Parkinson's disease (PD) is a neurological disorder characterised by progressive degeneration of dopaminergic neurons in the substantia nigra (SN), resulting in dopamine deficiency with deregulation of a variety of substances/neurotransmitters (Kalia and Lang, 2015). Environmental factors appear to play an important role in the development of PD. There is an association between PD and pesticides in different exposure settings (industrial, agricultural, residential: Freire and Koifman, 2012; Islam et al., 2021; Anirudhan et al., 2023). The staining of tyrosine hydroxylase (TH), the enzyme responsible for dopamine synthesis, is reduced in the SN of rats microinjected with fipronil, a broad-spectrum insecticide also used in veterinary medicine (Park et al., 2016). This reduction paralleled changes in motor activity and nociception due to degeneration of nigrostriatal dopaminergic neurons (Bharatiya et al., 2020a). In addition, chronic oral fipronil treatment for 21 days significantly reduced dopamine and its metabolites in most striatal areas, including the nucleus accumbens and SN (Bharatiya et al., 2020b). The VGF gene (not abbreviated), which is regulated by nerve growth factor (NGF) in PC12 cells and cultured cortical neurons (Salton et al., 1991), encodes a VGF precursor protein (or pro-VGF). Pro-VGF has a molecular weight (MW) of about 75 kDa and consists of 617/615 aa in rat/mouse and human, respectively, with >85% identity (minor sequence differences between rat/mouse and human) (Ferri et al., 2011). It can give rise to a variety of truncated peptides, different in length and biological activity, found in rat and human brain (Noli et al., 2017, Cocco et al., 2010), but also in rat/mouse and human blood (Noli et al., 2017, D'Amato et al., 2015). Truncated peptides include the so-called TLQP family, which consists of pleiotropic neuropeptides possibly involved in various physiological processes (Noli et al., 2020, Corda et al., 2021, Lewis et al., 2017, Fairbanks et al., 2014, Skorput et al., 2018) and the NAPP-19, identified in human blood (D’Amato et al., 2015). In the SN, using an antibody against the nonapeptide at the C-terminal (C-t) of the rat pro-VGF, staining was found in a large number of neuron terminals, containing glutamic acid decarboxylase (GAD) and Substance P. VGF staining decreased in the SN of 6-hydroxydopamine-(6-OHDA) treated rats, but it was restored by levodopa (L-dopa) treatment (Cocco et al., 2020). These results are consistent with those obtained in PD patients. Indeed, the VGF levels in PD patients were analyzed by a home-made competitive enzyme-linked immunosorbent assay using an antibody directed against the nonapeptide at the C-t of the human pro-VGF. Blood samples were collected from patients at the time of diagnosis (drug-free, n = 23) or after dopamine replacement (n = 40) and compared with age-matched controls (n = 21) (Cocco et al., 2020). A strong decrease (>50%) was observed in drug-free patients, whereas long-term L-dopa treatment caused an increase in the VGF levels. VGF C-t levels were also correlated with disease duration, L-dopa equivalent dose and severity of the olfactory dysfunction. The VGF changes observed in the blood of PD patients have been verified in other body fluids, such as cerebrospinal fluid (CSF) and urine, using proteomics approach (Rotunno et al., 2020, Virreira Winter et al., 2021). In CSF, downregulation was observed for peptides containing the C-t portion, whereas in urine downregulated peptides covered most of the VGF sequence (Karayel et al., 2022). Because it is unclear which VGF forms are expressed specifically in the nigrostriatal regions, the goal of this study was to first identify which types of VGF fragments are present in the SN and striatum, and then to determine the possible VGF response to fipronil intranigral microinjection and whether it is associated with fipronil-induced changes in locomotor activity.