Localization of the delta-opioid receptor and dopamine transporter in the nucleus accumbens shell: implications for opiate and psychostimulant cross-sensitization.

Opiate- and psychostimulant-induced modulation of dopamine transmission in the nucleus accumbens shell (AcbSh) is thought to play a key role in their potent reinforcing and locomotor effects. To investigate the cellular basis for potential functional interactions involving opiates active at the delta-opioid receptor (DOR) and psychostimulants that bind selectively to the dopamine transporter (DAT), we examined the electron microscopic localization of their respective antisera in rat AcbSh. DOR immunoperoxidase labeling was seen primarily, and DAT immunogold particles exclusively, in axon terminals. In these terminals, DOR immunoreactivity was prominently associated with discrete segments of the plasma membrane and the membranes of nearby small synaptic and large dense core vesicles. DAT immunogold particles were almost exclusively distributed along nonsynaptic axonal plasma membranes. Thirty-nine percent DOR-labeled profiles (221/566) either apposed DAT-immunoreactive terminals or also contained DAT. Of these 221 DOR-labeled profiles, 13% were axon terminals containing DAT and 15% were dendritic spines apposed to DAT-immunoreactive terminals. In contrast, 70% were morphologically heterogeneous axon terminals and small axons apposed to DAT-immunoreactive terminals. Our results indicate that DOR agonists in the AcbSh can directly modulate the release of dopamine, as well as postsynaptic responses in spiny neurons that receive dopaminergic input, but act principally to control the presynaptic secretion of other neurotransmitters whose release may influence or be influenced by extracellular dopamine. Thus, while opiates and psychostimulants mainly have differential sites of action, cross-sensitization of their addictive properties may occur through common neuronal targets.