Effect of chronic lithium and withdrawal from chronic lithium on presynaptic dopamine function in the rat

Bipolar affective disorders can be successfully treated with long-term use of the mood stabilizer lithium. However, discontinuation of lithium treatment is followed by a high incidence of manic episodes. In the present study, we attempted to identify neurobiological changes that might mediate this rebound mania. In vivo microdialysis in the anaesthetized rat and in situ hybridization histochemistry were used to study the effect of chronic lithium treatment and withdrawal from chronic lithium treatment on presynaptic dopamine (DA) function. Rats were maintained for 28 days on a lithium diet or control diet. The lithium-withdrawn treatment group had their lithium diet substituted for control diet from day 25 of the treatment period. Microdialysis probes were implanted in the shell of the nucleus accumbens and both basal extracellular DA levels and DA levels in the presence of the DA uptake inhibitor bupropion (1 mu M) were collected. Basal DA levels did not differ between any of the treatment groups. However, during local perfusion of bupropion, the increase in DA was significantly attenuated in the lithium-treated animals compared to controls or lithium-withdrawn animals. In situ hybridization of DA transporter mRNA in the ventral tegmental area revealed no difference in the abundance of this mRNA in any of the groups. These data suggest that there is impaired DA release in rats during chronic lithium treatment, but DA release returns to normal levels on withdrawal from lithium treatment, and is therefore unlikely to underlie the rebound mania associated with lithium withdrawal.