title: Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat.
abstract: 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.
authors.affiliation: CNS Therapy Area, Neurobiology Unit, Roche Bioscience R2-101, 3401 Hillview Avenue, Palo Alto, CA 94304, USA. renee.martin@roche.com
authors.forename: Renee S
authors.initials: RS
authors.lastname: Martin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Secchi
authors.forename: Eric
authors.initials: E
authors.lastname: Sung
authors.forename: Martine
authors.initials: M
authors.lastname: Lemaire
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Bonhaus
authors.forename: Linda R
authors.initials: LR
authors.lastname: Hedley
authors.forename: David A
authors.initials: DA
authors.lastname: Lowe
mesh_terms: 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
chemical_list: 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