Psychostimulants depress excitatory synaptic transmission in the nucleus accumbens via presynaptic D1-like dopamine receptors

Abstract

The effects of dopamine (DA) and the psychostimulants cocaine and amphetamine on excitatory transmission in the nucleus accumbens (NAc) were examined in rat NAc slices using both extracellular-field and whole-cell patch-clamp recording. DA, cocaine, and amphetamine reversibly reduced the excitatory synaptic responses (EPSPs/EPSCs) elicited by stimulation of prelimbic cortical afferents. DA and amphetamine increased paired-pulse facilitation, reduced the frequency of spontaneous miniature EPSCs (mEPSCs), and had no effect on mEPSC amplitude, suggesting a presynaptic mechanism for the observed reduction in excitatory synaptic transmission. The effects of DA and amphetamine were attenuated by the D1 receptor antagonist SCH23390 but not by the D2 receptor antagonist sulpiride. The broad-spectrum DA receptor agonist 6,7-ADTN mimicked the effects of DA and the psychostimulants, but neither the D1 receptor agonists SKF38393 and SKF81297 nor the D2 receptor agonist quinpirole caused a significant reduction in EPSP magnitude. SKF38393 at a higher concentration (100 microM) was effective in reducing the EPSP, however, and this reduction was sensitive to SCH23390. There was no difference in the effects of DA in cells from mutant mice lacking D1a receptors and cells from wild- type control mice. Unilaterally lesioning the dopaminergic afferents to the NAc using 6-hydroxydopamine attenuated the amphetamine-induced reduction in EPSP magnitude in slices from the lesioned hemisphere but not the control (unlesioned) hemisphere. These results indicate that DA and psychostimulants (acting indirectly by increasing endogenous extracellular DA levels) reduce excitatory synaptic transmission in the NAc by activating presynaptic DA receptors with D1-like properties.