In this study, the regulation of striatal cyclic-3',5'-adenosine monophosphate (cAMP) formation and GABA release by dopamine D1 and metabotropic glutamate receptors (mGluR) was studied in brain slices. In the absence of adenosine A2 receptor blockade, the mGluR agonist, 1- aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) stimulated cAMP accumulation through a pertussis toxin-insensitive mechanism that could be blocked by L-serine-O-phosphate, but not by L(+)-2-amino-3-phosphonopropionic acid. However, in the presence of the adenosine antagonist, 3-isobutyl-1- methylxanthine, 1S,3R-ACPD had no significant effect on basal cAMP, but it inhibited cAMP formation stimulated by the D1 agonist, SKF 38393. This inhibitory response was prevented by pertussis toxin pretreatment and mimicked by L(+)-2-amino-3-phosphonopropionic acid, but it was unaffected by L-serine-O-phosphate. Thus, 1S,3R-ACPD was determined to activate distinct mGluRs in the striatum that mediate either inhibition or activation of cAMP accumulation, with the latter effect being dependent on the activation of adenosine A2 receptors. A potential physiological role for the interaction between the D1 and adenosine-dependent stimulatory metabotropic receptor was sought by examining this interaction on striatal GABA release. SKF 38393 and 1S,3R-ACPD together were found to potentiate striatal GABA release induced by 15 mM K+. The potentiation was blocked by the D1 antagonist, SCH 23390. However, this effect was only partially mimicked by a high concentration of forskolin (100 μM) and was not blocked by L-serine-O-phosphate, thereby suggesting that the stimulatory mGluR does not mediate this potentiation. However, when forskolin was combined with phorbol 12,13-dibutyrate, the potentiating effect of SKF 38393 and 1S,3R-ACPD on GABA release was reproduced. These data suggest that D1 and mGluR receptor stimulation interact to facilitate GABA release by a mechanism that involves mGluR activation of the phospholipase C/protein kinase C pathway and activation of adenylyl cyclase by D1 receptors, but the stimulatory adenylyl cyclase coupled mGluR is not involved.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Dec 1 1995|
ASJC Scopus subject areas
- Molecular Medicine