CNS mechanisms of alcohol self-administration.
Neurochemical and neuropharmacological studies were undertaken to examine the possible involvement of the ventral tegmental area (VTA) dopamine (DA) system and the dorsal raphe nucleus (DRN) serotonin (5-HT) system in regulating oral alcohol self-administration. In vivo microdialysis studies demonstrated that either i.p. ethanol administration (1.0-2.0 g/kg) or local perfusion with ethanol (100 mM) could enhance the extracellular concentrations of both DA and 5-HT in the nucleus accumbens (ACB). Furthermore, the effects of local perfusion with ethanol on DA release in the ACB could be blocked by co-perfusion with a 5-HT3 antagonist. In the selectively-bred alcohol preferring P line of rats, there appears to be abnormal 5-HT and/or DA systems in certain limbic structures, i.e., ACB, olfactory tubercles (OTU) and medial prefrontal cortex (MPF). This is indicated by (a) lower contents of DA and 5-HT; (b) fewer 5-HT immunostained fibers; (c) lower densities of 5-HT1B, 5-HT2 and D2 receptors; and (d) higher densities of 5-HT1A receptors in the CNS of P rats compared to the alcohol-nonpreferring NP line of rats. Neuropharmacological studies demonstrated that local microinfusion of the D2 antagonist, sulpiride, or, at low doses, the DA releaser, d-amphetamine, could increase alcohol drinking by P rats. Intracranial self-administration (ICSA) studies showed that the P line of rats, but not the NP line, will self-administer 50-150 mg% ethanol directly into the VTA. Overall, these results suggest an innate abnormal functioning of the VTA DA and DRN 5-HT systems may be key factors facilitating the rewarding actions of ethanol in the CNS of P rats.
McBride
W J
WJ
Department of Psychiatry, Indiana University, School of Medicine, Indianapolis, USA.
Murphy
J M
JM
Gatto
G J
GJ
Levy
A D
AD
Yoshimoto
K
K
Lumeng
L
L
Li
T K
TK
D000428:Alcohol Drinking / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism; D013469:Sulpiride / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012701:Serotonin; D000431:Ethanol; D013469:Sulpiride; D003913:Dextroamphetamine; D004298:Dopamine