Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1

Department of Anatomy and Neurobiology, University of Maryland School of Medicine Baltimore, MD, USA.
Frontiers in Molecular Neuroscience (Impact Factor: 4.08). 05/2013; 6:13. DOI: 10.3389/fnmol.2013.00013
Source: PubMed


Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function.

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Available from: Mary Kay Lobo
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    • "Grueter et al. (2013) suggested that FosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type-and subregionspecific fashion. Recently, Chandra et al. (2013) reported that repeated ChR2 activation of D1R-MSNs but not D2R-MSNs caused a down-regulation of Tiam1 gene, a protein involved in the rearrangement of the actin cytoskeleton, similar to the effects of cocaine. Therefore, to understand the mechanisms that yield lasting effects of drug-induced behaviors it will be important to delineate the cell-selective induction of molecular events in these MSNs that control synaptic adaptation to repetitive drug exposure. "
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    ABSTRACT: Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc) have been proposed to contribute to drug-mediated addictive behaviors. Here we have used an optogenetic approach to examine the role of NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs) in cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding channelrhodopsin-2 (ChR2) were delivered into the NAc of D2R-Cre transgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2R-MSNs form local inhibitory circuits, because photostimulation of D2R-MSN evoked inhibitory postsynaptic currents (IPSCs) in neighboring MSNs. Photostimulation of NAc D2R-MSN in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. However, photostimulation during the drug withdrawal period attenuated expression of cocaine-induced behavioral sensitization. These results show that D2R-MSNs of NAc play a key role in withdrawal-induced plasticity and may contribute to relapse after cessation of drug abuse.
    Full-text · Article · Oct 2014 · Frontiers in Behavioral Neuroscience
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    • "Our behavioural findings implicate the D1-type neurons in the modulation of analgesic tolerance to morphine. For our optogenetic stimulation protocol, we selected a 10-Hz stimulation that has been used by several investigators (Lobo et al, 2010; Chandra et al, 2013) and selected stimulation durations that do not affect baseline Rgs9-2 levels or pain thresholds. Interestingly, activation of D1- type neurons in the presence of morphine leads to an increase in Rgs9-2 expression in the NAc. "
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    ABSTRACT: 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 which involves interactions with Gα subunits, the Gβ5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposure to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools which 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 (AAV) 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.Neuropsychopharmacology accepted article preview online, 24 February 2014; doi:10.1038/npp.2014.45.
    Full-text · Article · Feb 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Rats were implanted with chronic indwelling jugular catheters and allowed 7 days to recover following surgery as previously described [26], [27]. Catheters were flushed daily with 0.2 ml solution of enrofloxacin (4 mg/ml) mixed in a heparinized saline solution (50 IU/ml in 0.9% sterile saline) to preserve catheter patency. "
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    ABSTRACT: The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1) expression in the nucleus accumbens (NAc) following periods of withdrawal from cocaine self-administration (SA) and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i) repeated systemic injections (cocaine or saline), or (ii) self-administration (cocaine or saline) and underwent a period of forced abstinence (either 1 or 7 days of drug cessation). Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction.
    Full-text · Article · Dec 2013 · PLoS ONE
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