Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice.
BACKGROUND
The novel antipsychotic aripiprazole in use for treatment of schizophrenia is a partial agonist at dopamine D2 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 D2 receptors.


OBJECTIVE
As a partial agonist, aripiprazole may antagonize effects at D2 receptors and we accordingly tested whether aripiprazole could antagonize self-administration of cocaine. Because D2-like receptor agonists are self-administered, a D2 receptor partial agonist like aripiprazole might itself be reinforcing. Thus, we also assessed whether mice would acquire self-administration of aripiprazole.


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.
Sørensen
Gunnar
G
Laboratory of Neuropsychiatry, Rigshospitalet University Hospital, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark.
Sager
Thomas N
TN
Petersen
Jørgen H
JH
Brennum
Lise T
LT
Thøgersen
Peter
P
Hee Bengtsen
Cecilie
C
Thomsen
Morgane
M
Wörtwein
Gitta
G
Fink-Jensen
Anders
A
Woldbye
David P D
DP
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001921:Brain / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D012646:Self Administration
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; D000068180:Aripiprazole; D003042:Cocaine