The K‐Opioid Agonist, U‐69593, Decreases Acute Amphetamine‐Evoked Behaviors and Calcium‐Dependent Dialysate Levels of Dopamine and Glutamate in the Ventral Striatum

Abstract

Abstract:The effects of a -opioid receptor agonist on acute amphetamine-induced behavioral activation and dialysate levels of dopamine and glutamate in the ventral striatum were investigated. Amphetamine (2.5 mg/kg i.p.) evoked a substantial increase in rearing, sniffing, and hole-poking behavior as well as dopamine and glutamate levels in the ventral striatum of awake rats. U-69593 (0.32 mg/kg s.c.) significantly decreased the amphetamineevoked increase in behavior and dopamine and glutamate levels in the ventral striatum. Reverse dialysis of the selective -opioid receptor antagonist, nor-binaltorphimine, into the ventral striatum antagonized the effects of U-69593 on amphetamine-induced behavior and dopamine and glutamate levels. Reverse dialysis of low calcium (0.1 mM) into the ventral striatum decreased basal dopamine, but not glutamate, dialysate levels by 91% 45 min after initiation of perfusion. Strikingly, 0.1 mM calcium perfusion significantly reduced the 2.5 mg/kg amphetamine-evoked increase in dopamine and glutamate levels in the ventral striatum, distinguishing a calciumdependent and a calcium-independent component of release. U-69593 did not alter the calcium-independent component of amphetamine-evoked dopamine and glutamate levels. These data are consistent with the view that a transsynaptic mechanism augments the increase in dopamine and glutamate levels in the ventral striatum evoked by a moderately high dose of amphetamine and that stimulation of -opioid receptors suppresses the calcium-dependent component of amphetamine's effects.

Acute Amphetamine Exposure Selectively Desensitizes κ-Opioid Receptors in the Nucleus Accumbens

“…The observation that an effect of amphetamine administration can be mimicked by KOP receptor agonists appears paradoxical to several studies showing that KOP receptor agonists prevent many of the behavioral effects of amphetamine (Gray et al, 1999;Tzaferis and McGinty, 2001). However, these immediate effects of KOP receptor stimulation can be distinguished from their longer-lasting modulatory effects on the endogenous opioid system.…”

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

“…U50,488H and U69,593, commonly used in microdialysis studies. When given alone, U50,488H (You et al, 1999) and U69,593 (Rawls and McGinty, 1998;Gray et al, 1999), do not affect glutamate levels within the striatum. We are first to confirm, through microdialysis, that the clinically useful kappa receptor agonist, nalfurafine, does not affect glutamate levels in the striatum.…”

“…Since activation of kappa opioid receptors decreases glutamate release intrastriatally (Hill and Brotchie, 1995;Rawls and McGinty, 1998;Gray et al, 1999;Hill and Brotchie, 1999; and extrastriatally (Gannon and Terrian, 1992;Maneuf et al, 1995;Sbrenna et al, 1999), we cannot establish how icilin acts to increase glutamate levels in the dorsal striatum or how a kappa agonist, like nalfurafine, reverses the behavioral or neurochemical action of icilin in rats. Although we have shown that icilin increases glutamate release we have not observed overt seizures in rats following intraperitoneal, intrastriatal or intracerebroventricular injection of icilin (data not shown).…”

“…Rawls and McGinty (2000) perfused naltrindole into the striatum and significantly reduced amphetamine-evoked glutamate levels in this region. Likewise, Gray et al (1999) perfused NBNI directly into the striatum and reversed U69,593 inhibition of amphetamine-evoked glutamate stimulation within this region. Shippenberg et al (1993) blocked the development of conditioned place preference induced by systemic morphine by infusing the D1 antagonist, SCH-23390, unilaterally into the ventral striatum.…”

“…Since kappa opioid receptors are located presynaptically on dopaminergic (Spanagel et al, 1993) and glutamatergic (Meshul and McGinty, 2000) terminals within the striatum and activation of these receptors decreases neurotransmitter levels Brotchie, 1995,Rawls andMcGinty, 1998;Gray et al, 1999;Hill and Brotchie, 1999;Rawls et al, 1999;Sbrenna et al, 1999), we investigated whether an effective dose of nalfurafine (0.04 mg/kg) blocks icilin (0.50 mg/kg)-induced wet-dog shakes by inhibiting glutamate release intrastriatally. In doing so, we can confirm involvement of the dorsal striatum following icilin administration and suggest a possible mechanism for kappa opioid mediated inhibition of icilin-induced wet-dog shakes.…”