Systemic administration of the neurotensin NTS₁-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats.

Neurotensin is a neuropeptide neurotransmitter that produces effects similar to those produced by antipsychotic drugs in preclinical models (Richelson, Fredrickson, & Boules, 2005; Tanganelli et al., 2012), but unlike currently available antipsychotic drugs neurotensin does so through binding only to neurotensin receptors (Pettibone et al., 2002; Schotte et al., 1996). Brain-penetrant agonists for neurotensin NTS1 receptors, such as NT69L (Cusack et al., 2000) and PD149163 (Petrie et al., 2004), demonstrate antipsychotic-like efficacy in animal models including inhibition of conditioned avoidance responding (Hertel, Olsen, & Arnt, 2002; Holly, Ebrecht, & Prus, 2011), reversal of amphetamine-induced hyperactivity (Boules et al., 2001; Cusack et al., 2000; Feifel et al., 2008), and prevention of amphetamine-induced disruptions of prepulse inhibition of startle (PPI) (Feifel, Reza, Wustrow, & Davis, 1999; Shilling, Richelson, & Feifel, 2003). Moreover, several results from animal studies indicate that NTS1 receptor agonists produce effects similar to those produced by atypical antipsychotic drugs. Like atypical antipsychotic drugs, NTS1 receptor agonists reverse PPI disruption induced by NMDA and serotonin (5-HT)2A receptor antagonists (Feifel, Melendez, & Shilling, 2003; Feifel et al., 1999; Shilling, Melendez, Priebe, Richelson, & Feifel, 2004). Moreover, NTS1 receptor agonists do not elicit catalepsy (Cusack et al., 2000; Feifel, Melendez, & Shilling, 2004; Holly et al., 2011; Sarhan, Hitchcock, Grauffel, & Wettstein, 1997), which generally does not occur for atypical antipsychotic drugs at therapeutically-effective doses (Meltzer, 2004). A particularly attractive feature of NTS1 receptor agonists may be an efficacy for cognitive deficits, which are a core feature of schizophrenia. Current antipsychotic drugs only modestly alleviate these deficits (Meltzer & McGurk, 1999; Woodward, Purdon, Meltzer, & Zald, 2005), which strongly contribute to poor functional outcomes, such as an inability to carry out daily living activities and gain employment, in patients with this disorder (Green, Kern, Braff, & Mintz, 2000; Harvey et al., 2012). Intracerebroventricular administration of PD149163 has been shown to reverse scopolamine-induced working memory deficits in novel object recognition (Azmi, Norman, Spicer, & Bennett, 2006), and systemic administration of PD149163 has been shown to improve social discrimination in Brattleboro rats (Feifel et al., 2009) and to selectively increase hippocampal-dependent aversive trace conditioning (Grimond-Billa, Norman, Bennett, & Cassaday, 2008), although improvements were not shown for appetitive trace conditioning (Norman, Grimond-Billa, Bennett, & Cassaday, 2010). Microinjection of neurotensin or PD149163 into the entorhinal cortex in rats was also shown to enhance firing rates and to improve spatial learning in a Barnes Maze test (Xiao et al., 2014). Further, Tirado-Santiago and colleagues (2006) demonstrated that administration of an NTS1 antagonist, SR48692, into the nucleus accumbens prior to training sessions was shown to increase working and reference memory errors in a radial arm maze. Li and colleagues (2011) identified two single nucleotide polyphormisms of the NTS1 receptor (rs4334545 and rs6090453) that were significantly correlated with working memory performance in humans, and based on these associations, the study authors concluded that the NTS1 receptor was important for cognitive functioning. The present study sought to further evaluate the role of NTS1 receptors in memory function by assessing the effects of the NTS1 receptor agonist PD149163 on memory errors in a delayed non-match to position radial arm maze task in rats. Further, this study explored these effects using two different strains of rats -- Long Evans (LE) rats and Brown Norway (BN) rats. LE rats are commonly used in learning and memory studies, as well as for tasks used to study drugs of abuse, such as self administration. BN rats have been shown to exhibit innate deficits associated with schizophrenia including deficits in latent inhibition (Conti, Palmer, Vanella, & Printz, 2001) and prepulse inhibition (PPI) (Conti, Costill, Flynn, & Tayler, 2005; Feifel, Shilling, & Melendez, 2011; Palmer et al., 2000; Parwani et al., 2000). Moreover, antipsychotic drugs have significantly improved PPI in BN rats (Feifel et al., 2011). Due to evidence suggesting the involvement of NTS1 receptors in memory processing and research revealing innate cognitive deficits in BN rats, we hypothesized that BN rats would exhibit significant impairments compared to LE rats and that the NTS1 receptor agonist PD149163 would reduce memory errors. The study also evaluated the effects of the NTS1/2 receptor antagonist SR141948, which we hypothesized to increase the number of memory errors.