Abstract
Background: Synaptic vesicle glycoprotein 2A (SV2A) is a prototype protein specifically expressed in the synaptic vesicles and regulates action potential-dependent neurotransmitter release. Although the precise mechanisms of SV2A in modulating synaptic release remain to be clarified, SV2A has been suggested to be involved in the development of neuropsychiatric disorders. In the present study, we conducted behavioral and in vivo microdialysis experiments using SV2A-mutant (Sv2aL174Q) rats, which carry a missense mutation (L174Q) in the Sv2a gene, to clarify the role of SV2A in modulating the methamphetamine (MAP) susceptibility.
Methods: Male SV2A-mutant (Sv2aL174Q) rats or F344 rats (control) were used. Animals were acutely (1 mg/kg, i.p.) or repeatedly (0.3 mg/kg/day, i.p., 12 days) treated with MAP and the MAP-induced locomotor activity was measured by the ANY-maze video tracking system. Animals were also subjected to in vivo microdialysis experiments to evaluate dopamine release in the nucleus accumbens.
Results: In behavioral experiments, hyperactivity induced by the acute treatment with MPA (1 mg/kg, i.p.) was significantly enhanced by the Sv2aL174Q mutation. In addition, development of supersensitivity (reverse tolerance) to the repeated MAP treatments (0.3 mg/kg/day, i.p., 12 days) was also significantly augmented by the Sv2aL174Q mutation. In vivo microdialysis studies revealed that dopamine release induced by MAP (100 µM) in the nucleus accumbens was markedly enhanced in Sv2aL174Q rats, as compared to the control (F344) rats, while the basal dopamine release remained unaltered. In addition, immunofluorecent double staining studies revealed that SV2A was co-stained with glutamate decarboxylase 67 (a GABAergic neuron marker), but not with tyrosine hydroxylase (a dopamergic neuron marker), both in Sv2aL174Q and F344 rats. Furthermore, the GABAA receptor antagonist bicuculline (100 µM) applied through the dialysis probe completely suppressed the enhancement of dopamine release by the Sv2aL174Q mutation, suggesting a possible involvement of SV2A-GABA interaction.
Conclusions: The present study demonstrates that dysfunction of SV2A by the Sv2aL174Q mutation augments the MAP susceptibility by enhancing dopamine release in the nucleus accumbens possibly via the GABA interaction. These results imply that SV2A play an important role in modulating the vulnerability to psychotic disorders.
