Corticotropin-Releasing Hormone (CRH) mRNA Expression in Rat Central Amygdala in Cannabinoid Tolerance and Withdrawal: Evidence for an Allostatic Shift?

Abstract

Chronic treatment with cannabinoid agonists leads to tolerance. One possible mechanism for this is receptor internalization, but tolerance has also been reported with compounds that only cause internalization to a low degree. Furthermore, cannabinoid antagonist administration precipitates a characteristic withdrawal syndrome in tolerant subjects, accompanied by neuronal activation and enhanced release of corticotropin-releasing hormone (CRH) in the central amygdala. The underlying molecular mechanisms are unknown. We examined the role of cannabinoid tolerance and withdrawal for the expression of the cannabinoid 1 (CB1) receptor and of CRH in rats. Tolerance was first established functionally. An acute dose (100 mg/kg) of the CB1 agonist HU-210 suppressed locomotor activity, and had an anxiogenic-like effect on the elevated plus-maze. Both effects were absent following daily treatment with the same agonist or a lower (40 mg/kg) dose for 14 days. Next, withdrawal was reliably precipitated by a single dose (3 mg/kg) of the CB1 antagonist SR141716A in rats treated subchronically with 14-day HU-210. Using in situ hybridization, a robust suppression of CB1 mRNA expression was found in the caudate-putamen, indicating a downregulation of CB1 expression levels as one mechanism for tolerance to the locomotor suppressant effects of HU-210. The CRH transcript was upregulated in the central amygdala in precipitated withdrawal compared to nonwithdrawn tolerant subjects, suggesting that increased gene expression contributes to the previously reported CRH release in withdrawal. Most importantly, this increase occurred from a suppressed level in tolerant subjects, and behavioral signs of withdrawal, presumably mediated by CRH, were seen at the CRH expression that had only returned to normal nontolerant levels. This suggests the possibility of an allostatic shift, as previously proposed on theoretical grounds. The expression of CRH-R1, CRH-R2a, NPY, and its Y1 receptor mRNA was analyzed in search of neural substrates for the allostatic shift observed, but did not seem to contribute to the dysregulated state.

Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

“…The observed anxiogenic effects of cannabinoids agree with previous results in the emergence and EPM tests (Rodriguez de Fonseca et al, 1996;Arevalo et al, 2001;Caberlotto et al, 2004;Marco et al, 2004) and the social interaction test (Genn et al, 2004). Adolescent behavior in rodents is characterized by greater social interaction and exploratory behavior relative to adults (Spear, 2000) and such effects were evident in control rats in the social interaction and EPM tasks in the present study.…”

HU210-Induced Downregulation in Cannabinoid CB1 Receptor Binding Strongly Correlates with Body Weight Loss in the Adult Rat

“…Previous studies suggest that tolerance to the behavioural effects of HU210 develops after repeated chronic or subchronic administration of the drug [5,9,11,16,18,40]. It has been suggested that the development of behavioural tolerance to cannabinoids such as THC, CP55,940 and WIN55,212-2 is mainly a pharmacodynamic event and can be correlated with a downregulation and desensitization of CB1 receptors in the brain [18,28,57].…”

“…Studies involving other cannabinoids such as THC, CP55,940 and WIN55,212-2 have shown that the development of behavioural drug tolerance is mainly a pharmacodynamic event and can be correlated with a downregulation and desensitization of CB1 receptors in the brain [18,28,57]. Although Caberlotto et al [5] described a downregulation in CB1 mRNA expression in the striatum only after chronic HU210 administration, the regional effects of HU210 treatment on CB1 receptor density in the rat brain is yet to be assessed.…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…Rimonabant, an antiobesity drug, increases CRH levels 84 while decreasing ACTH and cortisol at low doses, but increases both at high doses. 85 Traditional antidepressants such as fluoxetine, citalopram and imipramine all decrease CRH, ACTH and cortisol levels.…”