The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats

Abstract

Human cocaine users report that the initial “high” produced by cocaine administration is followed by an anxiogenic “crash”. Given that cocaine has such robust and opposing properties, it is likely that both the positive and negative effects of cocaine contribute to an individual’s motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine’s dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug’s negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine’s opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1 mg/kg/0.1 ml) three hours after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine’s immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug’s negative/anxiogenic properties.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

“…Interestingly, Wenzel et al (2013) found that dopamine receptor blockade with a similar dose of cisflupenthixol reduced cocaine-induced place preference but did not affect the more delayed place aversion (Wenzel et al, 2013). These findings are consistent with the dissociation between the effects of cis-flupenthixol on MDPV-induced locomotor activity and functional connectivity changes and provide a potential link between reductions in functional connectivity and negative affect induced by MDPV.…”

“…Administration of this dose of the dopamine antagonist has been reported to reduce the conditioned reinforcing effects of cocaine (Wenzel et al, 2013) and cocaine taking and seeking, without affecting similar parameters for sucrose intake (Veeneman et al, 2012). In addition, this dose does not produce catatonia or other extrapyramidal motor effects in rats (Veeneman et al, 2012;Wenzel et al, 2013). Rats in this group were imaged 60 min after MDPV (90 min after cisflupenthixol).…”

Identification of SARS-CoV-2 entry inhibitors among already approved drugs

“…Apart from H 1 receptor antagonists, other active agents identified in our screen included flupenthixol, a dopamine receptor antagonist used in antipsychotic treatment. Flupenthixol has an extensive receptor spectrum and interacts with a variety of dopamine and serotonin binding sites to exert antipsychotic and antidepressant effects [ 28 ]. We found no reports on the antiviral activity of flupenthixol, but the related drug chlorprothixene may have anti-herpes simplex virus 2 activity [ 29 ].…”

Dopamine and Addiction

“…Low doses of cocaine elicit increased 22-kHz vocalizations, indicative of aversion (Barker et al 2014). Such aversive effects as adrenergic or serotonergic signaling may be caused directly by cocaine or its aftereffects that result from the prior wearing off of cocaine's positive effects (Wenzel et al 2013). Rats also learn that cues paired with delayed access to cocaine are aversive (Grigson & Twining 2002, Wheeler et al 2008.…”