Prolonged Effects of Repeated Social Defeat Stress on mRNA Expression and Function of μ-Opioid Receptors in the Ventral Tegmental Area of Rats

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Abstract
Social defeat stress alters the activity of mesocorticolimbic dopamine projections from the ventral tegmental area (VTA), a process that has been implicated in the development of sensitization and drug-seeking behavior. We showed previously that acute brief social defeat stress increased short-term expression of μ-opioid receptor mRNA in the VTA. The present study assessed the presence and functional significance of μ-opioid receptor mRNA expression 1 week after the last episode of social defeat stress. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat, and subsequent exposures behind a protective screen once a day for 5 days. Regional μ-receptor mRNA levels were assessed by in situ hybridization histochemistry, and the amount of mRNA labeling was measured in the VTA and the substantia nigra (SN). Expression of μ-opioid receptor mRNA was significantly higher in defeated rats relative to handled control animals in the VTA, but not in the SN. In an additional group of rats, bilateral local intra-VTA injection of the selective μ-opioid receptor agonist DAMGO (1.0 μg per side) was performed 7–10 days after the last defeat stress or handling control procedure. Baseline motor activity did not differ between control and stressed rats. Intra-VTA DAMGO significantly increased locomotor activity in stressed rats compared to handled control rats. These results suggest that repeated social stress upregulates VTA μ-opioid receptors and can produce locomotor activation via stimulation of these receptors. This locomotor effect is probably the consequence of enhanced disinhibition of mesolimbic dopamine neurons.