Dual Ultrastructural Localization of μ-Opioid Receptors and NMDA-Type Glutamate Receptors in the Shell of the Rat Nucleus Accumbens

Abstract

The effectiveness of NMDA antagonists in modulating the motor and motivational effects of opiates is attributed, in part, to functional associations involving NMDA receptors and -opioid receptors (MORs) in the shell of the nucleus accumbens (Acb). To determine the subcellular sites for potential functional interactions between opiate ligands and NMDA receptors in this region, we examined the ultrastructural localization of antipeptide antisera against MOR and the R1 subunit of the NMDA receptor in the Acb shell of the adult rat brain. MOR-like immunoreactivity (MOR-LI) was seen primarily in dendrites, whereas NMDAR1-like immunoreactivity (NMDAR1-LI) was detected more often in axon terminals forming asymmetric synapses. In these profiles, MOR labeling was localized mainly to extrasynaptic plasma membranes, whereas NMDAR1-LI was associated with both synaptic and extrasynaptic sites. Of 307 MOR-labeled processes, 17.9% of the dendrites and 9.4% of the axon terminals also contained NMDAR1-LI. In addition, 24.7% of the dendrites containing only MOR-LI were apposed to NMDAR1-labeled axons or terminals. We conclude that in the shell of the Acb, the output of single neurons can be dually modulated by (1) activation of MOR and NMDA receptors in the same dendrites or (2) combined activation of presynaptic NMDA receptors in afferents contacting dendrites containing MOR. In addition, the colocalization of MOR and NMDAR1 in certain axon terminals in the Acb suggests their dual involvement in the presynaptic release of neurotransmitters in this region.

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

“…However, this study and a previous study of a drug known to attenuate glutamate release (Anand et al 2000;Langosch et al 2000) suggest that voltage-gated cation channel antagonists attenuate the perceptual and amnestic effects of ketamine without reducing its stimulant effects. Preclinical reports suggest that the rewarding or stimulating effects of NMDA antagonists reflect blockade of NMDA receptors postsynaptic to corticofugal projections to limbic regions, such as the nucleus accumbens (Carlezon and Wise 1996a;Carlezon and Wise 1996b;Gracy et al 1997). If so, then the current findings may suggest that a component of the interactive effects observed in this study reflect a reduction in the hyperglutamatergic effects of ketamine by nimodipine pretreatment.…”

Differential Subcellular Localization of mGluR1a and mGluR5 in the Rat and Monkey Substantia Nigra

“…As discussed in our previous study (Hanson and Smith, 1999), three possibilities should be considered: (1) extrasynaptic diffusion of glutamate from subthalamonigral synapses (Asztely et al, 1997;Barbour and Hausser, 1997), (2) release of glutamate from astrocytes (Antanitus, 1998;Araque et al, 1999), and (3) corelease of GABA and glutamate from striatonigral terminals (Dubinsky, 1989;White et al, 1994). The extrasynaptic localization of G-protein-coupled receptors is a general phenomenon in the CNS (Yung et al, 1995;Gracy et al, 1997;Dournaud et al, 1998;Bernard et al, 1999). Although the functions and mechanisms of activation of these receptors still remain to be established, their pattern of distribution indicates that they may play much more subtle and complex modulatory functions in neuronal activity than previously thought.…”

Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism

“…However, little is known about psychopharmacologic aspects of the interplay of drugs acting at these receptors in humans. Binding studies describe colocalization of NMDA and m-opiate receptors in the nucleus accumbens (Gracy et al, 1997) and nucleus tractus solitarius (Huang et al, 2000). In the raphe nucleus, nucleus accumbens, and prefrontal cortex, the excitatory effects of NMDA receptor stimulation are opposed by the inhibitory effects of m-opiate receptor stimulation.…”