The effect of lithium on the adrenoceptor-mediated second messenger system in the rat brain

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 alpha-adrenoceptor (alpha-AR) and beta-AR subtypes and linked second messenger systems in the rat brain.

Methods: The densities of alpha(1)-ARs, alpha(2)-ARs, and beta(1)-ARs and beta(2)-ARs in the cortex and cerebellum of rats treated with lithium (0.4%), orally, for 30 days were measured using [(3)H]prazosin, [(3)H]clonidine and [(3)H]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 [(3)H]ATP and [(3)H]myoinositol, respectively.

Results: A significant decrease in the densities of cortical alpha(1)-ARs (85%, p < 0.0001), alpha(2)-ARs (50%, p < 0.0001), beta(1)-ARs (26%, p < 0.0001) and beta(2)-ARs (25%, p < 0.0001) was observed after lithium treatment. However, only the density of alpha(1)-ARs was significantly decreased (25%, p < 0.0001) in the cerebellum. The affinity of [(3)H]prazosin for cerebellar alpha(1)-ARs was increased. A small, but statistically significant, increase (19%, p < 0.0001) in the density of total beta-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 alpha(2)-AR-linked and beta-AR-linked AC, was significantly increased (66%, p < 0.0001). Both basal IP3 formation and norepinephrine-stimulated IP3, which represents alpha(1)-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, alpha(1)-ARs, alpha(2)-ARs, beta(1)-ARs and beta(2)-ARs. Thus, it may be concluded that lithium induces region-specific and differential functional downregulation of alpha-AR and beta-AR subtypes in the rat brain.

Fig. 1: Scatchard graph of [³H]prazosin (A) and [³H]clonidine (B) binding to α₁-adrenoceptors (α₁-ARs) and α₂-ARs, respectively, in the cortex of rats treated with lithium (Li) (0.4%), orally (0.5 mL), for 30 days. Binding experiments were done using [³H]prazosin (0.05–0.6 nmol/L) and [³H]clonidine (0.06–0.8 nmol/L) in cortical membranes, as described in the Methods section. Data points are the means of 3 experiments, each assayed in duplicate. The inset represents saturation curves for both binding experiments. Data points are the means (and standard deviation) of 3 experiments, each assayed in duplicate.

Fig. 2: Scatchard graph of [³H]CGP-12177 binding to β-adrenoceptors (β-ARs) in the cortex of rats treated with lithium (0.4%), orally (0.5 mL) for 30 days. Binding experiments were done using [³H]CGP-12177 (0.08–0.9 nmol/L) in cortical membranes, as described in the Methods section. Data points are the means of 3 experiments, each assayed in duplicate. The inset represents saturation curves for the [³H]CGP binding experiment. Data points are the means (and standard deviation) of 3 experiments, each assayed in duplicate.