Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model

Abstract

The responses of olfactory bulbectomized (OBX) rats to antidepressant treatment are similar to those of depressed patients since chronic administration of an antidepressant reverses OBX-induced behavioral and physiological changes. Previously, using several animal models, it was demonstrated that single treatment with delta-opioid receptor agonists produced an antidepressant-like effect. This study examined the antidepressant effects resulting from subchronic exposure for 8 days to the delta-opioid receptor agonist SNC80 in an OBX rat model of depression. The olfactory bulbs were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed a significant increase in emotionality score and a decrease in the time spent and entries in the open arm of a plus-maze. In the case of OBX rats, these changes were dose- and time-dependently reversed by chronic SNC80 treatment (1–10 mg/kg, s.c.) for 7 days, as same as desipramine (10 mg/kg, i.p.). Moreover, the concentration of 5-HT and its metabolite 5-HIAA in the frontal cortex, hippocampus, and amygdala were decreased in OBX rats, and these changes were also normalized by SNC80 treatment, rather than desipramine treatment. In addition, SNC80 also significantly reversed the loss of TH-positive cells produced by OBX in the dorsal raphe. In conclusion, we demonstrated that subchronic SNC80 treatment could completely reverse OBX-induced behavioral abnormalities and defects in serotonergic function.

Introduction

Several lines of evidence have suggested the involvement of the opioid system in the mechanisms underlying the physiopathology of depression and the action of antidepressants. Recent studies with knockout mice that lack delta-opioid receptors (Filliol et al., 2000) or preproenkephalin-derived peptides (Konig et al., 1996, Ragnauth et al., 2001) revealed that both types of knockout mice showed high anxiety levels. In addition, compounds that the delta-opioid receptor agonists have been shown to have antidepressant-like properties in several animal models. The selective delta-opioid agonist Tyr-_D-Ser-(O-C(CH₃)₃)-Gly-Phe-Leu-Thr-(O-C(CH₃)₃ produced antidepressant-like effects in the learned helplessness model of depression (Tejedor-Real et al., 1998). Similarly, the treatment with enkephalinase inhibitors such as RB101 was associated with antidepressant-like effects in mice and rat models of depression (Baamonde et al., 1992, Tejedor-Real et al., 1998). More recently, the nonpeptidic delta-opioid agonists (+)-4-[α(R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide [(+)BW373U86] and (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) have been shown to produce antidepressant- and anxiety-like effects in several rodent models (Broom et al., 2002, Jutkiewicz et al., 2004, Jutkiewicz et al., 2005a, Jutkiewicz et al., 2005b, Saitoh et al., 2004, Saitoh et al., 2006, Torregrossa et al., 2005, Torregrossa et al., 2006, Perrine et al., 2006). We also demonstrated that single treatment with delta-opioid receptor agonists inhibited the depressant- and anxiety-like behavior in mice and rats using forced-swim test, conditioned-fear stress test, and elevated plus-maze test, on the contrary delta-opioid receptor antagonists produce anxiety-like behavior in rats in the elevated plus-maze test (Saitoh et al., 2004, Saitoh et al., 2005). Overall, these findings suggest that the delta-opioid receptor system may be related to depression or anxiety.

The following behavioral abnormalities have been observed following bilateral olfactory bulbectomy: stress-induced increase in locomotor activity and increases in various measures of irritability or hyperemotionality to given stimuli (Thorne and Rowles, 1988, Redmond et al., 1997, Okuyama et al., 1999, Ho et al., 2001, Ho et al., 2004, Saitoh et al., 2003, Saitoh et al., 2006, Saitoh et al., 2007, Chaki et al., 2004). It has been reported that OBX-induced behavioral abnormalities are reversed by chronic administration of a wide range of clinically effective antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (for a review, see Kelly et al., 1997, Song and Leonard, 2005). These reports suggest that impairment of the central serotonergic system may play an important role in mediating the behavioral changes observed following OBX. In addition, using autoradiographic method, it was reported that the decrease in 5-HT synthesis enzyme in dorsal raphe observed in the OBX rats and lower 5-HT synthesis rates in OBX rats was reversed by the chronic treatment with SSRI citalopram (Watanabe et al., 2003, Hasegawa et al., 2005). Previously, it was reported that many types of neurotransmitter contents were decreased in OBX animals. Specifically, it was demonstrated that an imbalance in the serotonergic system is observed in the OBX syndrome since there have been consistent observations of abnormal 5-HT concentration/synthesis and receptor expression throughout the limbic system (Lumia et al., 1992, Zhou et al., 1998, Watanabe et al., 2003). Indeed, many investigators demonstrated that behavioral and neurochemical changes induced by OBX were attenuated by chronic (but not acute) antidepressant treatment (see review Song and Leonard, 2005). Thus, it has been suggested that the OBX syndrome is a useful model for detecting antidepressant activity since many of the behavioral and neurotransmitter changes observed in OBX are qualitatively similar to those observed in depressed patients.

Previously, it was reported that the OBX procedure decreased the time spent in the open arm of a plus-maze, and this behavioral changes were significantly reversed by treatment with antidepressants and anxiolytic agents for 7 days (Yamaguchi et al., 2002). Similarly, we also reported that in comparison with sham-operated rats, OBX rats exhibited hyperemotionality score and a decrease in the time spent in the open arm of a plus-maze; these behavioral changes were attenuated by subchronic 7 day treatment with the antidepressant desipramine (Saitoh et al., 2003, Saitoh et al., 2007). Thus, the evaluation of hyperemotionality and the time spent in the open arms of a plus-maze in OBX rats may provide a suitable model for evaluating antidepressants.

No previous study has tried to demonstrate the antidepressant activity by subchronic administration of delta-opioid receptor agonists using an animal model of depression. Thus, we investigated the effects of subchronic administration of SNC80 on the hyperemotionality and the time spent in the open arms of a plus-maze in OBX rats. Furthermore, to clarify the mechanism of action of SNC80, we examined the changes in the amounts of 5-HT and its metabolite 5-HIAA in OBX rat brains after subchronic SNC80 treatment and the effects of chronic SNC80 treatments on 5-HT synthesis in OBX rats, using antibodies against tryptophan hydroxylase (TH), rate-limiting enzyme of 5-HT synthesis.