) significantly reduced the time spent in active social interaction, and decreased motor activity. Analyses of covariance indicated that these were two independent effects. In the elevated plus-maze, l-fenfluramine (1.25-5 mg/kg) significantly decreased the percent number of entries made onto open arms, and (2.5 and 5 mg/kg) significantly decreased the percent of times spent on the open arms. The total number of arm entries was reduced by all doses (0.625-5 mg/kg). Analysis of covariance indicated that the decrease in percent of time spent on the open arms was secondary to the drop in overall activity. Thus there was no evidence of anxiolytic action in either of these tests, the changes indicating, if anything, anxiogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic diazepam administration and appetitive discrimination learning: acquisition versus steady-state performance in pigeons.

Chronic injections of 2 mg/kg diazepam disrupted both steady-state performance and new discrimination learning in pigeons. However, the time course of disruption differed for each of the two tasks, i.e., steady-state performance was briefly disrupted early, whereas acquisition showed a more persistent delayed disruption. The difference was interpreted as resulting from a dual effect of diazepam on behavior. The early performance disruption was thought to reflect a general nonspecific sedative action of the drug, while the delayed disruption of learning was interpreted as the result of diazepam's selective interference with acquisition processes. Some support for rapid adjustment to the sedative effects of diazepam was found, but there was no evidence for the development of physiological tolerance to diazepam-induced acquisition deficits.

Do lorazeam-induced deficits in learning result from impaired rehearsal, reduced motivation or increased sedation?

1 The effects of 1.0 mg and 2.5 mg lorazepam on learning performance were examined in a double-blind cross-over study using student volunteers. 2 Test conditions were manipulated to prevent rehearsal and to vary the subjects' motivation to perform well. Self-ratings of alertness, motivation to perform well and state anxiety were obtained prior to each test. 3 Performance in arithmetic tasks of varying difficulty was also studied. 4 Lorazepam produced dose-related deficits in verbal and nonsense-syllable learning tasks. A greater proportion of errors in the number of problems attempted in the arithmetic tests reflected an impairment in cognitive function. Lorazepam reduced the number of arithmetic problems that were correctly solved as well as increasing the percentage of errors in the problems attempted. 5 Lorazepam did not significantly decrease motivation to perform well and the lorazepam impairment was found even when the test conditions were manipulated so as to prevent rehearsal. Therefore the learning deficits cannot be explained solely by changes in motivation or impairments in rehearsal. 6 Performance in the learning tasks correlated with ratings of alertness and therefore the deficits observed after administration of lorazepam seem likely to result from the non-specific sedative effect of the drug.

Centrally acting oral skeletal muscle relaxants

A critical examination of the literature on centrally acting, orally administered skeletal muscle relaxants (SMRs) is presented. The available comparative clinical studies are reviewed, and the pharmacology, metabolism and adverse effects of the oral SMRs are discussed briefly. The drugs covered are carisoprodol, chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine hydrochloride, diazepam, metaxalone, methocarbamol, and orphenadrine citrate. The mechanism of action of these agents is not well defined, and their effects are measured mainly by subjective responses. Thus, acceptable evidence of efficacy is difficult to obtain, especially if clinical studies continue to be designed inadequately. There are inadequate data to support the superiority of any one drug. Further, unique clinical efficacy of any oral SMR in comparison to nonspecific sedation has not been established. Based on subjective responses, all agents, except diazepam, have been shown to be superior to placebo in acute disorders; cyclobenzaprine has not been evaluated in acute conditions. SMRs are less effective in chronic disorders. Combination muscle relaxant-analgesic products appear to be superior to their individual components, but the relative efficacy of these combination products in comparison to combined use of individual sedative and analgesic agents is unknown.

Penfluridol: An open phase III study in acute newly admitted hospitalized schizophrenic patients

An open study was carried out in 17 acutely ill, newly admitted, floridly psychotic schizophrenic patients to a city hospital in New York. Penfluridol was given on a daily basis up to doses of 120 mg and patients were rated objectively by means of different psychometric evaluations; vital signs were monitored daily as were side effects. The drug was found to be a rapid acting, well-tolerated, and highly effective antipsychotic agent within the population of patients explored and within the dose range used. It was particularly effective in acutely agitated floridly paranoid schizophrenics; a statistically significant impact was achieved by 7 days and usually within 72 h after initiating treatment. The drug appears unique in that (1) its effects are realized without the untoward and usually troublesome effects of nonspecific sedation attendant upon the use of many other 'neuroleptic' medications, and (2) even within the relatively high doses used it produced no hypotensive effects. It is concluded that this appears to be a unique antipsychotic agent and a potentially important addition to the treatment armamentarium of both acute and chronic schizophrenic individuals.