Although still speculative in some aspects, sensitization and kindling as described by Post et al74 may be helpful in understanding the course of BD, starting from a molecular level and evolving towards behavioral changes. Kraepelin75 had already noticed in 1921 that a marked psychosocial stressor usually preceded the first affective episode, whereas subsequent episodes showed minor or even absent

Inhibitors,research,lifescience,medical notable life events. At the same time, the frequency of episodes tends to increase, in some patients to the point of autonomous rapid cycling, with decreasing efficacy of mood-stabilizing drugs. Post and Contel76 developed the model of cocaine-induced behavioral sensitization (CIBS). Cocaine administration causes hypcrlocomotion in rats and hypomanic-likc Inhibitors,research,lifescience,medical symptoms

in man. Repeated cocaine administration, however, may cause a shift of symptomatology toward signs of dysphoric mania (which has a high incidence in BD, as shown by the EPIMAN study) or even paranoid symptoms. Lcsioning experiments in the amygdala show that CIBS involves different neuromodulatory changes depending on the duration and frequency of cocaine administration. Thus, not only the symptomatology can shift, but also the neuronal Inhibitors,research,lifescience,medical pathways involved, becoming independent of a direct action on the amygdala. Furthermore, cocaine is also capable of influencing neuromodulators in a similar fashion to stress, Inhibitors,research,lifescience,medical ie, by causing an increase in CRF, ACl’H, Cortisol, cytokines, catecholamines, and indolamines. Relating these findings to intracellular transcriptional processes, another important analogy to stress sensitization can be noted. Both conditions, CIBS and repeated stress, lead at the end of the intracellular signal-transducing cascade to the expression of immediate early genes (c-fos and zif -268) in the amygdala and Inhibitors,research,lifescience,medical related limbic structures as well as late effector genes (LEG).77 The research composition of early genes and their occupation of the activator protein- 1 (AP-1) receptor is partially specific for different stressors, eg, electroconvulsive seizures or cocaine, as well as

for mode of application, ie, acute, repetitive or chronic.78, 79 This may provide a molecular background for speculation as to why psychosocial Phosphatidylinositol diacylglycerol-lyase stressors may be more likely to cause symptoms of depression, whereas others, like acute pain, do not. Whereas activation of early immediate genes primarily induces expression of genes, such as neurotransmitter transporter genes, and finally modulates the acute symptomatology, induction of LEGs such as neurotropins and nerve growth factor (NGF) will modulate synaptic connectivity and nerve end sprouting, thereby giving rise to neuroanatomical changes. Taken together, CIBS is a useful model to study acute events and long-term changes in symptomatology caused by episodes of affective disorders.