Effects of a neurotensin analogue (PD149163) and antagonist (SR142948A) on the scopolamine-induced deficits in a novel object discrimination task

Abstract

Various lines of evidence suggest a role in cognition for the endogenous neuropeptide, neurotensin, involving an interaction with the central nervous system cholinergic pathways. A preliminary study has shown that central administration of neurotensin enhances spatial and nonspatial working memory in the presence of scopolamine, a muscarinic receptor antagonist which induces memory deficits. Utilizing similar methods, the present study employed a two-trial novel object discrimination task to determine the acute effect of a neurotensin peptide analogue with improved metabolic stability, PD149163, on recognition memory in Lister hooded rats. Consistent with previous findings with neurotensin, animals receiving an intracerebroventricular injection of PD149163 (3 microg) significantly discriminated the novel from familiar object during the choice trial. In addition, a similar dose of PD149163 restored the scopolamine-induced deficit in novelty recognition. The restoration effect on scopolamine-induced amnesia produced by PD149163 was blocked by SR142948A, a nonselective neurotensin receptor antagonist, at a dose of 1 mg/kg (intraperitonial) but not at 0.1 mg/kg. In conclusion, the present results confirm a role for neurotensin in mediating memory processes, possibly via central cholinergic mechanisms.

Activation of Neurotensin Receptor 1 Facilitates Neuronal Excitability and Spatial Learning and Memory in the Entorhinal Cortex: Beneficial Actions in an Alzheimer's Disease Model

“…2A), suggesting the requirement of NTS1 receptors. Because PD149163 is a small-molecule NTS1 agonist that crosses the blood-brain barrier (Feifel et al, 2004(Feifel et al, , 2010Azmi et al, 2006), we tested the effects of PD149163 on neuronal excitability recorded from stellate neurons in the EC. Bath application of PD149163 (0.25 M) robustly increased the AP firing frequency (n ϭ 10, p ϭ 0.002; Fig.…”

“…NT binding sites are varied as a function of age and cognitive status with decreased NT binding sites in the brains of aged and cognitively impaired rats (Rowe et al, 2006). Application of NT or NT receptor agonists improves memory (Azmi et al, 2006;Ohinata et al, 2007;László et al, 2010), whereas administration of NT receptor antagonists impairs cognitive processes (Tirado-Santiago et al, 2006). Whereas the effects of NT on memory are usually considered to be mediated by NTS1 (Azmi et al, 2006;Tirado-Santiago et al, 2006;Ohinata et al, 2007;László et al, 2010), reduced fear memory has also been observed in NTS2 KO mice (Yamauchi et al, 2007).…”

“…Application of NT or NT receptor agonists improves memory (Azmi et al, 2006;Ohinata et al, 2007;László et al, 2010), whereas administration of NT receptor antagonists impairs cognitive processes (Tirado-Santiago et al, 2006). Whereas the effects of NT on memory are usually considered to be mediated by NTS1 (Azmi et al, 2006;Tirado-Santiago et al, 2006;Ohinata et al, 2007;László et al, 2010), reduced fear memory has also been observed in NTS2 KO mice (Yamauchi et al, 2007). Although these data generally support a role for NT in learning and memory, the cellular and molecular mechanisms whereby NT facilitates memory have not been determined.…”

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

“…For example, rats microinjected with NT showed enhanced spatial learning (Laszlo et al, 2010). NT analogs have also been shown to enhance working memory, memory consolidation, and associative learning (Azmi et al, 2006;Grimond-Billa et al, 2008;Ohinata et al, 2007), while infusion of a NTSR1 antagonist impairs working memory (Tirado-Santiago et al, 2006). In humans, a previous study showed an association between NTSR1 gene polymorphisms and schizophrenia (Lee et al, 1999).…”

ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone

“…In a broader context, both ACE and RAS can be viewed as stress response mediators, which could explain their relationship to immune and neuroendocrine response and anxiety-related behaviors (Bali and Jaggi, 2013). Another relevant issue is that ACE has other potential substrates, some of which were also independently associated with SCZ, as for instance, substance P (Arinami et al, 1996) and neurotensin (Azmi et al, 2006). Therefore, ACE activity levels can represent either a biomarker of several different processes underlying SCZ risk, or it is actually involved in the cascade of events associated with SCZ-related phenotypes.…”