Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat.
BACKGROUND
Marijuana is known to have psychotropic effects in humans. In this study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to explore whether CB(1) receptor stimulation or blockade induces behavioral changes consistent with psychotomimetic or antipsychotic agents, respectively.


OBJECTIVE
We determined whether (a) the cannabinoid agonist CP 55940 decreased pre-pulse inhibition (PPI) as might be expected from a psychotomimetic agent, and (b) the selective CB(1) receptor antagonist, SR 141716A, had any effect on PPI on its own or following disruptions by psychotomimetic agents. In addition, we investigated the effects of SR 141716A on elevated levels of hyperactivity and stereotypy elicited by d-amphetamine.


METHODS
These studies were conducted in rats using standard methodologies for determination of PPI following acoustic stimuli, and d-amphetamine-induced hyperactivity and stereotypies.


RESULTS
Decreased startle responses to 120 dB stimuli were observed in rats treated with CP 55940 (0.1 mg/kg IP) in the absence and presence of a 73 dB pre-pulse. These effects were reversed by SR 141716A (5 and 10 mg/kg, respectively). SR 141716A (0.1, 5, 10 mg/kg) had no effect on PPI on its own or following disruptions by apomorphine, d-amphetamine or MK-801. Conversely, in separate experiments different antipsychotic agents reversed disruptions in PPI induced by d-amphetamine (haloperidol), apomorphine (haloperidol or clozapine) or MK-801 (clozapine or olanzapine). In addition, unlike haloperidol, SR 141716A (5 mg/kg) did not reverse d-amphetamine-mediated increases in hyperactivity or stereotypy.


CONCLUSIONS
The CP 55940-mediated decreases in startle amplitude confound assessment of the effects of CB(1) receptor activation on PPI. The failure of SR 141716A to reverse disruptions in PPI, hyperactivity or stereotypy induced by non-cannabinoid psychotomimetic agents suggests that blockade of the CB(1) receptor on its own is not sufficient for antipsychotic therapy.
Martin
Renee S
RS
CNS Therapy Area, Neurobiology Unit, Roche Bioscience R2-101, 3401 Hillview Avenue, Palo Alto, CA 94304, USA. renee.martin@roche.com
Secchi
Robert L
RL
Sung
Eric
E
Lemaire
Martine
M
Bonhaus
Douglas W
DW
Hedley
Linda R
LR
Lowe
David A
DA
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003511:Cyclohexanols / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011605:Psychoses, Substance-Induced / Q000503:physiopathology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects* / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects; D000077285:Rimonabant; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D003511:Cyclohexanols; D006213:Hallucinogens; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016291:Dizocilpine Maleate; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D001058:Apomorphine; D000077285:Rimonabant; D003913:Dextroamphetamine