A clozapine-like effect of cyproheptadine on progressive ratio schedule performance.

The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT2) and histamine (H1) receptor antagonist effects, are shared by the non-selective 5-HT receptor antagonist cyproheptadine. Atypical antipsychotics have a characteristic profile of action on operant behaviour maintained by progressive ratio schedules, as revealed by Killeen's (1994) mathematical model of schedule controlled behaviour. These drugs increase the values of a parameter that expresses the 'incentive value' of the reinforcer (a) and a parameter that is inversely related to the 'motor capacity' of the organism (δ). This experiment examined the effects of acute treatment with cyproheptadine and clozapine on performance on a progressive ratio schedule of food reinforcement in rats; the effects of a conventional antipsychotic, haloperidol, and two drugs with food intake-enhancing effects, chlordiazepoxide and Δ9-tetrahydrocannabinol (THC), were also examined. Cyproheptadine (1, 5 mg kg⁻¹) and clozapine (3.75, 7.5 mg kg⁻¹) increased a and δ. Haloperidol (0.05, 0.1 mg kg⁻¹) reduced a and increased δ. Chlordiazepoxide (3, 10 mg kg⁻¹) increased a but reduced δ. THC (1, 3 mg kg⁻¹) had no effect. Interpretation based on Killeen's (1994) model suggests that cyproheptadine and clozapine enhanced the incentive value of the reinforcer and impaired motor performance. Motor impairment may be due to sedation (possibly reflecting H1 receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H1 and 5-HT2 receptors, which has been proposed as the mechanism underlying the food intake-enhancing effect of cyproheptadine. In agreement with previous findings, haloperidol impaired motor performance and reduced the incentive value of the reinforcer. Chlordiazepoxide's effect on a is consistent with its food intake-enhancing effect.

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.

Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms.

Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies. However, four other putative D3-preferring antagonists (PD 152255, (+)-S14297, nafadotride and (+)-AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU-99194A, which has been suggested to induce a stimulus mediated specifically by D3 antagonism, the D3-preferring antagonist (+)-UH 232 and clozapine both induced full generalization. However, the PNU-99194A-trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU-99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M1-M5 receptors indicated that (with the possible exception of the M4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU-99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU-99194A had high affinity for the D3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU-99194A and muscarinic antagonists may be mediated by common effects 'downstream' from either muscarinic or D3 receptors; (2) D3 antagonism does not play a critical role in the clozapine stimulus (since D3-preferring antagonists did not consistently induce generalization to clozapine); (3) although D3 antagonism plays a role in the PNU-91994A stimulus (since the D3-preferring antagonist (+)-UH 232 induced full generalization, in accord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU-99194A and other D3-preferring antagonists should be borne in mind when this agent is used as a tool to study D3 receptor functioning in vivo. The similarities between the PNU-99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU-99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU-99194A.

Discriminative stimulus properties of antipsychotics.

Drug discrimination methodology has been used in a number of ways to analyze the actions of novel and putative novel antipsychotics in vivo. Recent studies suggest (a) in contrast to earlier theorizing, antagonism of the low-dose d-amphetamine stimulus in rats may not be an effective screen for novel antipsychotics; (b) dopamine D2-like agonists and antagonists, some of which are putative antipsychotics, can be studied in vivo as discriminative cues, although there is a pressing need for more selective drugs that differentiate the various members of the D2 family. (c) antagonism of the cue induced by the noncompetitive NMDA antagonist MK-801, which has been proposed as a possible screen for clozapine-like compounds, may be an unreliable assay; and (d) the clozapine stimulus is probably a compound cue (a drug "mixture"), which can be used to screen for novel clozapine-like antipsychotics, although the precise receptor mechanisms involved in mediating the clozapine stimulus, and its direct relevance to the antipsychotic action of clozapine remains to be proven conclusively.

Does MK-801 discrimination constitute an animal model of schizophrenia useful for detecting atypical antipsychotics?

Two groups of female Wistar rats were trained to discriminate two doses (0.075 and 0.0375 mg/kg) of the noncompetitive NMDA antagonist MK-801 (dizocilpine) in a food-rewarded operant FR30 drug discrimination task. The atypical neuroleptic clozapine (2-6 mg/kg) produced only minimal antagonism (max. 32%) of the MK-801 cue at either training dose, and the "antagonist" effects were not clearly dose related. Furthermore, in the 0.075 mg/kg trained animals clozapine at 3 mg/kg failed to shift the MK-801 dose-response curve to the right. The alpha1-adrenoceptor antagonist prazosin (1-8 mg/kg) was also tested for antagonism of the 0.0375 mg/kg MK-801 cue, and again, only partial antagonism was seen (maximum 36%). Recently, it was suggested [4] that as the discriminative stimulus produced by MK-801 (0.075 mg/kg) was fully antagonized by clozapine at 3 mg/kg, but not by the typical neuroleptic haloperidol, this assay may be a useful screen for detecting atypical neuroleptics. It would seem, however, that this is not necessarily the case, and that the MK-801 discriminative cue may not be psychotomimetic. However, as this was a food rewarded rather than an avoidance paradigm that was used in the prior study [4], it may be that the drug discrimination procedure itself is a critical factor, although this hypothesis requires empirical testing.

Clozapine as a drug of dependence.

RATIONALE: In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment. OBJECTIVE: The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures. METHODS: Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study. RESULTS: Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal. CONCLUSIONS: Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs.

Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands.

The interoceptive stimulus induced by clozapine (5 mg/kg, i.p.) has been characterized in an operant drug discrimination procedure in the rat using a wide range of receptor subtype-selective agonists and antagonists. Only the muscarinic receptor antagonist scopolamine generalized fully to clozapine (>80%). Partial generalization (defined here as 40% maximal generalization) was seen with the D1 receptor antagonist SCH 23390 (43% maximal generalization), the alpha1-adrenoceptor antagonist prazosin (67%) and the alpha2-adrenoceptor antagonist methoxyidazoxan (42%). All other specific agents tested induced <25% maximal generalization, including the alpha2-adrenoceptor antagonist yohimbine (24%), the histamine H1 receptor antagonist mepyramine (21%), the D2 antagonist typical neuroleptic haloperidol (23%), the D4 receptor antagonist L-745,870 (14%), the 5-hydroxytryptamine-1A (5-HT1A) receptor agonist S-14506 (8%), the 5-HT2A receptor antagonists ketanserin (0%) and M100907 (12%), the 5-HT2B/2C receptor antagonists SB 200646A (8%) and SDZ SER 082 (6%), and the 5-HT3 receptor antagonist ondansetron (0%). The clozapine discriminative stimulus was not blocked by the dopamine D1 receptor antagonist SCH 23390, or by the 5-HT1A receptor antagonist WAY 100635, when given concomitantly with clozapine. Although the results suggest that muscarinic antagonism plays a major role in the clozapine cue, the results have to be considered in the light of the full generalization to clozapine seen with various antipsychotic agents which have very low affinity for muscarinic receptors, including zotepine, quetiapine, JL13 and PNU 96415 (a finding replicated in rats from the same breeding colony as those which generalized to scopolamine). Thus, generalization to clozapine for antipsychotics with multiple affinities but with low muscarinic affinity is probably mediated by additive or perhaps supra-additive actions at other receptors, although extensive studies with various combinations of drug mixtures are required to validate this hypothesis.

Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data.

Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.

Effects of the CCKB antagonist L-365, 260 on benzodiazepine withdrawal-induced hypophagia in rats.

The effect of the selective CCKB antagonist L-365, 260 on chlordiazepoxide (CDP) withdrawal-induced hypophagia was assessed in two related studies in rats pretreated for 21 days with CDP at doses escalated from 10 to 30 mg/kg per day (b.i.d). L-365, 260 was studied at doses from 0.001 to 10 mg/kg (b.i.d). There was no evidence that L-365, 260 at any dose alleviated CDP withdrawal-induced hypophagia. These data contrast with reports that CCKB antagonists alleviate behavioural benzodiazepine (BZ) withdrawal symptoms considered to be indicative of "anxiogenesis". Presumably, such positive effects of CCKB antagonists are due to "functional antagonism", with enhanced anxiety during BZ withdrawal being attenuated by anxiolytic actions of CCKB antagonists. Collectively, studies with CCKB antagonists and other agents involving a number of different BZ withdrawal signs suggest that BZ withdrawal is a heterogeneous syndrome, with various different underlying mechanisms. CCKB antagonists appear to alleviate only a subset of possible BZ withdrawal signs.

Assessment of the benzodiazepine-like dependence potential in rats of the putative 5-HT(1A) agonist anxiolytic S-20499.

The dependence potential of the putative 5-HT(1A) agonist anxiolytic S-20499 was assessed in rats in a study in which the benzodiazepine chlordiazepoxide (CDP) was used as a "positive control". S-20499 was administered b.i.d. (at 10.00 and 16.00h) for 21 days, at constant doses of either 0.5, 3 or 18mg/kg i.p. Subsequently, spontaneous withdrawal from S-20499 was studied over 7 days. Acutely, S-20499 decreased body weight and food intake and complete tolerance developed to these effects. When S-20499 was withdrawn there was no evidence of any effect on body weight or food intake. CDP was also administered b.i.d. (at 10.00 and 16.00h) for 21 days at doses escalated from 10 to 30mg/kg i.p. CDP differed from S-20499 in some of its acute effects, stimulating body weight and food intake. In contrast to S-20499 withdrawal, CDP withdrawal induced weight loss and aphagia. Acutely, S-20499 resembled CDP in inducing hypothermia. Full tolerance developed to this effect of both drugs. However, only CDP withdrawal induced hyperthermia. Thus S-20499 appeared to be devoid of benzodiazepine-like dependence potential after administration for a relatively long period of time, at doses that are substantially greater than "anxiolytic doses" in rats.

Assessment of the dependence potential of the potent high-efficacy 5-HT1A agonist S-14506 in rats.

This study assessed the dependence potential of S-14506 [ 1- [ 2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy napthyl) piperazine], a novel, potent 5-HT(1A) full agonist with anxiolytic and antidepressant actions in animal models. The dependence potential of S-14506 was compared with that of the benzodiazepine (BZ) chlordiazepoxide (CDP). BZ withdrawal caused weight loss, aphagia and hyperthermia after chronic b.i.d. treatment for 21 days. None of these withdrawal effects were seen after similar b.i.d. S-14506 treatment at high doses. However, the acute pharmacological actions of CDP and S-14506 differed on a number of indices. Specifically, CDP increased food intake and body weight, whilst S-14506 decreased these measures, possibly due to the induction of the serotonin syndrome. Of particular interest was the observation that S-14506 induced marked hypothermia, to which complete tolerance developed very rapidly (after only 1 day). The observation of marked, rapid tolerance to S-14506-induced hypothermia, in conjunction with the absence of withdrawal hyperthermia after prolonged chronic treatment at high doses, suggests that tolerance to this effect of S-14506 can be dissociated from dependence. Collectively, the data reported suggest that the full 5-HT(1A) agonist S-14506 is devoid of dependence potential, other human and animal studies having previously suggested that partial 5-HT(1A) agonists typically induce no, or minimal, dependence.

Actions of ritanserin, a 5-HT(2/1C) antagonist, in benzodiazepine-dependent rats.

The effects of ritanserin on spontaneous benzodiazepine (BZ) withdrawal-induced weight loss, anorexia and hypodipsia were studied. Groups of female rats initially received i.p. injections b.i.d. (11.00 and 17.00h) of either saline or chlordiazepoxide (CDP). CDP doses increased by 2mg/kg/day from 10mg/kg to a final does of 30mg/kg. Treatment was maintained for 26 days. Over the next 6 days animals were either treated b.i.d. with vehicle, CDP, or ritanserin at one of three doses (0.16,0.63 and 2.5mg/kg). In CDP-pretreated animals subsequently treated with vehicle, significant weight loss, anorexia and hypodipsia were seen, relative to controls. In saline-pretreated animals ritanserin had no effect on body weight. However, CDP withdrawal-induced weight loss was actually exacerbated by ritanserin, in a dose-related fashion. Thus, ritanserin potentiated withdrawal-induced weight loss, by a process which did not involve functional (additive) effects of withdrawal and ritanserin treatment. Ritanserin stimulated food intake in saline-pretreated animals. Despite this effect it failed to alleviate CDP withdrawal-induced anorexia. However, in contrast to the weight loss index, no evidence was obtained for potentiation of withdrawal-induced anorexia. In saline-pretreated animals ritanserin had no effect on water intake, nor did it alleviate or potentiate CDP withdrawal-hypodipsia. Thus the effects of ritanserin on somatic BZ withdrawal signs depended upon the specific sign studied, different signs showing potentiation or no effect. However, for none of the signs studied was there any evidence that ritanserin alleviated the effect of CDP withdrawal. 5-HT(2/1C) antagonists may therefore be of limited value in the treatment of somatic aspects of the BZ withdrawal syndrome. They may even exacerbate some BZ withdrawal signs, although a full characterization of the effects of such drugs on BZ withdrawal requires that a number of other different withdrawal signs and symptoms should be studied, since it seems likely that different BZ withdrawal signs involve different underlying mechanisms.

Evidence for a dissociation between benzodiazepine withdrawal signs.

The relationship between benzodiazepine-withdrawal induced weight loss and conditioned taste aversion was studied. Rats were treated with chlordiazepoxide (CDP) for 10 days (n = 37) or with vehicle (n = 39). Significant withdrawal-induced weight loss was observed. On day 11 all animals received an intra-oral infusion of saccharin. In a subsequent saccharin vs water choice test significant withdrawal-induced conditioned taste aversion was observed, as CDP pretreated animals drank less saccharin than controls. The two withdrawal indices were not correlated in the CDP pretreated animals [r = + 0.05], despite the fact that we studied a large group of rats. These data are in agreement with suggestions that drug withdrawal syndromes may be heterogeneous phenomena with a number of different underlying neural mechanisms.