HEP (2005) 168:691–717
©cSpringer-Verlag 2005
Cannabinoid Tolerance and Dependence
A.H. Lichtman ()·B.R.Martin
Department of Pharmacology and Toxicology, Virginia Commonwealth University,
410 North 12th Street, P.O. Box 980613, Richmond VA, 23298-0613, USA
[email protected]
1Introduction.................................... 692
2 Reinforcing Effects of Cannabinoids in Animals ................ 692
3 Overview of Cannabinoid Tolerance in Whole Animals............. 693
3.1 Cellular and Molecular Changes Associated with Cannabinoid Tolerance... 694
3.2 CB 1 ReceptorDownregulation .......................... 695
3.3 CB 1 Receptor-ActivatedGProteinsandEffectors ................ 696
3.4 ChangesinEndogenousCannabinoidLevels .................. 697
4 Characterization of Cannabinoid Dependence ................. 698
4.1 ClinicalSignificanceofCannabisWithdrawal .................. 698
4.2 Investigation of Cannabinoid Withdrawal in Laboratory Animal Models... 700
4.2.1 Abstinence Withdrawal Versus Precipitated Withdrawal
inLaboratoryAnimals .............................. 700
4.2.2 SR 141716 Inverse Activity ............................ 702
4.2.3 SR 141716 Precipitated Anandamide Withdrawal?................ 703
4.3 NeuroadaptiveChangesUnderlyingCannabinoidDependence......... 703
4.3.1 Role of the CB 1 ReceptorinCannabinoidDependence ............. 704
4.3.2CellularMechanismsUnderlyingCannabinoidDependence .......... 704
4.3.3BrainAreasImplicatedinCannabinoidDependence .............. 705
4.4 Influences of Other Neurochemical Systems on Cannabinoid Dependence.. 706
4.5 PharmacotherapiesforCannabisDependence.................. 707
5Conclusions.................................... 709
References ........................................ 710
AbstractThe use of marijuana for recreational and medicinal purposes has re-
sulted in a large prevalence of chronic marijuana users. Consequences of chronic
cannabinoid administration include profound behavioral tolerance and with-
drawal symptoms upon drug cessation. A marijuana withdrawal syndrome is only
recently gaining acceptance as being clinically significant. Similarly, laboratory
animals exhibit both tolerance and dependence following chronic administration
of cannabinoids. These animal models are being used to evaluate the high degree
of plasticity that occurs at the molecular level in various brain regions following
chroniccannabinoidexposure.Inthisreview,wedescriberecentadvancesthathave
increased our understanding of the impact of chronic cannabinoid administration
on cannabinoid receptors and their signal transduction pathways. Additionally,