Time-dependent differences of repeated administration with Δ 9-tetrahydrocannabinol in proenkephalin and cannabinoid receptor gene expression and G-protein activation by μ-opioid and CB 1-cannabinoid receptors in the caudate–putamen

Abstract

The purpose of the present study was to examine the time-related effects of repeated administration of Δ 9-tetrahydrocannabinol during 1, 3, 7 and 14 days on cannabinoid and μ-opioid receptor agonist-stimulated [ 35 S ]GTPγS binding, and CB 1 cannabinoid receptor and proenkephalin gene expression in the caudate–putamen. Repeated administration with Δ 9-tetrahydrocannabinol produced a time-related reduction in cannabinoid receptor synthesis and activation of signal transduction mechanisms in the caudate–putamen. Indeed, WIN-55,212-2-stimulated [ 35 S ]GTPγS binding decreased 24% on day 1 and then progressively decreased finding a 42% decrease on day 14. Similarly, CB 1 cannabinoid receptor mRNA levels decreased (22%) on day 3, reaching 50% reduction on day 7. In contrast, a pronounced increase is detected in DAMGO-stimulated [ 35 S ]GTPγS binding and proenkephalin mRNA levels in the caudate–putamen. The highest degree of increase was reached on day 7 of the treatment (35% of proenkephalin mRNA levels and 62% of DAMGO-stimulated [ 35 S ]GTPγS binding) and then values slightly decreased on day 14. Taken together, the results of the present study indicate that, in the caudate–putamen, repeated administration with Δ 9-tetrahydrocannabinol produces a time-related increase in proenkephalin gene expression and μ-opioid receptor activation of G-proteins, and a time-related decrease in CB 1 cannabinoid receptor gene expression and reduction in CB 1 cannabinoid receptor activation of G-proteins. These results also suggest a possible interaction between the cannabinoid and opioid systems in the caudate–putamen which may be potentially relevant in the understanding of the alterations of motor behavior that occur after prolonged exposure to cannabinoids.