Pimozide prevents the development of conditioned place preferences induced by rewarding locus coeruleus stimulation

doi:10.1016/S0166-4328(05)80290-6

Behavioural Brain Research

Volume 50, Issues 1–2, 28 September 1992, Pages 85-92

https://doi.org/10.1016/S0166-4328(05)80290-6 Get rights and content

Electrical stimulation in the vicinity of the cell bodies of the locus coeruleus (LC) has been shown to support self-stimulation behaviors in rats. In the present study, a Conditioned Place Test, sensitive to both rewarding and aversive qualities of brain stimulation, was employed to determine (a) whether rewarding locus coeruleus stimulation would result in place preferences and (b) if so, whether dopamine receptor antagonism would affect the development of such place preferences. Animals were pretreated with pimozide (0.0, 0.5 or 1.0 mg/kg) prior to exposure to two distinctive environments only one of which was paired with locus coeruleus stimulation. Rats that received vehicle injections prior to stimulation/place pairings developed strong preferences for the stimulation-paired environment while those animals pretreated with 0.5 mg/kg pimozide showed no reliable shift in preference from baseline performance. Additionally, animals injected with the 1.0 mg/kg dose of pimozide exhibited mild place aversions to the stimulation-paired environment. It is hypothesized that dopamine neurotransmission is important for the rewarding effects of locus coeruleus stimulation without which such stimulation appears to be aversive.

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The affective response to cocaine (COC) has been suggested to follow a time-course and pattern that adheres to the prediction of opponent-process models of drug actions. While the initial impact of the drug is positive, within a few minutes that effect wanes and is replaced by an aversive state characterized by anxiety and drug craving. We have demonstrated this phenomenon in animals by showing that rats prefer distinctive environments associated with the immediate effects of intravenous COC (1.0 mg/kg) but avoid environments associated with the state present 15-min postinjection. Human addicts have reported taking ethanol with their COC as a means of attenuating the negative aftereffects of COC administration. The combination of ethanol and COC results in the production of cocaethylene (CE), a metabolite of COC having psychostimulant properties. The current study was devised to assess whether the immediate and delayed affective responses to CE might account for the self-medication strategy of COC addicts pretreating themselves with ethanol. Rats developed conditioned place preferences for environments paired with the immediate effects of a 1.44-mg/kg intravenous dose of CE (equimolar to a 1.0-mg/kg dose of COC). While no aversive effects were observed at 0, 5, or 15 min postinjection, reliable place avoidance was detected for an environment paired with the internal state present 30-min post-CE. These data are consistent with the view that the development of CE may account for efficacy of ethanol to delay and weaken the aversive aftereffects of COC.
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Citation Excerpt :
In a sample of schizophrenic patients, D2 receptor binding in the putamen was in a positive significant correlation (r=0.64, P<0.05) with emotional impairment [427]. Interestingly, in the study by Duvauchelle et al. [136], a low dose of pimozide, a DA receptor antagonist, blocked conditioned place preference induced by LC stimulation, but at a high dose, pimozide produced a mild aversion. This suggests that the LC activation becomes aversive under conditions in which the DA-ergic hedonic or energizing circuitry is functioning subnormally.
A model for the pathophysiology of depression is discussed in the context of other existing theories. The classic monoamine theory of depression suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. More recent elaborations of the classic theory also implicitly include this postulate, other theories of depression frequently prefer to depart from the monoamine-based model altogether. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity, and concomitantly, exaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to dysregulation of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Concomitant impairments in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptivity to stressful stimuli.
Effects of cocaine context on NAcc dopamine and behavioral activity after repeated intravenous cocaine administration
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Citation Excerpt :
For example, though dopamine neurotransmission has been shown to increase during rewarding [25,39,45,47] and aversive events [1,13], these aversion-related changes occur primarily in cortical, rather than subcortical brain regions. In addition, aversive conditioning has been shown to decrease, rather than increase dopamine levels in the NAcc [8,24], and dopamine antagonists block stimulation-induced place preferences [15,17,18,21], but not place aversions [15]. Furthermore, dopamine neurons fire during presentation of conditioned reward-predicting stimuli [39,45,47], while stimuli previously paired with aversive events rarely elicit single-unit midbrain dopamine response [40].
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The present experiment was devised to test a prediction of the Opponent-Process Theory of drug action. This theory presumes that the initial affective experience of a subject treated with cocaine would be diametrically different immediately after administration compared to some point later in time when the positive impact of the drug had subsided. A conditioned place-preference procedure was employed in which a novel environment was paired with the effects of cocaine either immediately after, 5 min after, or 15 min after an intravenous injection of 0.75 mg/kg cocaine. It was hypothesized that animals would come to prefer environments associated with the immediate positive effects of cocaine and avoid environments associated with the drug's subsequent negative effects. The results confirmed this hypothesis. While the 0-min delay and 5-min delay groups exhibited conditioned preferences for the cocaine-paired environment, the 15-min delay group came to avoid the side of the preference apparatus paired with cocaine. These data, therefore, serve as additional support for an Opponent-Process account of cocaine's actions.
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This review gives an overview of recent findings and developments in research on brain mechanisms of reward and reinforcement from studies using the place preference conditioning paradigm, with emphasis on those studies that have been published within the last decade. Methodological issues of the paradigm (such as design of the conditioning apparatus, biased vs unbiased conditioning, state dependency effects) are discussed.
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Thus, although the paradigm has also been criticized because of some inherent methodological problems, it is clear that during the past decade place preference conditioning has become a valuable and firmly established and very widely used tool in behavioural pharmacology and addiction research.
Continued trends in the conditioned place preference literature from 1992 to 1996, inclusive, with a cross-indexed bibliography
1998, Neuroscience and Biobehavioral Reviews
SCHECHTER, M.D., and D.J. CALCAGNETTI, Continued trends in the conditioned place preference literature from 1992 to 1996, inclusive, with a cross-indexed bibliography. NEUROSCI BIOBEHAV REV 22(6) 827–846, 1998.—In light of the overwhelming response to the previous publication in Neuroscience and Biobehavioral Reviews (1993, 17, 21–41) regarding trends in place conditioning (either preference or aversion), the present work constitutes a five-year follow-up to review the empirical research in this behavioral paradigm from 1992 to 1996, inclusively. The behavioral technique has grown as indicated by the number of publications over the last five years which equals those authored over the 35 years covered by our last survey. The previous work used descriptive statistics to explore topical issues, whereas the present work discusses trends since that time and hopes to provide an exhaustive bibliography of the CPP literature, including articles, published abstracts, book chapters and reviews, as well as providing a cross-index of identified key words/drugs tested.

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^*: Present address: Boston University School of Medicine, Laboratory of Behavioral Pharmacology, 80 E. Concord Street, Boston, MA 02118, USA

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Pimozide prevents the development of conditioned place preferences induced by rewarding locus coeruleus stimulation

Brain Res.

Brain Res.

Behav. Biol.

Psychopharmacology

Pharmacol. Biochem. Behav.

Life Sci.

Brain Res.

Brain Res.

Pharmacol. Biochem. Behav.

Neurosci. Biobehav. Rev.

Brain Res.

Brain Res.

Brain Res.

Pharmacol. Biochem. Behav.

Brain Res.

Pharmacol. Biochem. Behav.

Brain Res.

Life Sci.

Brain Res. Bull.

Brain Res.

Life Sci.