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Comparative effect of therapeutic and toxic doses of imipramine administration on the levels of norepinephrine, dopamine and serotonin in discrete regions of rat brain

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Levels of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) were estimated by HPLC in different regions of adult rat brain after feeding therapeutic (25 mg/kg) or toxic (100 mg/kg) doses of imipramine for 60 days. Imipramine (25 mg/kg) significantly enhanced the growth rate compared to control but the 100 mg/kg dose significantly reduced the body growth rate (but not brain weight) and in addition induced tremors, lethargy, hyperpigmentation and alopecia.

Imipramine, 25 mg/kg, consistently decreased the levels of NE in cortex, striatum-accumbens, cerebellum and brainstem by about 24% (p < 0.01) and decreased DA levels in cortex, hippocampus and hypothalamus (p = 0.01). 5-HT levels were decreased in cortex, striatum-accumbens, hippocampus and brainstem by about 20% (p < 0.01) in imipramine-treated rats. On the contrary, 100 mg/kg of imipramine consistently increased NE levels in cortex, striatum-accumbens, hypothalamus (p < 0.01) and cerebllum (p < 0.05) and increased DA levels only in cerebllum by 39% (p = 0.01). Increased 5-HT levels were seen in all brain regions, of imipraminefed rats, by about 20% (p < 0.01). This study shows that the effects of imipramine on monoamine levels in brain is both region specific and dose dependent. The results suggest that decreased monoamine levels at 25 mg/kg of imipramine in humans might be responsible for the antidepressant effect of imipramine, and increased monoamine levels at higher doses might be responsible for various CNS toxic symptoms observed in patients with high doses of imipramine.


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