Interactions of the Tricyclic Antidepressant Drug Amitriptyline with L-DOPA in the Nucleus Accumbens, Prefrontal Cortex and Hippocampus of Unilaterally 6-OHDA-Lesioned Rats: Relevance to Depression in Parkinson's Disease.
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The effects of antidepressants on limbic structures, important in the context of the treatment of Parkinson's disease (PD)-associated depression, are relatively poorly explored in animal models. The present study investigated the impact of the tricyclic antidepressant amitriptyline (AMI), administered chronically alone or in combination with L-DOPA, on anhedonia, monoamine levels, and the binding of radioligands to their transporters in the limbic structures of unilaterally 6-OHDA-lesioned rats. Anhedonia, as a core symptom of depression, was evaluated using the sucrose preference test. Tissue concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) and their metabolites in the prefrontal cortex (PFC) and hippocampus (HIP) were assayed by HPLC method. Bindings of [3H]nisoxetine to noradrenaline transporter (NET), [3H]GBR 12,935 to dopamine transporter (DAT), and [3H]citalopram to serotonin transporter (SERT) in the nucleus accumbens (NAcc), PFC, and HIP were analyzed by autoradiography. Three weeks of treatment of unilaterally 6-OHDA-lesioned rats with AMI alone significantly reduced the intake of sucrose solution compared to the sham-operated control, but the combined administration of AMI+L-DOPA enhanced sucrose consumption. Administration of AMI+L-DOPA increased tissue DA concentrations in the lesioned and intact PFC and HIP more distinctly than L-DOPA alone. L-DOPA alone significantly decreased tissue 5-HT content in the lesioned PFC and HIP, while the addition of AMI reversed this effect. 6-OHDA administered unilaterally into the MFB drastically decreased DAT binding in the lesioned NAcc while increasing it on the intact side. Neither AMI nor L-DOPA, given alone or jointly, affected DAT binding in the lesioned NAcc. SERT binding was significantly reduced in the PFC, NAcc and HIP on both sides of the brain in the AMI- or AMI+L-DOPA-treated groups. NET binding decreased in the PFC and NAcc in the AMI-treated group, but no such effect was observed in the AMI+L-DOPA-treated group. The obtained results are discussed in relation to the impaired psychiatric functions in PD.