Andrew J. Goudie

Inter-animal olfactory cues in operant drug discrimination procedures in rats.

Olfactory cues from prior subjects in operant chambers were shown to be an effective stimulus which rodents could use to direct lever selection in a typical operant drug discrimination (DD) paradigm. Such cues persisted for very long periods of time (16h), and were deposited after very short (5 min) operant sessions. In extinction tests inter-animal olfactory cues exerted very strong stimulus control over lever selection. Furthermore, such cues were not specific to individual rodent subjects but were generalizable between subjects. Inter-animal cues directing lever selection could be abolished by cleaning operant manipulanda with a 10% alcohol solution. Reanalysis of some DD data previously reported by one of the authors (Goudie 1977) indicated that this specific earlier study (and by implication perhaps other studies) might have been confounded by inter-animal cues. In a DD study with nicotine it was found that the drug cue was antagonized by mecamylamine for all subjects except those who had a reliable olfactory cue from prior subjects to direct lever selection (subjects who possessed both an olfactory and a drug cue to direct lever selection responded in a way suggesting that the exteroceptive olfactory cue controlled behaviour rather than the interoceptive drug cue). These findings indicate that inter-animal olfactory cues could be of considerable methodological significance in DD studies. The possible significance of such cues has not previously been reported upon in detail, and in reports of many DD studies there do not appear to be explicit indications that interanimal cues have been adequately controlled.

Aversive stimulus properties of drugs.

Abstract A large number of psychoactive drugs have been considered to possess aversive stimulus properties, as demonstrated by their ability to induce conditioned taste aversion (CTA) in animals. However, the interpretation of the CTA effect is at present unclear. The hypothesis that drug-induced CTA is due to drug-induced conditioned “illness” is supported by the results of studies which implicate central emetic systems or their functional equivalents in the acquisition and recall of CTA induced by toxins. However, other data, obtained with agents which are not generally considered to be toxins, are not at present easily reconciled with this hypothesis. Conditioned taste aversion induced by self-administered drugs has been described as “paradoxical” in that some drugs will induce CTA at the same doses that maintain self-administration. A number of possible explanations for this apparent paradox are discussed, the majority of which are considered to be inadequate. The idea that the paradox of CTA induced by self-administered drugs is more apparent than real merits consideration. Possible relationships between studies of drug-induced CTA and operant studies of drugs as aversive agents are discussed. The most fruitful future avenues for research into the actions of drugs in the CTA procedure will probably be those that concentrate on providing answers to very basic questions such as whether or not drug-induced CTA is due to conditioned “illness”, and whether or not the phenomenon termed conditioned taste aversion actually involves conditioning with a drug-induced aversive stimulus.

Effects of Lilly 110140, a specific inhibitor of 5‐hydroxytryptamine uptake, on food intake and on 5‐hydroxytryptophan‐induced anorexia. Evidence for serotoninergic inhibition of feeding

nalorphine. The possibility therefore exists that this variable response to LAAM in monkeys could be due to the differential rates of formation of free and conjugated p-hydroxyacetylbisnormethadol or some other metabolite. This work was supported by NIDA grant DA-00061. ( -)-cc-[2-SH]Acetylmethadol and authentic samples of acetylnorrnethadol, acetylbisnormethadol, methadol, normethadol were provided by Research Triangle Institute, Chemistry and Life Sciences Division, Research Triangle Park, North Carolina, through the courtesy of National Institute on Drug Abuse (NIDA), Rockville, Maryland. The sample of bisnormethadol was a gift from Eli Lilly and Co., Indianapolis, Indiana. The authors are indebted to Dr. Catherine E. Costello of Massachusetts Institute of Technology (Chemistry Department) for the mass spectral studies on the LAAM metabolites. October 20, 1975

Risk-taking but not response inhibition or delay discounting predict alcohol consumption in social drinkers

Impulsivity and risk-taking are multi-dimensional constructs that have been implicated in heavy drinking and alcohol problems. Our aim was to identify the specific component of impulsivity or risk-taking that explained the greatest variance in heavy and problem drinking among a sample of young adults recruited from a university population. Participants (N=75) completed a test battery comprising two commonly used response inhibition tasks (a Go/No-Go task and a Stop signal task), a delay discounting procedure, and the Balloon Analogue Risk Task (BART) as a measure of risk-taking. Participants also completed the Barratt Impulsivity Scales (BIS) as a measure of trait impulsivity. In a hierarchical multiple regression model, risk-taking was identified as the only behavioural measure that predicted alcohol use and problems. In a secondary analysis, we demonstrated that risk-taking predicted unique variance in alcohol use and problems over and above that explained by trait impulsivity. Results suggest that among young adults, a behavioural measure of risk-taking predicts variance in alcohol consumption and alcohol problems, even when individual differences in trait impulsivity are statistically controlled. However, behavioural measures of response inhibition and delay discounting do not predict unique variance in alcohol use in young adult social drinkers.

Behavioural tolerance to amphetamine and other psychostimulants: The case for considering behavioural mechanisms

An hypothesis is presented about the nature of behavioural tolerance in animals to stimulant drugs. It is suggested that, in many behavioural procedures, tolerance is due to behavioural adaptation to those drug effects which cause disruption of ongoing rewarded behaviour. This unitary hypothesis accounts for the available data on tolerance and cross-tolerance to stimulants more effectively than all of the other more conventional explanations which are based upon dispositional or functional concepts, the most common of which are described, evaluated, and found to be inadequate. Furthermore, it is suggested that attempts to explain tolerance in terms of changes in synaptic functioning are subject to very considerable problems of interpretation and that an analysis of behavioural mechanisms may be of greater value in understanding the process of behavioural tolerance. Evidence for the basic behavioural hypothesis is outlined in some detail, and a theoretical justification presented for its major assumptions. Operant studies of chronic stimulant effects on behaviour have often produced very complex patterns of data, considerable differences being reported both between subjects and between studies. A speculative model is presented which attempts to account for this pattern of data in tolerance studies.

Cocaine-induced conditioned taste aversions in rats.

In two separate studies cocaine hydrochloride at doses between 10--36 mg/kg was found to induce a dose-related conditioned taste aversion (C.T.A.) to saccharin, and to be an effective conditioning agent even when injections of the drug were delayed 90 min after saccharin intake. These data contrast with conditioning agent when unjectuons of the drug were delayed 90 min after saccharin intake. These data contrast with an earlier report [3] which suggested that cocaine was totally devoid of aversive properties. However, they do indicate that cocaine is only a weak aversion-inducing agent. In contrast to other drugs, the doses of cocaine which are required to induce a C.T.A. are very large relative to those commonly employed in behavioural studies. The weak potency of cocaine in inducing C.T.A. may be related to the drugs marked potency in the self-administration paradigm. Some possible determinants of cocaines weak effects are discussed.

Characterization of olanzapine-induced weight gain in rats

Novel antipsychotic drugs (APDs) have enhanced therapeutic actions compared to ‘typical’ APDs. However,clinical studies indicate that some induce marked weight gain. We attempted to model this effect in female Wistar rats given olanzapine chronically at 4 mg/kg b.i.d (4.5 h between injections). Such rats showed marked weight gain, which was statistically significant after only a single day of treatment, although weight gain increased up to a plateau after 10 days of treatment. Cessation of treatment led to rapid weight loss, which was significant after a single day of withdrawal. The weight gain observed was characterized by marked individual differences. As some clinical reports suggest that novel APD-induced weight gain is most pronounced in patients with the lowest body weight, we examined the relationship between weight gain and baseline body weight. However, we observed no significant relationship between baseline body weight and weight gain. The observation that olanzapine can induce weight gain rapidly in rats, in conjunction with the observation of marked individual differences in weight gain, suggests that patients at risk of developing weight gain might be detectable early in treatment. Furthermore, the finding that weight gain is rapidly reversible suggests that patients at risk of weight gain could be switched to APDs with less pronounced tendencies to induce weight gain. The study of APD-induced weight gain in rodents may provide insights into the nature, causes, and treatments for, novel APD-induced weight gain in the clinic. However, it remains to be determined how closely rodent models mimic the clinical situation and whether the mechanism(s) involved in the weight gain we have observed are the same as those involved in the clinical use of these drugs.

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

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

Many of olanzapines (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. OLZs effects in humans can very clearly be most validly modelled in female rats, although the cause(s) of the sex difference in OLZs 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 OLZs 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 OLZs 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.

Abstract:  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.