Research reportThe effects of systemic NT69L, a neurotensin agonist, on baseline and drug-disrupted prepulse inhibition
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behaviors occur through direct NT69L–DA receptor interactions since this compound does not bind to DA receptors (unpublished data).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.
References (46)
- et al.
Alpha-1-adrenergic receptors mediate sensorimotor gating deficits produced by intracerebral dizocilpine administration in rats
Neuroscience
(1999) - et al.
A novel neurotensin peptide analog given extracranially decreases food intake and weight in rodents
Brain Res.
(2000) - et al.
A novel neurotensin analog blocks cocaine- and d-amphetamine-induced hyperactivity
Eur. J. Pharmacol.
(2001) - et al.
Neurotensin increases extracellular striatal dopamine levels in vivo
Neuropeptides
(1992) - et al.
Effects of a novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol
Brain Res.
(2000) - et al.
The effects of intra-accumbens neurotensin on sensorimotor gating
Brain Res.
(1997) - et al.
Amygdaloid N-methyl-d-aspartate and gamma-aminobutyric acid(A) receptors regulate sensorimotor gating in a dopamine-dependent way in rats
Neuroscience
(2000) - et al.
Nigral neurotensin receptor regulation of nigral glutamate and nigroventral thalamic GABA transmission: a dual-probe microdialysis study in intact conscious rat brain
Neuroscience
(2001) - et al.
Induction of tolerance to the suppressant effect of the neurotensin analogue NT69L on amphetamine-induced hyperactivity
Eur. J. Pharmacol.
(2001) - et al.
Prepulse inhibition of acoustic startle, a measure of sensorimotor gating: effects of antipsychotics and other agents in rats
Pharmacol. Biochem. Behav.
(1995)
Atypical neuroleptic-like behavioral effects of neurotensin
Brain Res. Bull.
Neurotensin microinjection into the nucleus accumbens antagonizes dopamine-induced increase in locomotion and rearing
Neuroscience
The neurobiology of neurotensin: focus on neurotensin-dopamine interactions
Regul. Pept.
Does neurotensin mediate the effects of antipsychotic drugs?
Biol. Psychiatry
A subpopulation of dopaminergic neurons in rat ventral mesencephalon contains both neurotensin and cholecystokinin
Brain Res.
Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs
Brain Res. Rev.
Clozapine and haloperidol in an animal model of sensorimotor gating deficits in schizophrenia
Pharmacol. Biochem. Behav.
Highly potent neurotensin analog that causes hypothermia and antinociception
Eur. J. Pharmacol.
M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats
Neuropsychopharmacology
Reversal of dizocilpine-induced disruption of prepulse inhibition of an acoustic startle response by the 5-HT2 receptor antagonist ketanserin
Eur. J. Pharmacol.
Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine
Psychopharmacol. (Berl.)
Phencyclidine-induced deficits in prepulse inhibition of startle are blocked by prazosin an alpha-1 noradrenergic antagonist
J. Pharmacol. Exp. Ther.
Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine
J. Neurosci.
Cited by (46)
Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: Assessing for tolerance and cross-tolerance to clozapine
2014, Pharmacology Biochemistry and BehaviorEffects of the neurotensin NTS<inf>1</inf> receptor agonist PD149163 on visual signal detection in rats
2013, European Journal of PharmacologyThe role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion
2012, Schizophrenia ResearchCitation Excerpt :As previously described, systemic SR142948A administration did not significantly affect baseline PPI in adult male rats (Cáceda et al., 2005). The antagonism of dizocilpine- and d-amphetamine- (at higher doses) induced PPI disruption by systemic administration of SR142948A was unexpected because of the large literature showing an APD-like effect when NT neurotransmission is increased, particularly NTR1, in the NAcc (Ervin et al., 1981; Robledo et al., 1993; Feifel et al., 1997; Cáceda et al., 2005), as well as after systemic treatment with NTR1 and NTR2 agonists (Feifel et al., 1999; Shilling et al., 2003; Boules et al., 2010). Paradoxically, this effect is lost or even reversed with chronic administration of NT or NT agonists, most likely though desensitization (Hertel et al., 2001; Norman et al., 2008).
The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats
2011, European NeuropsychopharmacologyCitation Excerpt :Moreover, PD149163 (Feifel et al., 2004), NT69L (Cusack et al., 2000), and KH28 (Hadden et al., 2005) have not been shown to exhibit catalepsy in rats, similar to the atypical APD clozapine, but not the typical APD haloperidol (Feifel et al., 2004). NT69L (Shilling et al., 2003), NT79 (Boules et al., 2010), and PD149163 (Feifel et al., 2008; Feifel et al., 2003; Feifel et al., 1999), also have been shown to prevent prepulse inhibition deficits produced by various psychotomimetic drugs, which might predict their efficacy for sensory gating deficits in schizophrenia. The conditioned avoidance response task is another standard method for behaviorally screening putative APDs and offers few false positive results (Wadenberg and Hicks, 1999).
Effects of neurotensin-2 receptor deletion on sensorimotor gating and locomotor activity
2010, Behavioural Brain ResearchHyperactivity of the dopaminergic system in NTS1 and NTS2 null mice
2010, Neuropharmacology