title: Reverse microdialysis of a dopamine uptake inhibitor in the nucleus accumbens of alcohol-preferring rats: effects on dialysate dopamine levels and ethanol intake.
abstract: BACKGROUND
  The mesolimbic dopamine (DA) system has been implicated in mediating the reinforcing actions of ethanol (EtOH). This study examines the effects of local perfusion of the DA uptake inhibitor GBR12909 (GBR) on (1) DA levels in the nucleus accumbens (NAc) and (2) EtOH drinking in alcohol-preferring rats.
  
  
  METHODS
  Stable drinking of a 15% (v/v) EtOH solution (minimum of 0.75 g/kg body weight) was established in daily 1 hr limited access sessions. Rats were then implanted with bilateral guide cannulae aimed 4 mm above the NAc. After recovery from surgery, concentric microdialysis probes (2 mm dialysis membrane surface) were inserted into the NAc. Most placements were in the shell or overlapping both shell and core. Two days later, the probes were perfused at 1.0 microl/min with artificial cerebral spinal fluid (aCSF) for at least a 90 min washout period followed by collection of five basal samples over 150 min. Rats were then perfused with either aCSF alone or 10, 25, 100, or 200 microM of GBR for 240 min on the first day of microdialysis. During the last 60 min of the drug treatment phase, rats were given their scheduled access to 15% EtOH. All rats were then perfused with aCSF for the last 90 min of the experiment. The following day, the procedure was repeated, but animals that received aCSF on the first day were given a dose of GBR and rats given GBR on the first day received only aCSF.
  
  
  RESULTS
  GBR perfusion increased extracellular NAc DA levels dose dependently to more than 800% of basal levels at 100 to 200 microM but failed to alter EtOH intake (p > 0.05, paired t test) at any concentration tested. Moreover, after 100 microM of GBR perfusion had terminated, the extracellular levels of DA in the NAc remained elevated for approximately 24 hr (790% of day 1 basal; p < 0.05). The increase in dialysate DA levels observed during GBR perfusion with 100 microM was significantly greater for EtOH-experienced rats than for EtOH-naïve rats [F(7,59) = 14.85, p < 0.0001, analysis of variance, Student-Newman-Keuls post hoc test].
  
  
  CONCLUSIONS
  The results suggest (1) that EtOH drinking experience induces neuroadaptations that increase DA release in the NAc, and (2) that additional elevation in synaptic levels of DA in the NAc does not influence the maintenance of ongoing alcohol drinking under scheduled access conditions in alcohol-preferring animals.
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, VA Medical Center, Indianapolis, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Engleman
authors.forename: W J
authors.initials: WJ
authors.lastname: McBride
authors.forename: A A
authors.initials: AA
authors.lastname: Wilber
authors.forename: S R
authors.initials: SR
authors.lastname: Shaikh
authors.forename: R D
authors.initials: RD
authors.lastname: Eha
authors.forename: L
authors.initials: L
authors.lastname: Lumeng
authors.forename: T K
authors.initials: TK
authors.lastname: Li
authors.forename: J M
authors.initials: JM
authors.lastname: Murphy
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005260:Female; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D012054:Reinforcement, Psychology
chemical_list: D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine; D004298:Dopamine