piperidines and nafadotride

Dopamine and glutamate receptors are densely expressed in the nucleus accumbens (NAc). Active interactions between these receptors contribute to the development of neuropsychiatric diseases, such as drug addiction and relapse. However, the molecular mechanisms underlying these interactions remain unclear.. This study established a mouse model of intermittent morphine-induced mouse behavioral sensitization model. Western blot and electrophysiological recording methods were performed to directly identify the affective components of morphine behavioral sensitization.. Interval morphine administration could cause significant locomotor sensitization. Hyperlocomotion and behavioral locomotor sensitization were significantly suppressed when ifenprodil (5 mg/kg), a selective NR2B subunit-containing N-methyl-d-aspartate (NMDA) receptor antagonist, or nafadotride (25 μg/kg), a dopamine D3 receptor (D3R)-preferring antagonist, was coadministered with morphine. Western blot analysis showed that morphine behavioral sensitization induced a region-specific increase in phosphorylation of NR2B (pNR2B) and total levels of NR2B (NR2B) expression in the NAc. Systemically administered nafadotride attenuated behavioral locomotor sensitization induced by morphine and significantly reversed the overexpression of pNR2B and NR2B subunit-containing NMDA receptor in the NAc. NMDA receptor-mediated excitatory postsynaptic currents in the NAc were also significantly reduced by nafadotride.. These findings suggest that D3Rs are involved in morphine-induced behavioral locomotor sensitization in mice by regulating the NR2B subunits of NMDA receptors in the NAc.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Gene Expression Regulation; In Vitro Techniques; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Morphine; Motor Activity; Naphthalenes; Neurons; Nucleus Accumbens; Patch-Clamp Techniques; Piperidines; Pyrrolidines; Receptors, Dopamine D3; Receptors, N-Methyl-D-Aspartate

The contribution made by specific dopamine receptor subtypes to the induction of motor behaviors has not been firmly established. Here, we first characterized the behavioral effects induced by a D(2)-class receptor agonist, bromocriptine, following injections into the nucleus accumbens (Acb). Bromocriptine showed an atypical D(2)-class receptor agonist profile, having no observable effect on a range of motor behaviors. However, when coadministered with the D(1)-class receptor agonist SKF 38393, bromocriptine showed a typical D(2)-class receptor agonist profile, enhancing locomotor activity and suppressing spontaneous yawning. We then administered the dopamine receptor antagonists L-741626 and nafadotride, which possess relative selectivity for D(2) and D(3) receptors, respectively, prior to injections of dopamine agonists into the Acb. Nafadotride significantly reduced the locomotor-enhancing effects elicited by the coadministration of SKF 38393 and the D(2)-class receptor agonist (+)-PD 128907 into the Acb, and also attenuated the effects induced by the combination of SKF 38393 and bromocriptine, although not significantly so. L-741626 mildly attenuated the locomotor effects elicited by both drug combinations. Taken together, these results suggest that both D(2) and D(3) receptors in the Acb contribute to the expression of heightened psychomotor activation.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Benzopyrans; Bromocriptine; Grooming; Indoles; Motor Activity; Naphthalenes; Nucleus Accumbens; Oxazines; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3