Mesolimbic dopamine drives the diurnal variation in opiate-induced feeding

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Abstract

Brain opioid peptides modulate feeding behavior and opiate drugs have powerful orexigenic effects in mammals. Recent studies have shown that opiate-induced eating depends, though not exclusively, on mu-opioid receptors located in the ventral striatum. Here we report that morphine orexigenic effects vary with the time of day according to a biphasic pattern. The effects first increase and then decrease during the light phase, with the peak effect occurring in the middle of this phase. This diurnal profile is shifted toward the dark phase after dopamine deafferentation of the ventral striatum. Consequently, the peak effect of morphine is delayed and occurs just before the dark phase. This finding suggests that mesolimbic dopamine transmission contributes to the neural mechanisms that normally drive the circadian timing of opioid-dependent feeding.

Introduction

A critical challenge for neuroscience is to understand the regulation of feeding behavior in mammals (Hoebel, 1997, Kelley et al., 2002, Saper et al., 2002, Schwartz et al., 2000). Several brain neurotransmitter systems influence and are influenced by food intake. Among them, mu-opioid neurotransmission exerts a strong modulatory control over ingestive behavior. Opiate agonists increase and antagonists decrease food intake in food sated rats (Glass et al., 1999, Levine and Billington, 2004). The orexigenic effects of opiate agonists are mediated by mu-opioid receptors located in several brain regions, including the paraventricular nucleus of the hypothalamus, the nucleus of the solitary tract, the central nucleus of the amygdala and the ventral striatum (Bakshi and Kelley, 1993, Giraudo and Billington, 1998, Kotz and Billington, 1997, Stanley et al., 1988). Recent studies suggest that ventral striatum mu-opioid receptors, more than delta- or kappa-opioid receptors, influence feeding by increasing taste hedonics, presumably through the strong functional and anatomical links between the ventral striatum and lateral hypothalamus (Kelley et al., 2002).

As for spontaneous feeding, both unconditioned and conditioned orexigenic effects of morphine vary with the time of day (Bhakthavatsalam and Leibowitz, 1986, Kavaliers and Hirst, 1985, Kavaliers and Innes, 1987, Kelley et al., 2000, Sanger and McCarthy, 1981). These circadian phenomena are associated with daily fluctuations in the primary neuropharmacological substrate of mu-opioid agonists. Both brain opioid peptide levels and receptors have been shown to vary during the light–dark cycle (Naber et al., 1981, Wesche and Frederickson, 1979). For instance, forebrain naloxone binding sites start to increase just before the dark phase and decrease during the light phase of the daily cycle (Naber et al., 1981). However, the mechanism that drives circadian fluctuations in mu-opioid transmission is currently unknown. In the ventral striatum, dopamine could serve as one of the local mediator of the daily rhythm generated by the hypothalamic circadian pacemaker. In support of this possibility, ventral striatal dopamine has been shown to influence the behavioral effects of both opiates and opioid peptides (Stinus et al., 1992) and to exhibit up and down variations during the day, with peak dopamine levels occurring during the dark phase (Paulson and Robinson, 1994). However, these findings are only suggestive. They show that there are diurnal variations in dopamine levels and in opiate-induced feeding but they do not provide evidence supporting a link between these two phenomena. The present study was designed to test the hypothesis of a link between ventral striatum dopamine and diurnal variations in opiate-induced feeding in nondeprived animals.

Section snippets

Subjects

A total of 53 male Sprague–Dawley rats (Iffa-Credo, France), weighing 199–220 g upon their arrival in the laboratory, were individually housed in a colony room maintained at a constant temperature of 23 °C and under a 14–10 h light–dark cycle (lights on from 6:00 to 20:00 h). Rats had ad libitum access to food and water. Rats were acclimated to these housing conditions for at least a week before the experiment began. All animal care was in strict accordance with institutional and international

Results

Twenty-eight out of thirty-four 6-OHDA-lesioned rats were hypersensitive to apomorphine (i.e., at least 2 standard deviations above the mean value of sham-operated rats [mean = 5.5; 1 SD = 10.5]) and had ventral striatum dopamine contents depleted by more than 90% of control values. Only these rats were considered in the subsequent analysis. The 6-OHDA lesion was specific to dopamine since it produced a large depletion in DOPAC [84%, F(1,41) = 110.79, p < 0.001] and dopamine contents [93%, F(1,41) = 

Discussion

The present study shows that morphine-induced eating varies with the time of day, with the maximum effect occurring during the middle part of the light phase. This diurnal profile in the orexigenic effects of morphine is dramatically altered by mesolimbic dopamine depletion. These data suggest that mesolimbic dopamine transmission contributes to the neural processes that normally drive the circadian rhythm of opioid-dependent behavior.

As expected, normal food intake in sham-operated rats is low

Acknowledgments

This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Université Victor-Segalen Bordeaux 2, the Institut National de la Santé et de la Recherche Médicale, the Conseil Régional d'Aquitaine and the Mission Interministérielle de Lutte contre les Drogues et la Toxicomanie (MILDT). We thank the reviewers for their constructive comments.

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