Acute reserpine treatment induces down regulation of D-1 dopamine receptor associated adenylyl cyclase activity in rat striatum

Abstract

Behavioural studies suggest a functional interaction between D-1 and D-2 systems in normal rat striatum to alter motor behaviour and which is disrupted by dopamine depletion induced by acute reserpine treatment. Consequently, we have investigated the effect of acute reserpine treatment on the biochemical interaction between D-1 and D-2 receptors present in rat striatal slices. Twenty-four hours following the administration of reserpine (5 μg/kg i.p.), striatal dopamine content was depleted by more than 73%; the density ( B max ) of D-1 receptor sites measured by the in vitro binding of [ 3H]SCH 23390 to striatal membranes was increased while the binding of [ 3H]spiperone to D-2 receptor sites was unaltered. Reserpine treatment had no effect on the affinity ( K d ) of [ 3H]SCH 23390 or [ 3H]spiperone for D-1 and D-2 sites. Basal levels of cyclic AMP accumulation in striatal slices prepared from reserpinetreated rats were lower than those observed in control slices. In striatal slices prepared from normal rats, dopamine (10–320 μM) and the D-1 agonist SKF 38393 (0.1–3.2 μm) induced concentration dependent increases in cyclic AMP accumulation. The D-1 antagonist SCH 23390 (10 μM) abolished the accumulation of cyclic AMP produced by dopamine or SKF 38393. The D-2 antagonist (±)-sulpiride (50 μM) enhanced the response to dopamine (10–320 μM) while the D-2 agonist quinpirole (10 μM) abolished the response to SKF 38393 (0.1–3.2 μM). However, 24 hr after reserpine treatment the ability of dopamine (10–320 μM) and SKF 38393 (0.1–3.2 μM) to elicit an increase in cyclic AMP accumulation was markedly reduced in striatal slices. SCH 23390 (10 μM) was able to attenuate the response to dopamine (10–320 μM). However, the inclusion of (±)-sulpiride (50 μM) did not enhance the trend for an increase in cyclic AMP accumulation produced by dopamine. Also, quinpirole (10 μM) did not affect the response to SKF 38393 (0.1–3.2 μM) in striatal slices from reserpine pretreated rats. The data confirm the positive linkage between D-1 receptors and adenylyl cyclase and the inhibitory coupling to D-2 sites in striatal slices from normal, rats. Acute reserpine treatment appears to cause an uncoupling of D-1 receptors associated with adenylyl cyclase.