Abstract
Objective: Lithium remains the most widely used treatment for bipolar disorder; however, the molecular mechanisms underlying its therapeutic actions have not been fully elucidated. We studied the in-vivo effect of lithium on the density of α-adrenoceptor (α-AR) and β-AR subtypes and linked second messenger systems in the rat brain.
Methods: The densities of α1-ARs, α2-ARs, and β1-ARs and β2-ARs in the cortex and cerebellum of rats treated with lithium (0.4%), orally, for 30 days were measured using [3H]prazosin, [3H]clonidine and [3H]CGP-12177, respectively. The activity of adenylyl cyclase (AC) and levels of inositol trisphosphate (IP3), both second messengers linked to these receptors, were estimated using [3H]ATP and [3H]myoinositol, respectively.
Results: A significant decrease in the densities of cortical α1-ARs (85%, p < 0.0001), α2-ARs (50%, p < 0.0001), β1-ARs (26%, p < 0.0001) and β2-ARs (25%, p < 0.0001) was observed after lithium treatment. However, only the density of α1-ARs was significantly decreased (25%, p < 0.0001) in the cerebellum. The affinity of [3H]prazosin for cerebellar α1-ARs was increased. A small, but statistically significant, increase (19%, p < 0.0001) in the density of total β-ARs was seen in the cerebellum, without altering the affinity of the radioligand for these receptors. Basal AC activity was not altered in the lithium-treated rat cortex. However, the norepinephrine-stimulated AC activity, which represents α2-AR-linked and β-ARlinked AC, was significantly increased (66%, p < 0.0001). Both basal IP3 formation and norepinephrine-stimulated IP3, which represents α1-AR-linked phospholipase C activity, were significantly decreased (50%, p < 0.0001) in the lithium-treated rat cortex.
Conclusion: Our results suggest that long-term administration of lithium treatment downregulates the cortical, but not cerebellar, α1-ARs, α2-ARs, β1-ARs and β2-ARs. Thus, it may be concluded that lithium induces region-specific and differential functional downregulation of α-AR and β-AR subtypes in the rat brain.
- Received September 19, 2005.
- Revision received December 15, 2005.
- Revision received February 6, 2006.
- Accepted March 20, 2006.