Reserpine-induced rat model for depression: Behavioral, physiological and PET-based dopamine receptor availability validation

Background: Reserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT₂) inhibitor agent, has been used in preclinical research for many years to create animal models for depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of RES as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes.

Methods: Experiment 1. Following baseline behavior testing sensitive to depression-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) RES dose for 20 days using a pre-determined schedule and reassessed for behavioral phenotypes (Phase 2). After 10 days washout period, and a final behavioral assessment (Phase 3), the brains were collected 16 days after the last injection for mRNA-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D_2/3 receptor PET scanning with [¹⁸F]DMFP following each Phase. The binding potential (BP_ND) of [¹⁸F]DMFP was quantified by kinetic analysis as a marker of striatal D_2/3R availability. Weight and welfare were monitored throughout the study.

Results: Significant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced exploration) were found for both the low and high dose groups with significant decrease in D₂R mRNA expression in the accumbal region for the low RES group after Phase 3. Both RES treated groups showed substantial increase in [¹⁸F]DMFP BP_ND (in line with dopamine depletion) during Phase 2 and 3 compared to baseline and Controls.

Conclusions: The longitudinal design of the study demonstrated that chronic RES administration induced striatal dopamine depletion that persisted even after the wash-out period. However, the behavior phenotype observed were transient. The data suggest that RES administration can induce a rodent model for depression with mild face validity.