Induction by Antipsychotics of “Win-Shift” in the Drug Discrimination Paradigm

Abstract

In a two-lever, food-rewarded drug discrimination paradigm, behavior seems to be governed by a win-stay/lose-shift rule; rats continue to press the lever that yields food, and, when not rewarded, they shift responding to the alternative lever. Here, we report on the effects that antipsychotics and further neuropharmacological agents exert in those conditions. At higher doses, antipsychotics disrupt most or all behavioral parameters in this paradigm. However, at lower doses, rats may select the appropriate lever with normal latency and accuracy, obtain a first food pellet (i.e., "win"), and then, remarkably, shift responding to the alternative lever ("win-shift"). This suggests that antipsychotics can block the effects of reward selectively, i.e., at doses where the initial, secondarily reinforced behavior including the initiation of lever pressing, remains intact. Indeed, saline-treated rats that are given no reward (i.e., "lose") after having selected a lever, also press the alternative lever ("loseshift"). The induction of selective win-shift is specific to antipsychotics, but it varies greatly among them. Perhaps relating to its alleged "incisive" action on delirium and hallucinations, and, surprisingly, in view of its extrapyramidal actions, acutely administered haloperidol (0.04 -0.08 mg/kg) demonstrates win-shift to an exceptional extent, shared only with the newly proposed agent (3-cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-amine fumarate (F 15063; 0.31-0.63 mg/ kg); the more sedative antipsychotic chlorpromazine demonstrated little selectivity. The paradigm offers a novel tool to characterize antipsychotics with regard to presumably pathogenic motivational processes; mixed D 2 -antagonist/5-hydroxytryptamine 1A -agonist agents such as F 15063 may conceivably share the powerful antipsychotic action of haloperidol while avoiding the sensitization that develops to extrapyramidal effects of haloperidol and consequent negative symptoms.In a typical drug discrimination (DD) experiment, subjects are trained to discriminate a given training drug from saline. For example, rats can be trained to press one of two levers (drug-appropriate lever; DL) for food in sessions preceded by the injection of the opioid fentanyl and to press the alternative lever (saline-appropriate lever; SL) in sessions preceded by saline injection (Colpaert and Janssen, 1984).Rats that have been trained to discriminate fentanyl from saline can demonstrate an exquisite discrimination; the lever selection that is to be made early in the session is correct in nearly 100% of the sessions and occurs with great speed (short latency) and accuracy [the animal pressing the inappropriate lever little if at all before completing the first fixed ration (FR)10 schedule on the appropriate lever]. After having selected the appropriate lever, the rats continue to lever press, totaling some 1500 responses/session, which typically are all made on the appropriate, reward-associated lever (Colpaert, 1978(Colpaert, ...

Behavioral flexibility is increased by optogenetic inhibition of neurons in the nucleus accumbens shell during specific time segments

“…Alterations in dopamine signaling have previously been associated with changes in behavioral flexibility. For example, Colpaert et al (2007) found that systemic dopamine D 2 antagonists increased win-shift behavior after a rewarded trial. Conversely, Halluk and Floresco (2009) found that infusions of the D2 agonist quinpirole directly into the NAcc impaired reversal learning without disrupting initial response learning.…”

An investigation of the behavioral mechanisms of antipsychotic action using a drug–drug conditioning paradigm

“…This finding suggests that the antagonism of either dopamine D 2 receptors, muscarinic receptors, or 5-HT 2A/2C receptors is sufficient to mimic the OLZ-induced interoceptive state. Colpaert et al (2007) used a two-lever, food-rewarded drug discrimination paradigm and found that HAL was more efficacious than OLZ in inducing ‘win-shift’ response pattern, possibly because of its strong D 2 receptor antagonism. As the ‘antipsychotic’ action, as well as the antiavoidance effect is thought to be mediated by antagonism against D 2 receptors (Wadenberg et al , 2001; Seeman, 2006), the compound cue mediated by multiple receptor actions of OLZ is apparently less effective in bestowing an antipsychotic property to CDP than the single cue mediated by D 2 blockade by HAL.…”

“…In contrast to the well-documented salience attenuation effect of antipsychotics (Fouriezos et al , 1978; Berridge and Robinson, 1998; Dickinson et al , 2000; Wise, 2004; Colpaert et al , 2007), the notion that the drug-induced interoceptive state(s) may be involved in the antipsychotic effects is relatively new, although preclinical studies such as those based on drug discrimination and state-dependent learning have long recognized the distinct drug states induced by typical and atypical antipsychotics (Overton, 1979; Goudie et al , 1998; Porter et al , 2000b; Porter et al , 2005). The primary goal of this study was thus to examine this mechanism further, using a novel drug–drug conditioning paradigm in the CAR model.…”

Dopamine and reward: The anhedonia hypothesis 30 years on

“…Here the animals are trained to continue responding on one of two levers as long as that lever yields food reward, and to shift to the other lever when no longer rewarded. With low-doses of haloperidol, animals inexplicably shift to the wrong lever as if they had earned no food with their initial lever-press (Colpaert et al , 2007). That is, haloperidol-treated rats that earned food on their initial lever-press behaved like normal rats that failed to earn food on their initial lever-press.…”