Sensitization and kindling-like phenomena in bipolar disorder: implications for psychopharmacology

Abstract

Behavioral sensitization to psychomotor stimulants and electrophysiological kindling are two different models of learning and memory that reveal progressively increasing responsiveness to repetition of the same inducing stimulus over time. Although cocain-induced behaviors in animals and humans show many different parallels with mania and the evolution into dysphoric mania and psychosis, the development of amygdala-kindled seizures and their progression to spontaneity is obviously a highly indirect and nonhomologous model for illness progression in the affective disorders. Nonetheless, both models offer new insights into the longitudinal course and recurrence of the affective disorders and potential neurobiological mechanisms involved at the level of gene expression. A complex spatio-temporal cascade of changes in gene expression involving a host of immediate early genes (IEGs), neurotrophic factors, and late effector genes (LEGs) are postulated that reflect both primary pathological and secondary adaptive processes whose ratio may determine the presence or absence of illness. New evidence suggests that the impact of both stressful environmental events and of antidepressants and mood stabilizers on neurotrophic factor gene expression reveals a potential basis for lasting illness-related biochemical and structural alterations in the central nervous system and their potential prevention or amelioration by therapeutic agents. Given the substantive evidence of both episode and stressor sensitization in the course of bipolar illness, the models of sensitization and kindling provide additional theoretical rationale to the growing empirical database on the importance of instituting early pharmacoprophylaxis and sustaining it for the long term.