Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gß5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

Haloperidol alters circadian clock gene product expression in the mouse brain.

OBJECTIVES: Circadian rhythms are patterns in behavioural and physiological measures that recur on a daily basis and are driven by an endogenous circadian timekeeping system whose molecular machinery consists of a number of clock genes. The typical anti-psychotic haloperidol has previously been shown to induce significant deficiencies in circadian timing in patients. In this study we examined the impact of haloperidol treatment on molecular components of the circadian clock in the mouse brain. METHODS: We examined how haloperidol treatment, either acute (both at day and night) or chronically over 14 days, alters the expression of three clock gene protein products (PER1, PER2, BMAL1) across the mouse brain by means of immunohistochemistry. RESULTS: Chronic haloperidol treatment significantly decreases the expression levels of PER1 in a number of brain areas, including the hippocampus, the prefrontal and cingulate cerebral cortex and the paraventricular nucleus of the hypothalamus. PER2 expression was only altered in the dentate gyrus and the CA3, and BMAL1 expression was only altered in the paraventricular nucleus of the hypothalamus. CONCLUSION: These data indicate that haloperidol has the potential to alter circadian rhythms via modulation of circadian clock gene expression.