Time-dependent differences of repeated administration with Delta(9)-tetrahydrocannabinol in proenkephalin and cannabinoid receptor gene expression and G-protein activation by mu-opioid and CB1-cannabinoid receptors in the caudate-putamen

The purpose of the present study was to examine the time-related effects of repeated administration of Delta 9-tetrahydrocannabinol during 1, 3, 7 and 14 days on cannabinoid and mu-opioid receptor agonist-stimulated [S-35]GTP gamma S binding, and CB1 cannabinoid receptor and proenkephalin gene expre ssion in the caudate-putamen, Repeated administration with Delta 9-tetrahyd rocannabinol produced a time-related reduction in cannabinoid receptor synt hesis and activation of signal transduction mechanisms in the caudate-putam en. Indeed, WIN-55.212-2-stimulated [S-35]GTP gamma S binding decreased 24% on day 1 and then progressively decreased finding a 42% decrease on day 14 . Similarly, CB1 cannabinoid receptor mRNA levels decreased (22%) on day 3, reaching 50% reduction on day 7. In contrast, a pronounced increase is det ected in DAMGO-stimulated [S-35]GTP gamma S binding and proenkephalin mRNA levels in the caudate-putamen. The highest degree of increase was reached o n day 7 of the treatment (35% of proenkephalin mRNA levels and 62% of DAMGO -stimulated [S-35]GTP gamma S binding) and then values slightly decreased o n day 14. Taken together, the results of the present study indicate that, i n the caudate-putamen, repeated administration with Delta 9-tetrahydrocanna binol produces a time-related increase in proenkephalin gene expression and mu-opioid receptor activation of G-proteins, and a time-related decrease i n CB1 cannabinoid receptor gene expression and reduction in CB1 cannabinoid receptor activation of G-proteins. These results also suggest a possible i nteraction between the cannabinoid and opioid systems in the caudate-putame n which may be potentially relevant in the understanding of the alterations of motor behavior that occur after prolonged exposure to cannabinoids. (C) 1999 Elsevier Science B.V. All rights reserved.