Signal transduction interactions between CB1 cannabinoid and dopamine receptors in the rat and monkey striatum.
Signal transduction interactions between the CB1 cannabinoid and 1 and D2 dopamine receptor systems were studied in rat (Sprague Dawley) and monkey (Macaca fascilaris) striatal membranes. The D2 agonist quinelorane inhibited forskolin (10 microM)-stimulated adenylyl cyclase in a dose-dependent manner (26% and 20% maximal inhibition; EC50 = 2 and 0.5 microM, in rats and monkeys, respectively) and maximal inhibition was completely blocked by the D2 antagonist sulpiride (10 microM). The CB1 agonist desacetyllevonantradol inhibited forskolin-stimulated adenylyl cyclase (18% and 36% maximal inhibition; EC50 = 160 and 73 nM, in rats and monkeys, respectively) and the CB1 antagonist SR141716A (10 microM) completely blocked the maximal inhibition. Combined addition of > EC(90) concentrations of quinelorane (10, 30 microM) and desacetyllevonantradol (1 microM) resulted in no greater inhibition than that produced by either drug alone, indicative of signal transduction convergence between the D2 and CB1 receptor systems. The D1 agonist 6-Br-APB (3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin) produced a dose-dependent stimulation of adenylyl cyclase (45% and 26% stimulation; EC50 = 24 and 32 nM, in rat and monkey, respectively), and maximal stimulation was completely blocked by the D1 antagonist SCH23390 (1 microM). D1 agonist-stimulated activity could be inhibited to basal levels with desacetyllevonantradol (1 microM), indicative of D1 and CB1 signal transduction convergence. The data suggest that CB1 receptors are co-localized with D1 or D2 receptors on the same population of striatal membranes and can interact at the level of G-protein/adenylyl cyclase signal transduction. Similar results obtained with both rat and monkey membranes indicate that striatal dopamine and cannabinoid interactions are conserved for these two species.
Meschler
J P
JP
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104, USA.
Howlett
A C
AC
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D008297:Male; D010617:Phenanthridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013045:Species Specificity
D000700:Analgesics; D018491:Dopamine Agonists; D010617:Phenanthridines; D011804:Quinolines; D043882:Receptors, Cannabinoid; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011955:Receptors, Drug; C074280:3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; C032426:desacetylnantradol; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C047726:quinelorane