INTERACTION OF DEXANABINOL (HU-211), A NOVEL NMDA RECEPTOR ANTAGONIST, WITH THE DOPAMINERGIC SYSTEM

The interaction of 7-hydroxy-Delta(6)-tetrahydrocannabinol 1,1-dimethy lheptyl (Dexanabinol; HU-211), a novel NMDA receptor antagonist, with the dopaminergic system was examined using in vitro and in vivo system s. HU-211 (50 or 100 mu M) inhibited the binding of -tetrahydro-3-meth yl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride ([H-3] SCH-23390), a do pamine D-1 receptor antagonist, by 29.7 +/- 1.8% and 52.7 +/- 6.3%, re spectively. HU-211 10 mu M, like the dopamine D-1 receptor agonist nyl -2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-383 93), enhanced the conversion of [H-3]adenine to cyclic AMP (cAMP) (51. 8 +/- 29.7% and 35.6 +/- 21.5% over control, respectively). The HU-211 -induced increase was not inhibited by SCH-23390. HU-211 together with the dopamine D-1 receptor agonist caused a synergistic elevation (314 .7 +/- 14.3%). HU-211 reduced the catalepsy induced by dopamine recept or antagonists. At 10 mg/kg, HU-211 significantly (P < 0.001) reduced the catalepsy time induced by D-1, D-2 and non-selective dopamine rece ptor antagonists. Overall, the results of the present study demonstrat e that HU-211 interacts with the dopaminergic system and enhances acti vity at the dopamine D-1 receptor level. This activity may have implic ations in diseases involving the dopaminergic system, such as Parkinso n's disease. (C) 1997 Elsevier Science B.V.