Lithium and bupropion antagonise the phasic changes in locomotor activity caused by dopamine infused into the rat nucleus accumbens

Abstract

Dopamine infused persistently (25 micrograms/24 h for 13 days) into the nucleus accumbens of rat brain caused phasic increases in spontaneous locomotor activity during the period of infusion. This phasic responding was prevented by lithium administered throughout the infusion period in divided doses (3 X daily administrations of 2.5 mg/kg IP) or as a continuous IP infusion (7.5 mg/kg/24 h), and by bupropion treatment (5-20 mg/kg 3 X daily). In contrast, imipramine, amitriptyline and nomifensine failed to prevent the phasic locomotor response to dopamine at doses which did not by themselves cause marked motor changes. Locomotor activity was measured using individual photocell cages, and rats preselected to (-)NPA were those initially showing a modest locomotor activity. Fourteen to twenty-eight days after discontinuing the dopamine infusion rats showed increased responsiveness to (-)NPA which persisted throughout the remainder of the 70-day withdrawal period. This long-term change was prevented when lithium was given continuously throughout the period of dopamine infusion, but not when lithium was given in divided doses, showing the importance of the mode of drug delivery. The long-term change caused by the dopamine infusion could also be prevented by bupropion but not by imipramine, amitriptyline or nomifensine to show again that the actions of classical antidepressant drugs may be differentiated from those of lithium and bupropion. Therefore, it is suggested that the model of phasic hyperactivity described may provide a means for more closely analysing, both behaviourally and biochemically, the site and mechanism of action of lithium (and bupropion) in the control of the short- and long-term consequences of an enhanced mesolimbic dopamine activity.

Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors

“…For instance, as early as in 1971, behavioral observations in rodents have shown that lithium, which is now known to inhibit GSK3, can antagonize locomotor activity induced by drugs elevating dopaminergic tone or by the direct injection of dopamine in the nucleus accumbens (Cox et al, 1971; Barnes et al, 1986; Aylmer et al, 1987). However, these studies were all conducted before the discovery of the effect of lithium on GSK3 (Klein and Melton, 1996; Stambolic et al, 1996), and the actions of lithium in these experimental systems were generally attributed to other mechanisms including changes in dopamine release or dopamine receptor blockade.…”

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

“…However, the signaling mechanisms mediating the action of DA on hyperactivity are still not fully understood. For instance, acute administration of lithium salts is known to antagonize the hyperactivity induced by various dopaminergic agonists (8)(9)(10)(11). Nevertheless, the mechanism by which lithium interferes with DA-associated behavior remains uncharacterized.…”

Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation

“…It is conceivable, therefore, that any effects of lithium and valproate could be due to direct attenuation of the effects following release of these neurotransmitters, particularly dopamine. Certainly there is some support for suggestions that dopamine-induced changes can be attenuated by chronic treatment with lithium in animal studies (Cox et al, 1971;Flemenbaum, 1977;Barnes et al, 1986), although not in all studies (Cappeliez and Moore, 1990), and may also inhibit amphetamine-induced behaviors (Lerer et al, 1984). There is also some evidence that in animals chronic lithium may reduce dopamine release in response to amphetamine or cocaine (Berggren, 1985;Gambarana et al, 1999).…”