The effects of chronic lithium on behavioral and biochemical indices of dopamine receptor supersensitivity in the rat

Abstract

The effects of dietary lithium on several indices of dopamine receptor supersensitivity were examined in rats during withdrawal from chronic administration of haloperidol. Chronic haloperidol enhanced the locomotor stimulant action of d-amphetamine, and this effect was attenuated by lithium. In contrast, lithium did not affect the amphetamine response in animals that had not previously received haloperidol. Apomorphine-induced hypothermia was not influenced by the chronic haloperidol treatment. On the other hand, during withdrawal from chronic haloperidol, spontaneous locomotor activity (20 h) and apomorphine-induced stereotypy were increased, but neither of these effects was attenuated by lithium. In addition, lithium did not affect the chronic haloperidol-induced increase in 3H-spiperone binding sites in the striatum. Lithium alone had no effect on any of these measures except for causing a slight prolongation of the hypothermic effect of apomorphine. The results indicate that not all DA-receptor-mediated responses are enhanced by chronic administration of neuroleptics (e.g., apomorphine-induced hypothermia). In addition, while lithium reduces the effects of chronic haloperidol administration on d-amphetamine-induced locomotor activity, this is not because lithium prevents haloperidol-induced supersensitivity of postsynaptic DA receptors because more direct measures of this phenomenon (e.g., 3H-spiperone binding, apomorphine-induced stereotypy) are not affected by lithium.

Chronic Lithium Chloride Administration to Unanesthetized Rats Attenuates Brain Dopamine D2-Like Receptor-Initiated Signaling Via Arachidonic Acid

“…LiCl-fed rats gained weight more slowly than did control rats, as has been reported (Pittman et al, 1984). At the time of surgery, the LiCl-fed rats weighed about 20% less than the control diet-fed group (254721 g, n ¼ 26 vs 308711 g, n ¼ 24, po0.0001).…”

“…However, lithium's effects on dopaminergic neurotransmission are not agreed upon, as lithium is reported to inhibit (Engel and Berggren, 1980;Friedman and Gershon, 1973), increase (Fadda et al, 1980;Hesketh et al, 1978), or have no effect (Bliss and Ailion, 1970;Ho et al, 1970) on brain dopamine turnover. Data on lithium's effects on brain dopaminergic D 2 -like receptor density also are conflicting (DziedzickaWasylewska and Wedzony, 1996;Reches et al, 1982;Staunton et al, 1982b;Wajda et al, 1983), as are data on its ability to modify haloperidol-induced supersensitivity (Carvey et al, 1990;Gallager et al, 1978;Pert et al, 1978;Pittman et al, 1984;Reches et al, 1982;Staunton et al, 1982a).…”

Adaptive changes in the rat dopaminergic transmission following repeated lithium administration

“…Original findings that chronic lithium administration interfered with the development of DA postsynaptic supersensitivity (Pert et al, 1978) could not be confirmed by subsequent studies (Bloom et al, 1983;Pittman et al, 1984;Reches et al, 1984;Staunton et al, 1982). In the report by Carli et al (1994) (Carli et al, 1994), which revealed biphasic curves, and increased inhibition constants of the high-affinity sites in the neostriatum after chronic lithium administration.…”

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

“…The significance of these observations is not clear. In many animal studies it is reported that lithium given by acute or divided treatments may prevent the changes in dopamine receptor sensitivity following dopamine antagonist treatments (Klawans et al 1977;Pert et al 1978;Gallagher et al 1978;Verimer et al 1980), but in other studies where dietary lithium preparations have been used, when administration may be considered to be more persistent, the reports have shown little or no effect of lithium to modify the behavioural and biochemical changes caused by the neuroleptic drugs (see Pittman et al 1984). Is it possible that the routes of lithium administrations to achieve persistent or fluctuating levels of lithium may contribute to the discrepancies observed in the above experiments?…”

“…Whilst in some animal models lithium has been found to antagonise hyperactivity or increased responding caused by drugs or electrical stimulation, such changes are non-cyclical and the role of dopamine is not clear, or is obscured by an involvement of noradrenaline (see review by Samuel and Gottesfeld 1973). Furthermore, animal studies investigating the possibility that lithium may exert its therapeutic effect by preventing the development of supersensitive dopamine receptors have produced conflicting data (see -Pittman et al 1984).…”