Acute effects of olanzapine on behavioural expression including the behavioural satiety sequence in female rats.

Olanzapine is a novel antipsychotic drug known to induce clinically significant weight gain. Although the cause of such weight gain is not fully known, drug-induced changes in appetite and food intake are likely to play a significant role together with other possible mechanisms enhancing weight and/or adiposity. We assessed acute drug effects on 1 hour intake and behavioural expression in female rats. Low doses of olanzapine (0.5 and 1 mg/kg) enhanced acute mash intake. Marked drug effects were seen on a number of behaviours following olanzapine over a range of doses. These effects included dose-related reductions in activity and exploratory behaviours and associated substantial dose-related increases in resting behaviour. Behavioural data were also used to plot drug effects over time, including behavioural satiety sequence (BSS) profiles, to evaluate whether olanzapine's hyperphagic effects might be a consequence of altered satiety development. BSS profiles reflected enhanced eating behaviour at low doses (0.5 and 1 mg/kg) but showed dose-related increases in resting, indicative of drug-induced sedation, which meant that it was impossible to fully discern olanzapine's effects on satiety. Acute olanzapine induces both hyperphagia and sedation, both of which may promote weight gain and adiposity, but which interact competitively.

Chronic clozapine treatment in female rats does not induce weight gain or metabolic abnormalities but enhances adiposity: implications for animal models of antipsychotic-induced weight gain.

The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various antipsychotics to enhance adiposity.

Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities.

Many of olanzapine's (OLZ) actions in humans related to weight regulation can be modelled in female rats (Cooper et al., 2005). Such effects include weight gain, hyperphagia, enhanced visceral adiposity and elevated Levels of insulin and adiponectin. As sex differences have been reported in the effects of antipsychotic drugs, including OLZ, in rats, the current study extended our study in female rats by directly comparing the actions of OLZ in maLes using identical methodology. Individually housed male Han Wistar rats were administered OLZ twice daily (i.p.), at 0, 1, 2, and 4 mg/kg over 21 days. Both differences from, and simiLarities to, the data obtained in females were obtained. Males treated with OLZ showed reduced weight gain, enhanced visceral adiposity and reduced lean muscle mass. There were no accompanying changes in food or water intake. OLZ did not induce changes in plasma levels of insulin, leptin or glucose. Significant elevation of adiponectin was observed. OLZ-treated males displayed elevated prolactin and suppressed testosterone. OLZ's effects in humans can very clearly be most validly modelled in female rats, although the cause(s) of the sex difference in OLZ's actions in rats are not clear. However, the finding that significantly enhanced adiposity is seen in both male and female rats, in other animal species (mice and dogs) and in humans suggests that studies in male rats of OLZ's effects may be of value, by highlighting the consistent ability of OLZ to increase visceral adiposity. It is hypothesized that such adiposity is a key, clinically relevant, common component of OLZ's actions which may be, at Least partially, independent of both OLZinduced weight gain and hyperphagia, and which is induced reliably in male and female rats and other animal species. Possible mechanisms involved in the effects reported are discussed.

Antipsychotic-induced weight gain.

Novel 'atypical' antipsychotic drugs represent a substantial improvement on older 'typical' drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. This interferes with compliance with drug taking and has expected effects on morbidity and mortality. In this review, we summarize current thinking on: (i) the extent to which different 'atypical' drugs induce weight gain; (ii) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction; and (iii) the state of development of animal models in this area. We also outline major areas for future research.

A parametric analysis of olanzapine-induced weight gain in female rats.

RATIONALE: Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear. OBJECTIVE: The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings. METHODS: Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration. RESULTS: Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg). CONCLUSIONS: These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

Contrasting phenotypes of C57BL/6JOlaHsd, 129S2/SvHsd and 129/SvEv mice in two exploration-based tests of anxiety-related behaviour.

Knockout mice are typically generated on a mixed genetic background and, as such, detailed behavioural characterisation of these background strains is essential to the valid interpretation of mutant phenotypes. In this context, recent research has revealed significant differences in anxiety-like behaviour among the most commonly used background strains (C57BL/6J and various 129 substrains), leading to the possibility that at least certain mutant phenotypes may not after all be due to the targeted mutation. However, these findings derive largely from behavioural test batteries in which there may well be an experiential confound, while the widely reported hypolocomotor profile of most 129 substrains may compromise the principal indices of anxiety-like behaviour. In the present study, we have compared the behavioural profiles of three commonly used background strains (C57BL/6JOlaHsd, 129/SvEv and 129S2/SvHsd) in two of the most popular animal models of anxiety-the elevated plus-maze (EPM) and light/dark exploration (LDE) tests. Naive animals were used for each procedure, ethological scoring methods were employed throughout, and the inbred phenotypes were also compared with that of an outbred strain (Swiss-Webster) widely employed in test validation and behavioural pharmacology. Our results show that, despite their hypolocomotor profile, both 129 substrains display higher levels of anxiety-like behaviour (conventional and/or ethological measures) relative to the C57BL/6JOlaHsd strain. Furthermore, all three inbred strains were less active in both tests when compared with the outbred Swiss-Webster strain. However, whereas C57BL/6JOlaHsd mice displayed lower levels of anxiety-like behaviour than their Swiss-Webster counterparts (both tests), 129S2/SvHsd (but not 129/SvEv) mice exhibited evidence of higher anxiety, particularly in the LDE test. The implications of these findings are discussed in relation to both the behavioural and pharmacological phenotyping of mutant mice.

Studies in REST. I. Reduced Environmental Stimulation Therapy (REST) and reduced alcohol consumption.

Reduced Environmental Stimulation Therapy (REST), formerly known as "sensory deprivation," was used in conjunction with pre-recorded anti-alcohol messages to reduce alcohol consumption. Subjects were college students of both sexes who were "heavy social drinkers," that is, early prodromal alcoholics. There were two studies. In the pilot study experimental subjects had two and a half hours of REST, during which they heard one of two differently worded anti-alcohol messages. After two weeks their alcohol intake dropped significantly from baseline levels (33% and 29%); control subjects showed no significant changes. In a replication and follow-up study experimental subjects had two and a half hours of REST, during which they heard a revised version of the most effective anti-alcohol message used in the pilot study. Two weeks later their alcohol consumption dropped 55% from baseline levels. These reductions in alcohol intake were fully sustained on follow-up three months and six months later. Untreated control subjects showed increased alcohol intake on follow-up.

Studies in REST. II. An overview of REST technology.

This paper briefly summarizes current knowledge about Reduced Environmental Stimulation Therapy (REST). Major effects consistently produced by REST include (a) superlearning, (b) optimal physiological and psychological functioning, and (c) diminished denial and defensiveness. Persons showing greatest impairment or psychological disturbance prior to REST typically show the greatest "improvement" or change toward optimal levels of functioning afterward. REST facilitates natural homeostatic processes. Despite three decades of overwhelmingly positive research findings, REST technology has thus far received little understanding or acceptance. Common misconceptions about REST (formerly known as "sensory deprivation") are critically assessed and shown to be unfounded.

Prediction of differences in Rorschach protocols from the Personality Assessment System.

The Personality Assessment System (PAS) is derived from certain subtest scores on any Wechsler test by rather simple calculations. It purports to measure, among other personality attributes, developmental changes in the Internalized-Externalized (I-E) dimension of personality, which is akin to the Introversion-Extroversion construct reflected by some Rorschach measures. PAS scores from a tightly defined sample of normal adults were contrasted with Experience Balance (EB) and Body-image (B) scores derived from Rorschach protocols by "blind" scorers. Significant relations were found between EB ratios produced via the Exner and Klopfer scoring systems and the primitive (early childhood) I-E scores from the PAS. The B scores produced by the Body Image scoring system were related to the basic (adolescent) I-E PAS scores. Although significant, the PAS-Rorschach correlations were relatively poor, in part because it was difficult to define the center of the internalization-externalization continuum in terms of the Rorschach protocols. It is, nevertheless, provocative that traditional scorings of the Rorschach responses of adults assess differences not only in this personality trait, but also in its development, as determined from scaled scores on Wechsler subtests.

Interviewer's role-playing and responses to sensory deprivation: a clinical demonstration.

10 Ss with a history of intransigent hypochondriacal personality disorder were subjected to 2-1/2 hr. of sensory deprivation preceded and followed by planned interviewing procedures. Each interview was designed to prestructure the interpersonal meaning of the experience of sensory deprivation and selectively reinforce social roles antithetical to S's characteristic, maladaptive interpersonal behavior. As predicted, Ss showed a significant (p smaller than .01) shift from passively hostile to an actively warm social role. The changes in social role were also reflected in a significant (p smaller than .01) reduction in number of medical clinic visits. These effects were still operative 30 days following the procedure, whereas an equated baseline group of 10 Ss showed no significant change in behavior over the same period of time.