Elsevier

Neuropharmacology

Volume 57, Issue 3, September 2009, Pages 295-301
Neuropharmacology

Blockade of neurokinin-3 receptors modulates dopamine-mediated behavioral hyperactivity

https://doi.org/10.1016/j.neuropharm.2009.05.008Get rights and content

Abstract

Acute activation or blockade of neurokinin-3 (NK-3) receptors has been shown to alter dopamine-mediated function and behaviors, however long-term effects of NK-3 receptor blockade remain largely unknown. The present study investigated whether acute and repeated administration of the NK-3 receptor antagonist SB 222200 altered hyperactivity induced by cocaine, and examined its effects on dopamine D1 receptor density in the striatum. Adult male CD-1 mice received either vehicle or SB 222200 (2.5 or 5 mg/kg, s.c.) 30 min before a cocaine injection (20 mg/kg, i.p.) and behavioral responses were recorded. Mice that were administered SB 222200 had an attenuated stereotypic response to cocaine compared to vehicle treated mice. Mice were also injected once daily with either vehicle or SB 222200 (5 mg/kg, s.c.) for 5 days, and after a 7-day drug-free period they were challenged with either saline, cocaine or the dopamine D1 receptor agonist SKF 82958 (0.125 or 0.25 mg/kg, i.p.). Mice injected with SB 222200 had significantly enhanced hyperactivity when challenged with cocaine or a low dose of SKF 82958 (0.125 mg/kg, i.p.) compared to control mice. Brains of mice administered vehicle or SB 222200 for 5 days were harvested after a 7-day drug-free period for dopamine D1 receptor quantification by radioligand binding. [3H] SCH 23390 homogenate binding studies showed a 19.7% increase in dopamine D1 receptor density in the striatum of SB 222200 treated mice. These data suggest that repeated blockade of NK-3 receptors enhances subsequent dopamine-mediated behaviors possibly resulting from dopamine D1 receptor up-regulation in the striatum.

Introduction

The mammalian tachykinin family of neuropeptides that includes substance P, neurokinin A, neurokinin B, neuropeptide K and neuropeptide gamma exert their biological actions through G-protein coupled receptors termed neurokinin-1, neurokinin-2, and neurokinin-3 (NK-3) (Maggi, 1995, Massi et al., 2000). Activation of NK-3 receptors primarily causes phosphoinositol 4, 5 biphosphate (PIP2) breakdown into 1,4,5 inositol triphosphate (IP3) and diacylglycerol through phospholipase C activation (Khawaja and Rogers, 1996, Maggi, 1995), eventually leading to Ca2+ mobilization and induction of Ca2+-dependent downstream signaling pathways.

NK-3 receptors are found peripherally on nerve endings of primary afferent neurons innervating the respiratory, gastrointestinal and urinary tracts (Patacchini and Maggi, 2001), however they are also differentially expressed in the central nervous system. NK-3 receptors localized in the substantia nigra, ventral tegmental area (VTA) and prefrontal cortex (Dam et al., 1990) are thought to regulate dopaminergic neurotransmission and locomotive behaviors (Elliott et al., 1991, Overton et al., 1992). Tyrosine hydroxylase-containing neurons in the substantia nigra and VTA have been shown to express NK-3 receptors (Chen et al., 1998). Activation of NK-3 receptors in the substantia nigra and VTA stimulates dopaminergic neuronal activity (Keegan et al., 1992, Overton et al., 1992), and increases dopamine release and metabolism in the nucleus accumbens, striatum, and prefrontal cortex (Bannon et al., 1995, Humpel et al., 1991, Marco et al., 1998). In addition, NK-3 receptor activation elicits behaviors such as locomotion, rearing, sniffing and wet dog shakes in rats (Deschamps and Couture, 2005, Elliott et al., 1991, Jocham et al., 2007, Stoessl et al., 1991), which are diminished by administration of the dopamine D1 receptor antagonist SCH 23390 (Deschamps and Couture, 2005). In addition, NK-3 receptor activation potentiates locomotion induced by cocaine in rodents (Jocham et al., 2007) and also potentiates cocaine-induced decreases in exploratory activity, aerial scanning, and terrestrial glancing in non-human primates (de Souza Silva, 2006a). Conversely, dopamine D1 receptor-mediated and cocaine-induced behaviors are attenuated after administration of NK-3 receptor antagonists in rats (Bishop and Walker, 2004, Jocham et al., 2006) and in cocaine responsive non-human primates (de Souza Silva, 2006b). These findings demonstrate that NK-3 receptors can modulate dopaminergic function and behavior.

To date, the majority of studies on NK-3 receptors and dopamine have examined modulation of dopaminergic function after acute administration of NK-3 receptor agonists and antagonists. However, effects of prior repeated blockade of NK-3 receptors on dopaminergic function have not been investigated. Since acute blockade of NK-3 receptors diminishes dopamine-mediated function and behavior, we hypothesized that repeated NK-3 receptor blockade may result in dopamine receptor super-sensitivity and enhancement of dopamine-mediated behaviors. Supporting evidence shows that dopamine-mediated behaviors are enhanced after previous chronic administration of dopamine receptor antagonists, and the change in dopamine-mediated behaviors results from up-regulation of dopamine receptors in the striatum (Hess et al., 1986, Hess et al., 1988). In particular, we propose that dopamine D1 receptor mediated behaviors and striatal dopamine D1 receptors may be altered after repeated NK-3 receptor blockade since previous studies have demonstrated that NK-3 receptor antagonists can attenuate dopamine D1 receptor-stimulated locomotion (Bishop and Walker, 2004). Therefore, the objectives of the present study were to investigate the effects of acute and repeated NK-3 receptor blockade on subsequent behavioral responses to cocaine, an indirect dopamine receptor agonist, and the selective dopamine D1 receptor agonist SKF 82958, and to examine changes in striatal dopamine D1 receptors that possibly underlie the change in behavioral response.

Section snippets

Animals

Adult male CD-1 mice (Charles River Laboratories, Raleigh, NC, USA) were group-housed (4–6 per cage) in a temperature and humidity controlled environment on a 12-h light–dark cycle (lights on at 7AM) with ad libitum access to food and water. Animals were handled daily prior to the beginning of experiments. All experiments were conducted in accordance with the National Institutes of Health guidelines for the Care and Use of Laboratory animals and with approval from Temple University School of

Effect of acute administration of the NK-3 antagonist SB 222200 on behavioral responses to cocaine

Ambulatory and stereotypic responses to cocaine in mice pretreated acutely with either vehicle or SB 222200 were measured. One-way ANOVA of ambulatory activity revealed a significant difference between the treatment groups (F(3,50) = 11.14, p < 0.0001, Fig. 1a). Bonferroni post hoc comparisons showed that cocaine significantly increased ambulatory activity in vehicle pretreated animals (p < 0.001, vehicle-saline vs. vehicle-cocaine groups). There was no effect of SB 222200 on ambulatory

Discussion

Modulation of NK-3 receptor activity has been shown to alter dopamine-mediated behaviors. Previous studies have reported that administration of NK-3 receptor agonists elicits dopamine-mediated behaviors which include hyper-locomotion and stereotypy (Deschamps and Couture, 2005, Elliott et al., 1991, Stoessl et al., 1991). The NK-3 receptor antagonist SR 142801 attenuates locomotion and stereotypic activity induced by the dopamine D1 receptor agonist SKF 82958 (Bishop and Walker, 2004) or

Acknowledgements

We would like to thank Ms. McCafferty, Drs. Pescatore and Simmons for their invaluable input and sharing their expertise in this study. This work was supported by the National Institutes of Health grant DA09580-S1.

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