[Abstract Title]. - Society for Neuroscience

Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 257.18/AA1
Topic: C.16.a. Alcohol
Support: AA016741
AA014874
Title: Naltrexone does not attenuate ethanol stimulated dopamine release in the nucleus
accumbens shell in ethanol naive rats
Authors: *M. JOB, R. A. GONZALES;
Pharmacol., Univ. Texas-Austin, Austin, TX
Abstract: Naltrexone is approved for the management of alcoholism, and though it‟s mechanism
of action has not been fully elucidated, it is thought to be due to the attenuation of ethanol
evoked mesolimbic dopamine by blockade of the µ opioid receptors. The effect of naltrexone
(ntx) on ethanol (etOH) stimulated dopamine (DA) release in the nucleus accumbens shell was
studied in adult, male Long Evans rats using in vivo microdialysis in freely moving animals, in
conjunction with HPLC for DA detection and GC for etOH detection. Rats weighing 280-407 g
were implanted with microdialysis probes 15-20 hours before the experiment. On the next day,
baseline samples were taken and afterwards the animals were intravenously (i.v.) pretreated with
ntx (0, 0.3 or 1 mg/kg bolus) 20 min before i.v. infusion with etOH (10% w/v, 1 g/kg in a
volume of 10 mL/kg delivered at a rate of 4 mL/min) or an equivalent volume of saline.
Sampling continued for an hour. The administration of both doses of ntx caused a transient
increase (first sample after infusion) in DA compared to baseline. The infusion of 1 g/kg etOH
increased extracellular DA concentrations to approximately 130% of baseline in the saline
pretreated group (n = 8). The two ntx pretreatment dose groups (n = 8 each) were not different
from the control in both the increase in DA (% of basal) over time and area under the curve
(AUC) (p > 0.05). The infusion of saline did not show an increase in DA for any of the
pretreatment doses (n = 4 - 6). Ntx did not affect the peak concentration and clearance of ethanol
in the brain. A positive control experiment was done to ensure that the ntx doses used were
effective in blocking the µ opioid receptors. Rats were pretreated i.v. with ntx (0, 0.01, 0.03, 0.1,
0.3 mg/kg), followed 20 min later by i.v. morphine (1 mg/kg). Morphine increased DA in the
control group (n = 7) to about 150% of baseline within 5 min, followed by an escalating,
prolonged increase for the next 25 min. Ntx dose dependently inhibited the effect of morphine on
DA release over time and AUC (within 30 min after morphine infusion) (n = 5 - 7). Interestingly,
ntx (0.3 mg/kg) (n = 7) was able to completely abolish the morphine evoked DA release, though
in the previous experiment it didn‟t attenuate etOH stimulated DA release. The results suggest
that the µ opioid receptors are not involved in the mechanism of etOH stimulated DA release in
the nucleus accumbens shell in ethanol-naïve male rats. This may suggest that the mechanism of
action of naltrexone in the management of alcoholism does not involve mesolimbic dopamine,
although further research is required using alcohol dependent models.