ABSTRACT
Besides clinical or psychological studies, animal studies have been a mainstay of the study of lithium effects on behavior. These animal studies were reviewed in 19911 and again in 20032. The overriding majority of studies in this field have used the concept of pharmacologically induced mania and depression and have attempted to show prevention by lithium. The usual agent for pharmacologic induction of mania has been amphetamine, although more specific and direct dopamine agonists such as quinpirole have also been used3. Reserpine or tetrabenazine to induce depression have also been studied4. A background concept has been the fact that low-dose amphetamine has effects primarily on open field activity, whereas
higher-dose amphetamine causes stereotypy5,6. Dopamine blockers are well known to block both the low-dose hyperactivity and the highdose stereotypy of amphetamine, and this fits their usefulness in both mania and schizophrenia7. Therefore, attempts have been made to look at the effect of lithium pre-treatment on low-dose amphetamine effects versus high-dose amphetamine effects, the hypothesis being that lithium as an antimanic agent will prevent the effects of low-dose amphetamine but, because it is devoid of true antipsychotic properties, it will not be able to affect amphetamine-induced stereotypy. Often an underlying biochemical hypothesis was that low-dose amphetamine released mostly serotonin and norepinephrine, whereas high-dose amphetamine released more dopamine. All of these assumptions, hypotheses and preconceptions are today viewed skeptically. They were heuristic as hypotheses that
generated much good research; however, the yield of robust replicable data has been poor. Given the fact that modern studies of psychopharmacologic agents often require hundreds of patients to show statistically significant effects, it may not be surprising that animal studies with 10-15 rats in each group often come up with conflicting results. The heterogeneity of the amphetamine response is well known8, and so the lithium response may also be heterogeneous in outbred rat strains9,10.
