The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

Abstract

Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the endocrine, autonomic, and behavioral responses to stress. Dysregulation of both hypothalamic and extrahypothalamic CRF systems have been reported in patients with major depression and post-traumatic stress disorder. Moreover, effective treatment of these conditions leads to normalization of these CRF systems. Although there is virtually no data concerning alterations of CRF systems in bipolar disorder (manic depressive illness), previous work indicates that valproic acid, an anticonvulsant also effective in the treatment of acute mania, alters central CRF neuronal systems. In the current studies, we chronically administered valproic acid and lithium, two clinically effective mood stabilizers, in nonstressed rats to extend our previous findings. Chronic valproic acid administration decreased CRF mRNA expression in the paraventricular nucleus of the hypothalamus; lithium administration increased CRF mRNA expression in the central nucleus of the amygdala. Although valproic acid increased CRF 1 receptor mRNA expression in the cortex, CRF 1 receptor binding was decreased in both the basolateral amygdala and cortex, suggesting that chronic valproate treatment may in fact dampen the overall tone in this central stress pathway. Valproate treatment decreased CRF 2A mRNA expression in both the lateral septum and hypothalamus, although CRF 2A receptor binding was unchanged. Lithium administration decreased CRF 1 mRNA expression in both the amygdala and frontal cortex, but CRF 1 receptor binding also remained unchanged. These results suggest that the therapeutic actions of these mood stabilizers may, in part, result from their actions on central CRF neuronal systems. The distinct actions of each drug on CRF systems may underlie their synergistic clinical effects.

Neuropeptide Y in the Amygdala Induces Long-Term Resilience to Stress-Induced Reductions in Social Responses But Not Hypothalamic–Adrenal–Pituitary Axis Activity or Hyperthermia

“…The LS and BNST are two key brain regions implicated in both social behaviors and PTSD (Insel, 1992;Grillon et al, 1996; Kool- haas et Gilmor et al, 2003). Here, we show that NPY, but not vehicle, attenuated restraint induced cellular responses in the LS and BNST, which is consistent with previous findings.…”

Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

“…Changes in BDNF can rectify behavioral deficits in an animal model of depression in learned helplessness and in the forced swim test (Siuciak et al, 1997). Chronic lithium also corrects disrupted circadian clocks (Abe et al, 2000;Schibler, 1998) and can affect the endocrine system while decreasing CRF1 mRNA in the amygdala and frontal cortex (Gilmor et al, 2003). Overall, studies suggest that chronic lithium can alter many neurochemical and endocrinological pathways, which modulate neuronal plasticity, and normalize behavioral defects in animal models.…”

The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers

“…Together, the data suggest that lithium does attenuate GR signaling in BD patients. It should be noted, however, that lithium and VPA have also been demonstrated to have marked effects on both the hypothalamic and extrahypothalamic CRF systems, precluding a simple interpretation of the clinical findings (Gilmor et al, 2003).…”