Tactile stimulation modulates glucocorticoid receptor and activates the BDNF Cascade in the substantia nigra of haloperidol-treated rats: A sequential investigation into nigrostriatal plasticity.

Abstract

Tactile stimulation (TS) is a sensory intervention successfully applied to premature neonates and extensively studied in various animal models of neuropsychiatric conditions, as well as in other contexts. Haloperidol is a first-generation antipsychotic, and its use leads to serious adverse effects such as the extrapyramidal syndrome, which promotes movement disorders including Parkinsonism, akathisia and tardive dyskinesia. We recently demonstrated that TS can reduce haloperidol-induced movement disorders, promoting changes in the dopaminergic and glutamatergic systems. Furthermore, studies have shown that TS can prevent the development of depressive-like behaviors and the negative effects of stress, and it can also reduce anxiety-like behaviors by enhancing neurogenesis and neuroplasticity. In this sense, we aimed to explore whether TS can modulate these mechanisms in haloperidol-exposed animals. Our findings showed that TS exposure restored Grβ mRNA levels, activating the glucocorticoid-responsive element Rack1, which in turn promotes Bdnf transcription. This effect was observed through the increased levels of the Bdnf long 3'UTR isoform and mBDNF, along with the activation of its signaling cascade, as indicated by increased levels of AKT and S6. Based on these outcomes, we can infer that, even when applied to adult animals, TS is capable of exerting favorable molecular neuroadaptations in the Substantia nigra, as evidenced by the promotion of neurogenesis and the enhancement of neuroplasticity. This study also provides, for the first time, evidence of the molecular effects of TS on the Substantia nigra of rats previously exposed to haloperidol, with changes reflected in glucocorticoid isoforms and the BDNF signaling cascade.