Dopamine D1/D5 receptor activation reverses NMDA receptor-dependent long-term depression in rat hippocampus

Activation of dopamine D1/D5 receptors (D1/D5Rs) in area CA1 of the rat hippocampus modulates the expression of synaptic plasticity in a manner that is dependent on the timing of the D1/D5R activation. Here, we measured field EPSPs in rat hippocampal slices to examine the modulation of long-term depression (LTD) in CA1 by D1/D5Rs when activated immediately after the induction of LTD by low-frequency stimulation (LFS) or bath application of NMDA or the metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine]. Activation of D1/D5Rs by SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide] completely reversed a moderate LFS-induced LTD in a time-dependent manner, presumably through an adenylate cyclase/cAMP cascade. In support of this, general adenylate cyclase activation by forskolin ([3R-(3 alpha,4a beta,5 beta,6 beta,6a alpha,10 alpha,10a beta,10b alpha)]-5-(acetyloxy)-3-ethenyldodecahydro-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamenthyl-1H-naphtho[2,1-b]pyran-1-one) immediately, but not 60 min, after LFS also reversed the LTD. Beta-adrenergic receptor activation by isoproterenol failed to reverse the LTD, indicating that reversal is specific to D1/D5R-mediated increased cAMP production. SKF 38393 only partially reversed a more robust LFS-induced LTD, indicating that some components of consolidated LTD are resistant to reversal. LTD induced by bath application of NMDA, but not DHPG, was also reversed by SKF 38393. Western blot analysis of postsynaptic density fractions after NMDA-induced LTD revealed that the LTD was attributable to dephosphorylation of the AMPA receptor subunit glutamate receptor 1 (GluR1) at serine 845, without a change in total GluR content. Reversal of the LTD by SKF 38393 was associated with rephosphorylation of this same residue. Together, these findings demonstrate a new role for dopamine in the neuromodulation of hippocampal LTD.