title: delta(9)-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory.
abstract: BACKGROUND
  Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB(1) antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆(9)-tetrahydrocannabinol (THC), the primary constituent in cannabis.
  
  
  OBJECTIVE
  Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation in hippocampal and cerebellar tissue from THC-dependent mice.
  
  
  RESULTS
  Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity in cerebellar, but not in hippocampal, membranes.
  
  
  CONCLUSIONS
  The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, P.O. Box 98061, Richmond, VA 23298, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Varvel
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Jason M
authors.initials: JM
authors.lastname: Wiebelhaus
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Long
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Middleton
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D008297:Male; D002189:Marijuana Abuse / Q000523:psychology*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000523:psychology; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D013037:Spatial Behavior / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D013759:Dronabinol; D000077285:Rimonabant