The Effects of Opioid Peptides on Dopamine Release in the Nucleus Accumbens: An In Vivo Microdialysis Study

Abstract

An involvement of the mesolimbic dopamine (DA) system in mediating the motivational effects of opioids has been suggested. Accordingly, the present study employed the technique of in vivo microdialysis to examine the effects of selective mu-, delta-, and kappa- opioids on DA release in the nucleus accumbens (NAC) of anesthetized rats. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA), using a reverse-phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of selective mu-opioid [D-Ala2, N-methyl-Phe4, Gly5-ol]-enkephalin (DAMGO) or delta-opioid [D-Pen2, D-Pen5]-enkephalin (DPDPE) agonists, at doses that function as positive reinforcers in rats, resulted in an immediate and significant increase in extracellular DA. DOPAC and HVA levels were also significantly increased. The effects of DAMGO were blocked by the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) whereas those of DPDPE were blocked by the delta-antagonist allyl2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). In contrast to mu- and delta-agonists, the kappa-agonist N-CH3-Tyr-Gly-Gly-Phe-Leu-Arg-N-CH3-Arg-D-Leu-NHC2H5 (E-2078), a dynorphin analog that produces aversive states, decreased DA release in a biphasic manner. Norbinaltorphimine, a selective kappa-antagonist, could block this effect. These results demonstrate that mu-, delta-, and kappa-opioid agonists differentially affect DA release in the NAC and this action is centrally mediated.

Association of the κ-opioid system with alcohol dependence

“…In neither case did [1][2][3] 0.015 CAG TGA SNP [2][3][4] 0.010 AGG GAA SNP [3][4][5] 0.044 GGG AAA SNP [4][5][6] 0.005 GGA AAG SNP [5][6][7] 0.065 GAA AGA* SNP [6][7][8] 0.027 AAC -SNP [7][8][9] 0.062 ACA* -SNP [8][9][10] 0.09 CAT** -SNP [9][10][11] 0.08 --SNP [10][11][12] 0.28 --SNP [11][12][13] 0.37 --SNP [12][13][14] 0.60 --SNP [13][14][15] 0.031 TGC TGT SNP [14][15][16] 0.057 GCA GTA SNP [15][16][17] 0.074 CCT** TAA SNP [16][17][18] 0.30 --Individual overtransmitted haplotypes for alcohol dependence are indicated in bold when P < 0.05; *P = 0.06, and **P < 0.10.…”

“…7 Stimulation of MOR and DOR in mouse brain increases the release of dopamine in the nucleus accumbens, whereas stimulation of KOR reduces the release of dopamine and generates aversive states. [8][9][10][11] Alcoholism (alcohol dependence) is a common complex genetic disease. Both twin and adoption studies show a strong heritable component involved in the risk for alcoholism.…”

Altered HPA Axis Responsivity to Metyrapone Testing in Methadone Maintained Former Heroin Addicts with Ongoing Cocaine Addiction

“…Microdialysis studies in rodents have demonstrated that administration of the endogenous kappa opioid ligand dynorphin A1-17 directly to the nucleus accumbens causes a significant reduction in basal levels of dopamine in the extracellular fluid (Claye et al 1997), and synthetic kappa opioid receptor ligands may directly reduce dopamine levels in extracellular fluid in the caudate putamen, nucleus accumbens, and related brain regions (Spanagel et al 1990). In humans, prolactin release, under tonic inhibition by tuberoinfundibular dopamine, may be used as a peripherally accessible window into some aspects of central dopaminergic tone.…”

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

“…GABAergic interneurons in the VTA inhibit dopamine firing in mesolimbic-mesocortical dopaminergic neurons, thus mu-opioid receptor agonists stimulate dopamine release through disinhibition (Di Chiara and Imperato, 1988;Spanagel et al, 1991). Systemically or locally administered synthetic and locally administered natural peptidic kappa-opioid receptor agonists (ie dynorphin) inhibit dopamine release in the mesolimbicmesocortical dopaminergic systems (Di Chiara and Imperato, 1988;Spanagel et al, 1990;Claye et al, 1997;Zhang et al, 2004a, b). While mu-and kappa-opioid receptor antagonists can each reverse these effects, neither administered alone have been shown to alter dopamine release in either rodent or non-human primate models (Deyo et al, 1979;Durham et al, 1996;Butelman et al, 2002).…”