Cocaine and SKF-82958 potentiate brain stimulation reward in Swiss-Webster mice.
BACKGROUND
The dopamine D(1)-like receptor agonist SKF-82958 reportedly blocks reinstatement of cocaine-seeking behavior in rats and non-human primates. It is not known if SKF-82958 reduces drug-seeking behaviors in animals exposed previously to cocaine by causing reward-like effects or withdrawal-like aversive effects.


OBJECTIVE
Intracranial self-stimulation (ICSS) studies were conducted to determine if SKF-82958 has reward-like or withdrawal-like effects in mice exposed previously to cocaine, or under the influence of cocaine at the time of testing.


METHODS
Swiss-Webster mice with lateral hypothalamic stimulating electrodes were trained to self-administer rewarding brain stimulation. The mice were tested in a "curve-shift" variant of the ICSS procedure after intraperitoneal administration of cocaine alone (2.5-20 mg/kg), SKF-82958 alone (0.03-0.3 mg/kg), or a mixture of both drugs (SKF 0.03 mg/kg + 2.5 or 5.0 mg/kg cocaine). Each treatment was given twice.


RESULTS
Cocaine and SKF-82958 each caused dose-dependent decreases in brain stimulation reward thresholds that were largest immediately after administration. A dose of SKF-82958 with no reward-related effects of its own potentiated the reward-related effects of low doses of cocaine. Repeated administration did not cause progressive changes in the ability of any treatment to decrease thresholds.


CONCLUSIONS
Cocaine and SKF-82958 each potentiate the rewarding effects of lateral hypothalamic brain stimulation in Swiss-Webster mice, implying that these drugs have rewarding effects of their own. The reward-facilitating effects of low doses of cocaine and SKF-82958 are additive (or synergistic). These data suggest that SKF-82958 may decrease cocaine-seeking behavior by mechanisms related to reward rather than aversion.
Gilliss
Brian
B
Department of Psychiatry, Harvard Medical School and McLean Hospital, MRC 217, 115 Mill Street, Belmont, MA 02478, USA.
Malanga
C J
CJ
Pieper
Jeanne O
JO
Carlezon
William A
WA
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D051379:Mice; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012201:Reward
D001552:Benzazepines; C071262:SK&F 82958; D003042:Cocaine