Separate GABA Afferents to Dopamine Neurons Mediate Acute Action of Opioids, Development of Tolerance, and Expression of Withdrawal

Abstract

Summary GABA release from interneurons in VTA, projections from the nucleus accumbens (NAc) and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg inputs, but not local interneurons or NAc inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons.

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

“…As the RMTg gained recognition as a distinct structure (Jhou, 2005;Jhou and Gallagher, 2007;Jhou et al 2009a, b;Perrotti et al, 2005;Kaufling et al, 2009Kaufling et al, , 2010, its capacity to control the activity of midbrain DA neurons (Hong et al, 2011;Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui et al, 2014) and the implications of this action in aversion (Jhou et al, 2009b), reward (Hong et al, 2011), and neurobiological responses to certain drugs of abuse (Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Jhou et al, 2013;Wasserman et al, 2013;Matsui et al, 2014) continue to concern investigators. Despite this wealth of interest, a fundamental behavior-locomotor activation-has been overlooked, yet we show here that modulation of RMTg activity has profound effects on locomotion.…”

“…The rostromedial tegmental nucleus (RMTg), a recently discovered structure located in the mesopontine tegmentum (Jhou, 2005;Jhou et al, 2009a, b;Kaufling et al, 2009), projects preferentially and strongly to (Jhou et al, 2009a, b, Balcita-Pedicino et al, 2011Bourdy et al, 2014) and thus is a strong inhibitor of (Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Matsui et al, 2014) dopamine neurons in the VTA and substantia nigra compacta (SNc). RMTg is implicated together with the VTA in behavioral responding to reward omission, aversive stimuli, feareliciting stimuli, and certain drugs of abuse (Jhou et al, 2009a(Jhou et al, , 2013Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Wasserman et al, 2013) and, more recently, with the SNc in motor skill and motor learning (Bourdy et al, 2014).…”

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

“…Since ablation of either Girk1 or Girk2 correlated with diminished opioid analgesia (Mitrovic et al, 2003;Marker et al, 2004Marker et al, , 2005, and since Girk2 ablation correlated with decreased opioid-induced hypothermia (Costa et al, 2005), we predicted that mice lacking GIRK1 and/or GIRK2 would exhibit diminished systemic morphine-induced motor activity. Surprisingly, however, the motor-stimulatory effect of systemic morphine was enhanced in (white; n ϭ 6) and GAD-Cre(ϩ):Girk2 flox/flox (gray; n ϭ 5) mice.…”

“…In support of this contention, loss of GIRK1 or GIRK2 correlates with diminished opioid inhibition of locus ceruleus and spinal cord neurons (Torrecilla et al, 2002;Marker et al, 2006) and blunted intrathecal morphine and DAMGO (C26H35N5O6) analgesia (Marker et al, 2004(Marker et al, , 2005. Moreover, loss of GIRK2 correlates with diminished systemic morphine-induced analgesia (Mitrovic et al, 2003), and ablation of GIRK channels in the locus ceruleus precludes the induction of opioid dependence (Cruz et al, 2008).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Nucleus Accumbens Core Efferents. The NAcore sends projections primarily to GABAergic basal ganglia nuclei, but it also contains neurons that send inputs directly to glutamatergic neurons in the subthalamus and dopaminergic neurons in the paranigral part of the VTA (Groenewegen et al, 1999;Tripathi et al, 2010;Watabe-Uchida et al, 2012;Bocklisch et al, 2013;Matsui et al, 2014;Kupchik et al, 2015). The NAcore also projects to the substantia nigra pars reticulata and sends a striatopallidal projection to the dorsolateral VP and lateral globus pallidus (Heimer et al, 1991;Tripathi et al, 2010).…”