Transient receptor potential vanilloid 2 (TRPV2) channels modulate the nigrostriatal dopaminergic activity in rats

Abstract

Thermosensitive TRPV1-4-channels have emerged as novel regulators of neuronal function and behaviour. In midbrain, while TRPV1/TRPV3 regulates ventral tegmental area dopamine (DA) (VTA^DA) neurons, TRPV1/TRPV3/TRPV4 play a role in the modulation of substantia nigra DA (SN^DA) neurons. Although TRPV2 is widely expressed in the brain, its significance in the regulation of VTA^DA/SN^DA neurons is unclear. Herein, we test the occurrence of TRPV2 in midbrain and probe its relevance in the modulation of the nigrostriatal-DAergic pathway in male rats. PCR analysis detected Trpv2 mRNA expression in the midbrain and anti-TRPV2 specific antiserum distinctly labelled neurons in the VTA, SN-pars compacta (SNc), and other midbrain nuclei. Tyrosine hydroxylase (TH) and TRPV2 were co-expressed in the VTA and SNc neurons with the latter displaying especially high TRPV2-enrichment. The SNc TH neurons projecting to the dorsal striatum co-expressed TRPV2. While intra-SNc administration of TRPV2-agonist probenecid increased the locomotor activity, pre-treatment with intra-SNc TRPV2-antagonist SET2 or intra-dorsal striatum DA-D₂-receptor antagonist, sulpiride blocked the probenecid-induced response. In ex-vivo midbrain slices, probenecid treatment enhanced TH-ir and [Ca²⁺]_i levels in SNc. Pre-treatment with SET2 blocked probenecid-induced changes in TH-ir. We next examined whether probenecid alters the striatal DA-levels during progressive degeneration of the nigrostriatal-DAergic pathway. In 6-hydoxydopamine (6-OHDA)-treated rats, probenecid/SET2 were injected intra-SNc and the changes in striatal-DA levels were analyzed. While intra-SNc probenecid enhanced striatal-DA levels, pre-treatment with SET2 reduced PB-induced response. We suggest TRPV2 as a novel regulator of the nigrostriatal-DAergic pathway and a potential target for the treatment of Parkinson's disease.