Spontaneous cannabinoid withdrawal produces a differential time-related responsiveness in cannabinoid CB1 receptor gene expression in the mouse brain

Abstract

This study aimed to examine the behavioural and neurochemical (cannabinoid CB₁ receptor gene expression) changes induced by spontaneous cannabinoid withdrawal in mice. Tolerance was assessed by measuring rectal temperature and motor activity in the open-field test after CP-55, 940 administration. Cannabinoid withdrawal symptoms were determined by measuring motor activity and behavioural signs of abstinence. Cessation of CP-55, 940 treatment in tolerant mice induced a spontaneous time-dependent behavioural withdrawal syndrome consisting of marked increases (140%) in motor activity, number of rearings (170%), decreases in grooming (57%), wet dog shakes (73%) and rubbing behaviours (74%) on day 1, progressively reaching values similar to vehicle-treated mice on day 3. Interestingly, this spontaneous cannabinoid withdrawal resulted in CB₁ gene expression upregulation (20–30%) in caudate-putamen, ventromedial hypothalamic nucleus, central amygdaloid nucleus and CA1, whereas in the CA3 field of hippocampus, a significant decrease (15–20%) was detected. Taken together, the results of this study suggest that cessation of CP-55, 940 administration in tolerant mice produces a behavioural cannabinoid withdrawal syndrome and a selective and differential responsiveness in CB₁ receptor gene expression in several brain regions of the mice. These findings further suggest a time and regional differential role for cannabinoid receptors in short- and long-term neuroadaptations that occur after exposure to cannabis derivatives.

Get full access to this article

View all access options for this article.

References

Abood M E, Martin B R (1992) Neurobiology of marijuana abuse . Trends Pharmacol Sci 13: 201–207

Aceto M D, Scates S M, Lowe J A, Martin B R (1996) Dependence on delta-9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal . J Pharmacol Exp Ther 278: 1290–1295

Aceto M D, Scates S M, Martin B R (2001) Spontaneous and precipitated withdrawal with a synthetic cannabinoid, WIN 55212-2 . Eur J Pharmacol 416: 75–81

Beardsley P M, Martin B R (2000) Effects of the cannabinoid CB1 receptor antagonist, SR141,716A, after δ9-tetrahydrocannabinol withdrawal . Eur J Pharmacol 387: 47–53

Cook S A, Lowe J A, Martin B R (1998) CB1 receptor antagonist precipitates withdrawal in mice exposed to δ9-tetrahydrocannabinol . J Pharmacol Exp Ther 285: 1150–1156

Costa B, Giagnoni G, Colleoni M (2000) Precipitated and spontaneous withdrawal in rats tolerant to anandamide . Psychopharmacology 149: 121–128

Diana M, Melis M, Muntoni A L, Gessa G L (1998) Mesolimbic dopaminergic decline after cannabinoid withdrawal . Proc Natl Acad Sci USA 95: 10269–10273

Doherty J, Dingledine R (2003) Functional interactions between cannabinoid and metabotropic glutamate receptors in the central nervous system . Curr Opin Pharmacol 3: 46–53

Gonzalez S, Manzanares J, Berrendero F, Wenger T, Corchero J, Bisogno T, Romero J, Fuentes J A, Di Marzo V, Ramos J A, Fernandez-Ruiz J (1999) Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland . Neuroendocrinology 70: 137–145

10.

Hutcheson D M, Tzavara E T, Smadja C, Valjent E, Roques B P, Hanoune J, Maldonado R (1998) Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydro-cannabinol . Br J Pharmacol 125: 1567–1577

11.

Jones R T, Benowitz N, Bachman J (1976) Clinical studies of cannabis tolerance and dependence . Ann NY Acad Sci 282: 221–239

12.

Jones R T, Benowitz N L, Herning R I (1981) Clinical relevance of cannabis tolerance and dependence . J Clin Pharmacol 21: 143S-152S

13.

Lichtman A H, Sheikh S M, Loh H H, Martin B R (2001) Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice . J Pharmacol Exp Ther 298: 1007–1014

14.

Nestler E J (2002) Common molecular and cellular substrates of addiction and memory . Neurobiol Learn Memory 78: 637–647

15.

Paxinos G, Franklin K (2001) The mouse brain in stereotaxic coordinates. Academic Press, San Diego, CA

16.

Rodriguez de Fonseca F, Gorriti M A, Fernandez-Ruiz, J J, Palomo T, Ramos J A (1994) Downregulation of rat brain cannabinoid binding sites after chronic delta-9-tetrahydrocannabinol treatment . Pharmacol Biochem Behav 47: 33–40

17.

Romero J, Berrendero F, Manzanares J, Perez, A., Corchero J, Fuentes J A, Fernandez-Ruiz J J, Ramos J A (1998) Time course of the cannabinoid receptor down regulation in the adult rat brain caused by repeated exposure to delta-9-tetrahydrocannabinol . Synapse 30: 298–308

18.

Rubino T, Patrini G, Massi P, Fuzio D, Vigano D, Giagnoni G, Parolaro D (1998) Cannabinoid-precipitated withdrawal: a time course study of the behavioral aspect and its correlation with cannabinoid receptors and G protein expression . J Pharmacol Exp Ther 285: 813–819

19.

Rubino T, Vigano D, Massi P, Parolaro D (2000) Changes in the cannabinoid receptor binding, G protein coupling, and cyclic AMP cascade in the CNS of rats tolerant to and dependent on the synthetic cannabinoid compound CP55 940 . J Neurochem 75: 2080–2086

20.

Sim L J, Hampson R E, Deadwyler S A, Childers S R (1996) Effects of chronic treatment with δ9-tetrahydrocannabinol on cannabinoidstimulated [35S]-GTPS autoradiography in rat brain . J Neurosci 16: 8057–8066

21.

Tsou K, Patrick S L, Walker J M (1995) Physical withdrawal in rats tolerant to delta 9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist . Eur J Pharmacol 280: R13–R15

22.

Vizi E S, Kiss J P (1998). Neurochemistry and pharmacology of the major hippocampal transmitter systems: synaptic and non–synaptic interactions . Hippocampus 8: 566–697

23.

Wiesbeck G A, Schuckit M A, Kalmijn J A, Tipp J E, Bucholz K K, Smith T L (1996) An evaluation of the history of a marijuana withdrawal syndrome in a large population . Addiction 91: 1469–1478

24.

Young S III, Bonner T, Brann M (1986) Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain . Proc Natl Acad Sci USA 83: 9827–9831