Induction of catalepsy in rats by NK1 receptor antagonist and early-life maternal separation synergistically: the involvement of CRF1 receptors

A lower level of brain substance P (SP) is detected in Parkinson’s disease; apparently, central SP-ergic deficiency takes place in Parkinsonian patients. The pathogenic relevance of this abnormality is unknown.  Another understudied area is the influence of early-life adversities on Parkinsonism.  Here, we hypothesized that i) simulation of central SP hypoactivity by intracerebral injections of NK1 receptor antagonist can initiate catalepsy, a model of Parkinsonian bradykinesia and rigidity, ii) early-life maternal separation (MS) can influence the SP-dependent catalepsy; and iii) the above catalepsy can be regulated by the blockade of CRF1 receptors. The study was performed on Wistar rats. MS of pups was carried out at postnatal days 2-14 for 3 h per day. In adulthood (16-17 weeks of age), one hundred ninety-two males with MS history (weight 280-310 g) were examined behaviorally; catalepsy was assessed by a bar test. In undisturbed animals, i.c.v. administration of NK1 receptor antagonist L-733,060 at 10.0 ng produced clear catalepsy, the drug at the dose of 1.0 ng was ineffective.  MS  per se failed to exert catalepsy, however, in the MS-exposed rats, L-733,060 at 1.0 ng produced strong cataleptic response.  Thus, the blocker of NK1 receptors and MS supra-additively initiated  the development of catalepsy. This catalepsy was significantly reversed by NBI 35 965, an antagonist of CRF1 receptors.   Our findings show, for the first time, that the blockade of central NK1 receptors can induce catalepsy; this cataleptic response is synergistically potentiated by MS and is mediated by CRF1 receptors. These data suggests that the combination of central NK1 receptor hypofunctioning   and   neonatal stress may dysregulate  the extrapyramidal system. Apparently, the central processes mediated by NK1 and CRF1 receptors might  be potential therapeutic targets for Parkinsonism.

Induction of catalepsy in rats by NK1 receptor antagonist and early-life maternal separation synergistically: the involvement of CRF1 receptors Keywords:

NK1 receptors , CRF1 receptors , substance P , maternal separation , catalepsy