Lithium Administration to Preadolescent Rats Causes Long-Lasting Increases in Anxiety-Like Behavior and Has Molecular Consequences

Abstract

Lithium (Li) is frequently used in the treatment of bipolar disorder (BPD), a debilitating condition that is increasingly diagnosed in children and adolescents. Because the symptoms of BPD in children are different from the typical symptoms in adulthood and have significant overlap with other childhood psychiatric disorders, this disorder is notoriously difficult to diagnose. This raises the possibility that some children not affected by BPD are treated with Li during key periods of brain development. The objective of this investigation was to examine the long-term effects of Li on the developing brain via a series of behavioral and molecular studies in rats. Rat pups were reared on Li chow for 3 weeks. Parallel groups were tested while on Li chow or 2 and 6 weeks after discontinuation of treatment. We found increased measures of anxiety-like behavior at all times tested. Gene microarray studies of the amygdala revealed that Li affected the expression of gene transcripts of the synapse and the cytoskeleton, suggesting that the treatment induced synaptic adjustments. Our study indicates that Li can alter the trajectory of brain development. Although the effects of Li on the normal brain seems unfavorable, effects on the abnormal brain cannot be determined from these studies alone and may well be therapeutic. Our results indicate that Li administration to the normal brain has the potential for lasting adverse effects.

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

“…Recently, the effect of chronic lithium treatment during the developmental period was studied (Youngs et al, 2006). A prominent feature in adulthood of animals receiving lithium treatment during development is hyperactivity, similar to our finding in these IMPase-deleted mice.…”

The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

“…or subcutaneous (s.c.) injections administered within approximately one hour before the test is begun, therapeutic serum levels are achieved by doses between 1.5 and 3 mEq/kg. Chronic administration of 0.2% (rats and mice) to 0.4% (mice) LiCl by weight in rodent chow has yielded predictable serum levels within the therapeutic range, while rats treated with 0.15% to 0.2% Li 2 CO 3 chow have yielded the same (Lerer et al, 1980;HamburgerBar et al, 1986;O'Brien et al, 2004;Kitaichi et al, 2006;Youngs et al, 2006). For chronic administration in the drinking water, 20-30 mEq/L has been seen to be effective in rats (Prasad and Sheard, 1982;Hines, 1986b).…”

“…The reported effects of lithium on many tests of fear and anxiety are not consistent; for example, in the conditioned freezing model of fear, in which the duration of the freezing response of electric shock is measured, lithium has been shown to enhance, to inhibit, or to have no impact upon freezing (Table 11) (Muraki et al, 1999;Kitaichi et al, 2006;Youngs et al, 2006).…”

“…Some rodent biochemical studies have implicated inositol depletion in the induction of the lithium-pilocarpine seizures discussed earlier as a possible model of both status epilepticus and mania (Honchar et al, 1983;Honchar et al, 1990;Kofman et al, 1995;Williams and Jope, 1995b), and in the effect of lithium on rearing and anxiety-like behaviors Youngs et al, 2006). GSK-3 has attracted considerable attention since it was discovered, by Klein and Melton in 1996, to be directly inhibited by therapeutic levels of lithium (Klein and Melton, 1996).…”

Efeitos comportamentais da lesão eletrolítica da região do núcleo mediano da rafe como modelo experimental de mania no rato e no camundongo

“…Isso porque acredita-se que a facilitação da exploração dos braços abertos do LCE estaria relacionada à diminuição da disponibilidade de 5HT no prosencéfalo (Graeff et al, 1996) -a exemplo dos efeitos "ansiolíticos" produzidos pela lesão do MnR neste teste (Andrade & Graeff, 2001). Ao aumentar de forma geral a disponibilidade de serotonina, portanto, o LiCl produziria como efeito aumento no tempo de permanência nos braços fechados -conforme já demonstrado (Kakefuda et al, 2010;Youngs et al, 2006). No entanto, o papel da serotonina na regulação dos comportamentos de inibição/congelamento e luta/fuga não seria simples e linear.…”