Research report
The effects of systemic NT69L, a neurotensin agonist, on baseline and drug-disrupted prepulse inhibition

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Abstract

Centrally administered neurotensin (NT) produces behavioral and biochemical effects that are very similar to the effects of antipsychotic drugs. Therefore, there is much interest in the potential use of NT agonists as antipsychotic drugs. We have previously reported that PD149163, a NT(8–13) analogue, produced effects on prepulse inhibition (PPI) of startle after systemic administration that were suggestive of an atypical antipsychotic-like drug profile. To determine if these effects are shared by other peripherally administered NT agonists, we tested the effects of NT69L, a recently developed NT agonist that penetrates the CNS, on drug-induced PPI deficits. In the first experiment, rats received subcutaneous (s.c.) injections of NT69L (vehicle, 0.08, 0.25, and 1.0 mg/kg) followed 30 min later by subcutaneous saline or d-amphetamine (2.0 mg/kg). In the second experiment, NT69L injections were followed by saline or the non-competitive NMDA antagonist dizocilpine (0.1 mg/kg). Both d-amphetamine and dizocilpine significantly decreased PPI as expected. In the first experiment, NT69L significantly increased PPI levels at baseline and after d-amphetamine. In the second experiment, NT69L attenuated PPI deficits produced by dizocilpine, without increasing baseline PPI. In addition, NT69L had no effect on startle magnitude. The effects of NT69L in these studies were similar in some ways to the effects of PD149163 and were also consistent with the preclinical effects of atypical antipsychotic drugs. These data provide further support for the notion that NT agonists may have use as novel antipsychotic drugs. Furthermore, the ability of NT69L and PD149163 to attenuate dizocilpine-disrupted PPI, an antipsychotic drug effect not mediated by dopamine, suggests that NT agonists may produce some of their antipsychotic-like effects by modulating neurotransmitter systems other than dopamine, such as serotonin, noradrenaline or glutamate.

Introduction

Neurotensin (NT) is a neuropeptide that modulates neurotransmitter systems in brain areas that are highly relevant to the pathophysiology of schizophrenia [23], [31]. Centrally administered NT produces behavioral and biochemical effects that are similar to the effects of antipsychotic drugs [14], [15], [25], [26], [34]. In addition, antipsychotic drugs enhance NT neurotransmission and NT mRNA expression in rodent brain [6], [29], [33]. It is for these reasons that NT agonists have been proposed as potential antipsychotic drugs. However, the development of neuropeptides as psychotropic drugs has been limited by their inability to penetrate the blood–brain barrier and their short half-life. For example, a biologically active fragment of NT(8–13) [27] does not produce observable effects in the CNS after systemic administration [30]. Recently, novel NT analogs that cross the blood–brain barrier have been developed with increased metabolic stability [43], [46] making it possible to study the antipsychotic drug potential of these compounds. NT69L is a novel NT(8–13) analog [N-methyl-Arg, Lys, Pro, l-neo-Trp, tert-Leu, Leu] with high affinity for rat and human NT receptors, Kd=1.55 and 0.83, respectively [43] and has also been reported to produce behavioral effects that are similar to those of atypical antipsychotic drugs. For example, several investigators have reported that NT69L blocked stimulant-induced hyperactivity [9], [22]. In addition, Cusack et al. [12] found that NT69L blocked apomorphine-induced climbing behavior, but did not induce catalepsy. It is unlikely that these effects of NT69L on dopamine (DA)-mediated behaviors occur through direct NT69L–DA receptor interactions since this compound does not bind to DA receptors (unpublished data).

Considerable evidence suggests that NT plays an important role in the regulation of central DA transmission [28], [34]. In rats, NT is co-localized with DA in a proportion of mesolimbic DA cells originating in the mesencephalon [36] and complex interactions between NT and DA have been observed [28]. For example, NT stimulates the rate of DA neuronal firing in the substantia nigra, ventral tegmental area and frontal cortex. When NT is infused into the cerebral ventricles it increases DA turnover [11]. Intrastriatal NT infusion increases extracellular striatal levels in vivo and NT reduces D2 receptor affinity in striatal membranes [20].

In addition to altering DA levels in the brain, NT treatment increases glutamate levels in several brain regions. For example, microdialysis studies have shown that [19] intranigral NT administration increases glutamate concentrations in the striatum and NT infusion into the medial prefrontal cortex dose-dependently increases glutamate concentrations in this structure [35]. Furthermore, NT69L administration decreases norepinephrine (NE) and elevates serotonin concentrations in the nucleus accumbens [8].

Prepulse inhibition (PPI) describes the normal suppression of the startle response, when a weak lead stimulus immediately precedes the startle-eliciting stimulus. Unmedicated schizophrenia patients exhibit reduced PPI compared to normal subjects [10] and these deficits in PPI could reflect an alteration in the mechanisms which act to filter environmental information [10], [42]. Similar PPI deficits are produced in rats by the administration of psychotomimetic drugs such as DA agonists, e.g., d-amphetamine and apomorphine [32], or non-competitive N-methyl-d-aspartate (NMDA) antagonists, e.g., phencyclidine and dizocilpine. All antipsychotic drugs tested in this paradigm block PPI deficits produced by DA agonists. Therefore, these effects of antipsychotic drugs on PPI are considered a predictive test of antipsychotic efficacy in general. However, PPI deficits produced by non-competitive NMDA antagonists are not mediated by changes in DA transmission [21]. These PPI deficits are more consistently antagonized by the atypical class of antipsychotic drugs [21], [40] and are considered a predictive test of atypical antipsychotic drug features. We recently reported that another NT analogue, PD149163, antagonized d-amphetamine- and dizocilpine-induced disruption of PPI, effects that are similar to the effects of atypical antipsychotic drugs [17].

The effects of PD149163 on d-amphetamine-induced PPI deficits were an important confirmation of previous suggestions that NT agonists produce antipsychotic-like effects by modulation of DA neurotransmission [6], [29], [34]. Furthermore, the effects of PD149163 on dizocilpine-disrupted PPI suggested for the first time, that NT agonists may also produce antipsychotic effects via non-DArgic mechanisms. It is important to determine whether these effects are specific to PD149163 or shared by other systemically administered NT agonists. Therefore, our goal was to further test the notion that NT agonists produce atypical antipsychotic-like effects by investigating the effects of NT69L on PPI deficits induced by d-amphetamine and dizocilpine. We predicted that consistent with atypical antipsychotics and PD149163, NT69L would antagonize PPI disruption produced by d-amphetamine and dizocilpine.

Section snippets

Animals

Sixty-eight male Sprague-Dawley rats (225–249 g on arrival) were obtained from Harlan Laboratories, San Diego and housed in groups of two or three in clear plastic chambers in a climate controlled room on 12 h:12 h light/dark cycle (lights on 7:00 a.m.–7:00 p.m.). They were allowed free access to food and water for the extent of the study. Behavioral testing was performed between 8:30 a.m. and 3:00 p.m. beginning 7 days after arrival. All studies described in this publication were “… carried out in

Experiment 1: NT69L versus d-amphetamine

Fig. 1 displays the effects of NT69L on baseline and amphetamine-induced PPI deficits. There was a significant main effect of d-amphetamine as it disrupted PPI, F[1,30]=62.0, P<0.0001. There was also a main effect of NT69L, F[3,30]=5.2, P=0.0054 as it facilitated PPI. There was a significant main effect of prepulse intensity on percent PPI reflected in more intense prepulses producing greater PPI, F[2,64]=192.3, P<0.0001. In addition, there was not a significant d-amphetamine×NT69L interaction,

Discussion

The results of Experiment 1 indicate that NT69L decreased amphetamine-disrupted PPI. However, it is difficult to conclude whether this effect represents a specific pharmacological antagonism of the effects of d-amphetamine or a non-specific propensity of NT69L to increase PPI since baseline PPI was also increased in this experiment.

Inspection of the data reveals differences in dose-response effects of NT69L on baseline and d-amphetamine-disrupted PPI that suggest that these two effects are

Acknowledgements

PDS was supported in part by NIMH Psychopharmacology and Psychobiology Training grant #5T32 MH18399. This work was also supported by a NIMH grant (MH62451) to DF. ER was supported by MH27692, the Mayo Foundation for Medical Education and Research, and the Forrest C. Lattner Foundation, Inc. We thank Cameron Wilson for excellent technical assistance.

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