Reduced psychostimulant effects on dopamine dynamics in the nucleus accumbens of mu-opioid receptor knockout mice.
Dopamine neurotransmission in the nucleus accumbens plays a pivotal role in the reinforcing properties of drugs of abuse. Two interacting processes regulate nucleus accumbens dopamine overflow: release of dopamine from presynaptic terminals and the subsequent reuptake by dopamine transporters. Opioid neurotransmission, primarily through mu-opioid receptors has also been strongly implicated in drug reward. We have previously shown that mice lacking the mu-opioid receptor display decreased cocaine self-administration. In addition, we found decreased impulse activity of midbrain dopaminergic neurons and an increased GABAergic input to these neurons in mu-opioid receptor knockout mice. In the present study we investigated whether these changes in dopaminergic cell bodies are accompanied by altered dopamine dynamics at the terminal level. To that aim, we measured nucleus accumbens dopamine overflow using fast scan cyclic voltammetry. Our data demonstrate that in mu-opioid receptor knockout mice 1) the reuptake of dopamine in the nucleus accumbens is slower, and 2) the relative effect of cocaine and amphetamine on the reuptake of dopamine is smaller compared with wild type mice. These data provide a mechanism for the decreased reinforcing properties of cocaine observed in mu-opioid receptor knockout mice.
Mathon
D S
DS
Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Vanderschuren
L J M J
LJ
Ramakers
G M J
GM
D000661:Amphetamine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004563:Electrochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000172:deficiency*
D000697:Central Nervous System Stimulants; D017450:Receptors, Opioid, mu; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine