Reserpine-induced rat model of depression: behavioral, physiological and dopamine receptor PET based validation

Abstract

Background. Reserpine, a monoamine depleting agent, has been used in preclinical research for many years to create animal models of depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of reserpine as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes. Results. Experiment 1. Following baseline behavior testing sensitive to depressive-like phenotype and locomotion (Phase 1), 27 Sprague-Dawley (SD) rats received i.p. either vehicle solution (0.0 mg/kg), low (0.2 mg/kg) or high (0.8 mg/kg) resrpine dose for 20 days using a pre-determined schedule and reassessed for emerging behavioral phenotypes (Phase 2). After a 10 days washout period, a final behavioral assessment was done (Phase 3), and the brains were collected for gene-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D2 receptor (D2R) PET scanning with [18F]DMFP post Phases 1–3. The binding potential (BPND) of [18F]DMFP was quantified by kinetic analysis as a marker of striatal D2R availability. Weight and welfare were monitored throughout the experiment. Significant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced socialization) were found for both the low and high dose groups with significant decrease in D2R mRNA expression in the accumbal region for the low reserpine group. In addition, both drug treated groups showed a substantial increase in [18F]DMFP BPND (in line with dopamine depletion) during injection phase and washout phases compared to baseline and Controls. Conclusions. The longitudinal design of the study demonstrated that chronic RES administration induced anxiety and depressive symptoms that were moderately maintained even after the wash out period. The data suggests that the low dose RES administration can induce a rodent model of depression with good face validity.