Dopamine D1/D5 receptor activation fails to initiate an activity-independent late-phase LTP in rat hippocampus

Abstract

The role of dopamine in the hippocampus remains poorly defined. Numerous studies have suggested that it acts as a neuromodulator of late-phase long-term potentiation (L-LTP) in CA1, while other reports controversially indicate that D1/D5 receptor (D1/D5R) activation may directly initiate activity-independent LTP. We have further investigated this putative role of dopamine in area CA1 in rat hippocampal slices using field potential recording techniques. Application of the dopamine D1/D5 receptor agonists SKF 38393 and 6-bromo-APB at 100 μM for 20 min did not induce an activity-independent L-LTP. Varying the incubation conditions still did not permit either SKF 38393 or an alternative D1/D5R agonist, 6-chloro-PB, to induce L-LTP. To further determine if intracellular mechanisms, which may act to limit the expression of LTP, were preventing D1/D5R-induced L-LTP expression, we inhibited protein phosphatase 1 activity by reducing cyclin-dependent kinase 5 (cdk5) inhibition of inhibitor 1. Inhibition of cdk5 by roscovitine (10 μM, 40 min) did not facilitate the ability of SKF 38393 to induce L-LTP in CA1. Biochemical experiments confirmed that the concentration of agonist used significantly elevated intracellular cAMP levels, suggesting that effective D1/D5R activation was achieved. Furthermore, coactivation with NMDA receptors (NMDAR) resulted in a synergistic increase in cAMP. These findings demonstrate that D1/D5R activation in CA1 initiates intracellular second messenger accumulation, but that this is insufficient to induce an activity-independent L-LTP.