Enhancement of Anandamide Formation in the Limbic Forebrain and Reduction of Endocannabinoid Contents in the Striatum of Δ⁹‐Tetrahydrocannabinol‐Tolerant Rats

Abstract

Abstract:Recent studies have shown that the pharmacological tolerance observed after prolonged exposure to synthetic or plant-derived cannabinoids in adult rats is accompanied by down-regulation/desensitization of brain cannabinoid receptors. However, no evidence exists on possible changes in the contents of the endogenous ligands of cannabinoid receptors in the brain of cannabinoid-tolerant rats. The present study was designed to elucidate this possibility by measuring, by means of isotope dilution gas chromatography/mass spectrometry, the contents of both anandamide (arachidonoylethanolamide; AEA) and its biosynthetic precursor, N-arachidonoylphosphatidylethanolamine (NArPE), and 2-arachidonoylglycerol (2-AG) in several brain regions of adult male rats treated daily with ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) for a period of 8 days. The areas analyzed included cerebellum, striatum, limbic forebrain, hippocampus, cerebral cortex, and brainstem. The same regions were also analyzed for cannabinoid receptor binding and WIN-55,212-2-stimulated guanylyl-5Ј-O-(␥-[ 35 S]thio)-triphosphate ([ 35 S]GTP␥S) binding to test the development of the well known down-regulation/desensitization phenomenon. Results were as follows: As expected, cannabinoid receptor binding and WIN-55,212-2-stimulated [ 35 S]GTP␥S binding decreased in most of the brain areas of ⌬ 9 -THC-tolerant rats. The only region exhibiting no changes in both parameters was the limbic forebrain. This same region exhibited a marked (almost fourfold) increase in the content of AEA after 8 days of ⌬ 9 -THC treatment. By contrast, the striatum exhibited a decrease in AEA contents, whereas no changes were found in the brainstem, hippocampus, cerebellum, or cerebral cortex. The increase in AEA contents observed in the limbic forebrain was accompanied by a tendency of NArPE levels to decrease, whereas in the striatum, no significant change in NArPE contents was found. The contents of 2-AG were unchanged in brain regions from ⌬ 9 -THCtolerant rats, except for the striatum where they dropped significantly. In summary, the present results show that prolonged activation of cannabinoid receptors leads to decreased endocannabinoid contents and signaling in the striatum and to increased AEA formation in the limbic forebrain. The pathophysiological implications of these findings are discussed in view of the proposed roles of endocannabinoids in the control of motor behavior and emotional states. Key Words: Endocannabinoids-Anandamide-2-Arachidonoylglycerol-Cannabinoid receptor binding-Tolerance-⌬ 9 -Tetrahydrocannabinol.

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

“…All analytes were detectable in tissue punches of the vHip and were above the limit of quantitation for the assay (Table 1, Figure 5). The concentrations of all analytes in punched vHip tissue were similar to the range of concentrations reported in the literature for gross dissected rat hippocampal tissue [19,22,23,67]. Levels of AEA, 2-AG and PEA were all significantly higher in the vHip of fear-conditioned, formalin-treated rats which received intravHip vehicle, compared with their non-fear-conditioned counterparts (Table 1, …”

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

“…It has been recently suggested that the endocannabinoid system might be a component of the brain reward circuitry and thus play a role not only in CB tolerance/dependence but also in dependence/withdrawal to other drugs of abuse (Di Marzo et al, 2000;Gonzalez et al, 2003;Centonze et al, 2004). Changes in endocannabinoid ligands and their receptors have been shown in different brain regions, with particular attention to those areas related to reinforcement processes, during dependence on powerful addictive drugs.…”

Cannabinoids Influence Lipid–Arachidonic Acid Pathways in Schizophrenia

“…Longer lasting and sufficiently frequent exposure to D 9 -THC may cause an exhaustion of arachidonic acid reserves followed by downregulation of the endocannabinoid system, weakening of its protective power, and increasing severity of psychosis. This is supported by findings of CB 1 receptor downregulation and lower levels of anandamide in CSF in schizophrenia patients frequently using cannabis (Di Marzo, 1999;Di Marzo et al, 2000;Leweke et al, 2006). Following this model, attenuated skin flushing in healthy individuals and schizophrenia patients (as reported here) may be taken as peripheral correlate of a systemic exhaustion of arachidonic acid and its derivates after continuous exposure to D 9 -THC.…”