Endogenous opioids in dopaminergic cell body regions modulate amphetamine-induced increases in extracellular dopamine levels in the terminal regions.
Opioid antagonists attenuate behavioral effects of amphetamine and amphetamine-induced increases in extracellular dopamine levels in nucleus accumbens and striatum of rats but do not alter those effects of cocaine. This study was performed to determine 1) if the effect of opioid antagonists on the dopamine response to amphetamine is mediated in either the terminal or cell body region of the nigrostriatal and mesolimbic pathways, and 2) if the enkephalinase inhibitor thiorphan, which slows degradation of endogenous opioid peptides, increases the dopamine response to amphetamine but not to cocaine. Microdialysis probes were placed either into a dopaminergic terminal region or into both a terminal and cell body region of rats. Naloxone methiodide (1.0 microM), a lipophobic opioid antagonist, was administered into either the terminal or cell body region by reverse dialysis, whereas extracellular dopamine was collected in the terminal region. Increases in extracellular dopamine in nucleus accumbens and striatum caused by amphetamine (0.1-6.4 mg/kg, s.c.) were reduced significantly (28-39%) by naloxone methiodide administered into either substantia nigra or ventral tegmentum but not into terminal regions. Thiorphan (10 microM) administered into substantia nigra increased significantly the dopamine response to amphetamine in the ipsilateral striatum by as much as 42% but did not affect the dopamine response to cocaine (3.0-56 mg/kg, i.p.). These results suggest that amphetamine promotes release of endogenous opioids, which, through actions in the ventral tegmentum and substantia nigra, contribute to amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and striatum.
Schad
Christina A
CA
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
Justice
Joseph B
JB
Holtzman
Stephen G
SG
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000502:physiology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000502:physiology; D015244:Thiorphan / Q000008:administration & dosage / Q000494:pharmacology
D018765:Dopamine Uptake Inhibitors; D004723:Endorphins; D009292:Narcotic Antagonists; D011480:Protease Inhibitors; D009270:Naloxone; D015244:Thiorphan; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine