Time-dependent differences of repeated administration with Delta9-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 Delta9-tetrahydrocannabinol during 1, 3, 7 and 14 days on cannabinoid and mu-opioid receptor agonist-stimulated [35S]GTPgammaS binding, and CB1 cannabinoid receptor and proenkephalin gene expression in the caudate-putamen. Repeated administration with Delta9-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 [35S]GTPgammaS 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 detected in DAMGO-stimulated [35S]GTPgammaS 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 [35S]GTPgammaS 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 Delta9-tetrahydrocannabinol produces a time-related increase in proenkephalin gene expression and mu-opioid receptor activation of G-proteins, and a time-related decrease in CB1 cannabinoid receptor gene expression and reduction in CB1 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.
Corchero
J
J
Departamento de Farmacología, Facultad de Farmacia and Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Paseo Juan XXIII, 1, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Romero
J
J
Berrendero
F
F
Fernandez-Ruiz
J
J
Ramos
J A
JA
Fuentes
J A
JA
Manzanares
J
J
D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D013759:Dronabinol / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000235:genetics* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D017072:Neostriatum / Q000737:chemistry / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013462:Sulfur Radioisotopes; D013997:Time Factors
D000700:Analgesics; D000701:Analgesics, Opioid; D048588:Benzoxazines; D004745:Enkephalins; D009025:Morpholines; D009281:Naphthalenes; D011498:Protein Precursors; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; C029992:proenkephalin; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D019204:GTP-Binding Proteins