Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice

TY - JOUR

T1 - Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice

AU - Sørensen, Gunnar

AU - Sager, Thomas N

AU - Petersen, Jørgen H

AU - Brennum, Lise T

AU - Thøgersen, Peter

AU - Hee Bengtsen, Cecilie

AU - Thomsen, Mette

AU - Wörtwein, Gitta

AU - Fink-Jensen, Anders

AU - Woldbye, David P D

PY - 2008

Y1 - 2008

N2 - RATIONALE: The novel antipsychotic aripiprazole in use for treatment of schizophrenia is a partial agonist at dopamine D(2) receptors with actions at a variety of other receptors as well. Cocaine is believed to exert an important part of its rewarding effect by increasing extracellular levels of dopamine that subsequently act at dopamine D(2) receptors. OBJECTIVES: As a partial agonist, aripiprazole may antagonize effects at D(2) receptors and we accordingly tested whether aripiprazole could antagonize self-administration of cocaine. Because D(2)-like receptor agonists are self-administered, a D(2) receptor partial agonist like aripiprazole might itself be reinforcing. Thus, we also assessed whether mice would acquire self-administration of aripiprazole. MATERIALS AND METHODS: A single session, mouse self-administration procedure was used. RESULTS: Oral pretreatment with aripiprazole dose-dependently decreased cocaine self-administration under a fixed ratio 1 schedule at the peak cocaine dose (0.03 mg/kg/infusion), reaching significance at 0.2 and 0.4 mg/kg of aripiprazole. Using 0.4 mg/kg, aripiprazole decreased rates of cocaine self-administration without shifting the peak of the dose-response function. There was no effect of aripiprazole per se, suggesting that its inhibitory action was due to effects on cocaine self-administration rather than non-specific motor effects. Aripiprazole was not found to be self-administered in the tested dose range (0.0003-0.3 mg/kg/infusion). The three highest doses (0.03, 0.1, and 0.3 mg/kg/infusion) even caused significant decreases in nose-poking activity, possibly due to extrapyramidal side effects. CONCLUSIONS: These data are consistent with a potential role for aripiprazole in treatment of cocaine addiction without abuse potential per se.

AB - RATIONALE: The novel antipsychotic aripiprazole in use for treatment of schizophrenia is a partial agonist at dopamine D(2) receptors with actions at a variety of other receptors as well. Cocaine is believed to exert an important part of its rewarding effect by increasing extracellular levels of dopamine that subsequently act at dopamine D(2) receptors. OBJECTIVES: As a partial agonist, aripiprazole may antagonize effects at D(2) receptors and we accordingly tested whether aripiprazole could antagonize self-administration of cocaine. Because D(2)-like receptor agonists are self-administered, a D(2) receptor partial agonist like aripiprazole might itself be reinforcing. Thus, we also assessed whether mice would acquire self-administration of aripiprazole. MATERIALS AND METHODS: A single session, mouse self-administration procedure was used. RESULTS: Oral pretreatment with aripiprazole dose-dependently decreased cocaine self-administration under a fixed ratio 1 schedule at the peak cocaine dose (0.03 mg/kg/infusion), reaching significance at 0.2 and 0.4 mg/kg of aripiprazole. Using 0.4 mg/kg, aripiprazole decreased rates of cocaine self-administration without shifting the peak of the dose-response function. There was no effect of aripiprazole per se, suggesting that its inhibitory action was due to effects on cocaine self-administration rather than non-specific motor effects. Aripiprazole was not found to be self-administered in the tested dose range (0.0003-0.3 mg/kg/infusion). The three highest doses (0.03, 0.1, and 0.3 mg/kg/infusion) even caused significant decreases in nose-poking activity, possibly due to extrapyramidal side effects. CONCLUSIONS: These data are consistent with a potential role for aripiprazole in treatment of cocaine addiction without abuse potential per se.

U2 - 10.1007/s00213-008-1069-z

DO - 10.1007/s00213-008-1069-z

M3 - Journal article

C2 - 18481046

SN - 0033-3158

VL - 199

SP - 37

EP - 46

JO - Psychopharmacology

JF - Psychopharmacology

IS - 1

ER -