Activation of EPAC Inhibits the Aquisition of Nucleus Accumbens Amphetamine Place Preference in a Dose-Dependent Manner in Rats

Abstract

Reward-related learning occurs when previously neutral stimuli acquires an enhanced ability to elicit approach and other responses. Studies in the past have shown that dopamine receptor-mediated 3’,5’-cyclic adenosine monophosphate (cAMP)-dependent intracellular signalling is important for reward-related learning. Until recently, cAMP-dependent protein kinase (PKA) was the only known signalling molecule that was activated by cAMP. However, it has been discovered that another enzyme, exchange protein directly activated by cAMP (Epac), is also activated by cAMP. Thus, it is possible that cAMP mediates reward-related learning by an Epac-dependent signalling pathway. The present study used a conditioned place preference (CPP) paradigm to investigate whether Epac is involved in the acquisition of reward-related learning. Bilateral injections of amphetamine (20 µg/0.5μl/side) into the nucleus accumbens (NAc) have been shown in previous studies to reliably produce a CPP. Thus, amphetamine (20 µg) and Sp-adenosine 3’,5’-cyclic monophosphorothioate triethylamanine (Sp-cAMPS) (0.1, 1.0, 10, 15, 20 µg), an agent that activates both PKA and Epac, or amphetamine (20 µg) and 8-(4-chlorophenylthio)-2’-O-methyladenosine-3’,5’-cyclic monophosphate (8-pCPT) (0.73, 1.27, 1.45, 2.89, 5.78, 11.56 µg), an agent that selectively activates Epac, were co-injected into NAc to determine their effects on the acquisition of CPP. Results showed that 8-pCPT (1.45 µg), but not lower or higher doses, inhibited CPP. Sp-cAMPS (0.1, 15, 20 µg) also inhibited CPP, replicating the results of previous studies. The results implicate Epac in the acquisition of reward-related learning.