Ethanol Self-Administration Restores Withdrawal-Associated Deficiencies in Accumbal Dopamine and 5-Hydroxytryptamine Release in Dependent Rats

Abstract

Basal forebrain dopamine (DA) and 5-HT neurotransmission has been implicated in the mediation of the acute reinforcing actions of ethanol. Neuroadaptation theories predict that compensatory changes in neurochemical systems that are activated by alcohol acutely may underlie symptoms of withdrawal after chronic administration. To test this hypothesis, the release of DA and 5-HT was monitored by microdialysis in the nucleus accumbens of dependent male Wistar rats at the end of a 3-5 week ethanol (8.7% w/v) liquid diet regimen, during 8 hr of withdrawal, and during renewed availability of ethanol involving (1) the opportunity to operantly self-administer ethanol (10% w/v) for 60 min, followed by (2) unlimited access to the ethanol-liquid diet. Results were compared to control groups pair-fed with ethanol-free liquid diet and trained to self-administer either ethanol or water. In nondependent rats, operant ethanol self-administration increased both DA and 5-HT release in the NAC. Withdrawal from the chronic ethanol diet produced a progressive suppression in the release of these transmitters over the 8 hr withdrawal period. Self-administration of ethanol reinstated and maintained DA release at prewithdrawal levels but failed to completely restore 5-HT efflux. 5-HT levels recovered rapidly, however, within 1 hr of reexposure to ethanol liquid diet. These findings suggest that deficits in accumbal monoamine release may contribute to the negative affective consequences ethanol withdrawal and, thereby, motivate ethanol-seeking behavior in dependent subjects.

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

“…This hypothesis is consistent with the observation that withdrawal from other drugs of abuse, such as cocaine (Parsons et al 1995) or ethanol (Weiss et al 1996), also is characterized by decreased serotonergic neurotransmission as reflected in decreased in vivo dialysate serotonin levels. Further, considering the strong evidence implicating reduced serotonergic neurotransmission as one of the neurochemical abnormalities associated with depression (for reviews, see Caldecott-Hazard et al 1991;Caldecott-Hazard and Schneider 1992;Heninger et al 1996;Markou et al 1998;Meltzer and Lowy 1988;Willner 1985), it can be hypothesized that there is homology between the symptom of "diminished interest or pleasure" seen in individuals withdrawing from drugs of abuse and the same symptom seen in depressed patients.…”

“…Further, considering the strong evidence implicating reduced serotonergic neurotransmission as one of the neurochemical abnormalities associated with depression (for reviews, see Caldecott-Hazard et al 1991;Caldecott-Hazard and Schneider 1992;Heninger et al 1996;Markou et al 1998;Meltzer and Lowy 1988;Willner 1985), it can be hypothesized that there is homology between the symptom of "diminished interest or pleasure" seen in individuals withdrawing from drugs of abuse and the same symptom seen in depressed patients. Decreased dopaminergic neurotransmission is another neurobiological abnormality common to withdrawal from a variety of drugs of abuse, including nicotine (Hildebrand et al 1999;Parsons et al 1995;Weiss et al 1996).…”

Repeated Ethanol Intoxication Induces Behavioral Sensitization in the Absence of a Sensitized Accumbens Dopamine Response in C57BL/6J and DBA/2J Mice

“…These studies have consistently shown a profound reduction in the activity of mesolimbic DA neurons that is reversed by resuming ETOH exposure (Rossetti et al, 1992;Diana et al, 1993;Weiss et al, 1996). However, studies examining whether these changes persist beyond the acute withdrawal phase have been lacking.…”

“…Several reports have shown a pronounced decrease in basal extracellular DA levels in the nucleus accumbens during the initial phase of ETOH withdrawal Weiss et al, 1996). However, these studies were performed within 6-12 h after the cessation of ETOH administration.…”

Tryptophan Depletion Alters the Decision-Making of Healthy Volunteers through Altered Processing of Reward Cues

“…Also relevant are serotonin's acknowledged involvement in clinical depression (eg Schildkraut, 1965) and the more general observation that SSRI treatment is relatively effective in the treatment of clinical depressive illness, while the temporary reduction of central serotonin function in vulnerable individuals through rapid dietary tryptophan depletion has been shown to reinstate depressive symptoms and flat affect (Moore et al, 2000;Smith et al, 1997). Finally, depleted serotonin function within limbic structures associated with reward processing, such as the nucleus accumbens, has also been implicated as an important mediating factor in the affective/motivational aspects of withdrawal phenomena in drug-dependent individuals (Markou et al, 2001;Weiss et al, 1996).…”