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 05/2013; 6:13. DOI: 10.3389/fnmol.2013.00013
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Mary Kay Lobo, Jun 25, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2014; DOI:10.1038/npp.2014.45 · 7.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To examine the mechanisms of drug relapse, we first established a model for cocaine intravenous self-administration (IVSA) in mice, and subsequently examined electrophysiological alterations of medium-sized spiny neurons (MSNs) in the nucleus accumbens (NAc) before and after acute application of cocaine in slices. Three groups were included: master mice trained by active lever pressings followed by intravenous (IV) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of spontaneous excitatory postsynaptic currents (sEPSCs) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Further, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and post-synaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an action potential (AP)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative threshold for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction.
    ASN Neuro 09/2013; 5(4). DOI:10.1042/AN20130015 · 4.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.