AMPA Receptor Plasticity in the Nucleus Accumbens Mediates Withdrawal-Related Negative-Affective States

The Journal of Neuroscience, October 12, 2016 • 36(41):10505–10507 • 10505

Journal Club

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AMPA Receptor Plasticity in the Nucleus Accumbens Mediates Withdrawal-Related Negative-Affective States

X Gabor Egervari Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Review of Russell et al.

Addiction is a chronic, relapsing disorder neural plasticity underlying the emergence Naloxone induced a strong conditioned characterized by craving, compulsive drug of negative-affective states associated with place aversion in morphine-dependent rats, use, and loss of control over limiting drug withdrawal and compulsive drug seeking is and this effect was prevented by NBQX pre- intake (Koob and Volkow, 2010). The essential to guide the development of future treatment in the NAc shell (Russell et al., emergence of negative-affective states (e.g., therapeutic interventions targeting this crit- 2016, their Fig. 2B). The effects were specific dysphoria, anxiety, irritability) with chronic ical component of the addiction phenome- to the NAc shell, and none of the treatments drug use has been hypothesized to play a non (Koob and Mason, 2016). showed any effect in placebo-implanted crucial role in the transition from recre- Plasticity of glutamatergic synapses in rats. Somatic signs of withdrawal (e.g., irri- ational drug use (characterized by positive the NAc, a key area for integrating motiva- tability to touch, wet dog shakes) were not reinforcement) to full-blown addiction and tion, emotion, and reward, has been impli- affected by AMPA receptor blockade (Rus- compulsive drug seeking (driven mostly by cated as a critical component of long-term sell et al., 2016, their Fig. 3). These results negative reinforcement) This “dark side of neuronal maladaptations underlying addic- indicate that AMPA receptor function in the addiction” is thought to result from a com- tive behavior (Scofield et al., 2016). Chronic NAc shell might be selectively involved in pensatory decrease in the function of the morphine exposure, for example, potenti- the regulation of negative-affective but not normal reward neurocircuitry and persis- somatic signs of morphine withdrawal. tent recruitment of brain stress systems ates glutamatergic transmission at thalam- ostriatal projections by enhancing synaptic AMPA receptor function plays an im- (Koob, 2013). In addicted people, negative- portant role in both memory formation and insertion of AMPA receptors (Zhu et al., affective states associated with withdrawal forgetting (Migues et al., 2016). To confirm 2016). Further expanding this line of re- promote drug seeking and relapse; they that the observed effects were not due to search, a recent publication in The Journal of thus play a central role in the three-stage changes in associative learning or memory Neuroscience (Russell et al., 2016) investi- cycle of addictive behavior (binge/intoxica- impairments, Russell et al. (2016) measured gated the role of NAc AMPA receptor func- tion, withdrawal/negative affect, preoccu- the effects of naloxone and/or NBQX on pation/anticipation) (Koob, 2013). On the tion in regulating negative-affective states brain stimulation reward threshold in intra- circuit level, recreational drug use is medi- associated with withdrawal in morphine- cranial self-stimulation (ICSS), an operant ated by the nucleus accumbens (NAc), dependent rats. Animals were made de- paradigm in which rodents self-administer whereas compulsive drug-seeking is driven pendent by subcutaneous implantation of rewarding electrical stimulation via elec- by the dorsal striatum (Everitt and Robbins, morphine pellets, and withdrawal was trodes implanted in the brain (Carlezon and 2013). However, the molecular underpin- precipitated by subcutaneous delivery of Chartoff, 2007). Decreases and increases in nings of the transition to addiction remain ␮ naloxone, a potent -opioid receptor antag- ICSS threshold, defined as the amount largely elusive. A better understanding of onist. Withdrawal-induced negative-affec- of stimulation that is rewarding, indicate tive states were assessed by measuring heightened or attenuated reward sensitivity, conditioned place aversion. Selective inhibi- Received July 22, 2016; revised Aug. 24, 2016; accepted Aug. 26, 2016. respectively. Naloxone led to significant in- The authors declare no competing financial interests. tion of AMPA receptors was achieved by in- creases in ICSS thresholds, which were re- Correspondence should be addressed to Dr. Gabor Egervari, Depart- jecting antagonist NBQX into the NAc shell, versed by NBQX pretreatment in the NAc ments of Psychiatry and Neuroscience, Icahn School of Medicine at and behaviorally relevant doses were deter- shell (Russell et al., 2016, their Fig. 4D). This Mount Sinai, One Gustave L. Levy Place, New York, NY 10029. E-mail: mined based on observed decreases in [email protected]. is consistent with the hypothesis that NBQX DOI:10.1523/JNEUROSCI.2329-16.2016 AMPA-induced locomotion (Russell et al., exerts its inhibitory effects by blocking Copyright © 2016 the authors 0270-6474/16/3610505-03$15.00/0 2016, their Fig. 1). naloxone-induced negative-affective states 10506 • J. Neurosci., October 12, 2016 • 36(41):10505–10507 Egervari • Journal Club

Figure 1. AMPA receptor plasticity in the NAc underlies withdrawal-related negative-affective states. A, Glutamatergic synapse in the NAc. B, Morphine dependence leads to increased surface expression of AMPA receptors, including GluA2-lacking receptors, resulting in enhanced glutamatergic transmission that underlies the expression of negative-affective states that promote relapse. C, Drug-induced molecular adaptations can be counteracted by using AMPA receptor antagonists, leading to a decrease in receptor function and negative-affective signs. rather than by disrupting associative learn- was specific to GluA1 and the NAc shell AMPA receptors are consistent with en- ing during conditioned place aversion. (Russell et al., 2016, their Fig. 6). hanced synaptic transmission, which is Two mechanisms by which neurotrans- The increase of GluA1 on the cell surface necessary for the expression of morphine mission at AMPA-receptor-containing syn- and in synaptosomal membranes, along withdrawal signs (Zhu et al., 2016). The re- apses can be regulated are changes in with the lack of change of GluA2, potentially sulting negative-affective states in turn mo- receptor levels and changes in subunit com- suggests an enrichment of GluA2-lacking tivate compulsive drug-seeking behavior. position. These mechanisms have been AMPA receptors in the NAc shell of mor- This model is consistent with previous liter- strongly implicated in neuronal maladapta- phine-dependent rats. Compared with ature showing that elevated NAc GluA1 lev- tions accompanying chronic drug adminis- GluA2-containing receptors, GluA2-lack- els result in aversive states (Todtenkopf et tration. For example, both total (Churchill ing AMPA receptors are permeable to Ca 2ϩ al., 2006), and emphasizes the role of gluta- et al., 1999) and surface (Boudreau and and exhibit higher single-channel conduc- matergic inputs to the NAc in promoting Wolf, 2005; Conrad et al., 2008) expression tance, faster kinetics, increased depolariza- drug seeking (LaLumiere and Kalivas, of the GluA1 AMPA receptor subunit were tion, and activation of Ca 2ϩ-dependent 2008). In line with this hypothesis, chronic increased in the NAc after chronic cocaine signaling cascades (Man, 2011). Changes in morphine exposure potentiated AMPAR administration. Withdrawal and reinstate- AMPA receptor subunit composition in transmission at thalamostriatal synapses via ment paradigms also result in increased glutamatergic synapses might therefore insertion of GluA2-lacking receptors (Zhu surface expression of GluA1 in the NAc contribute to altered AMPA receptor func- et al., 2016). This AMPAR potentiation was (Anderson et al., 2008). In addition, somatic tion in morphine-dependent and nalox- necessary for morphine withdrawal signs, signs of morphine withdrawal were de- one-treated rats, which in turn underlies which were suppressed by optogenetic de- creased by AMPA antagonists or by genetic negative-affective states associated with potentiation (Zhu et al., 2016). deletion of GluA1 (Rasmussen et al., 1996; morphine withdrawal. Indeed, Russell et al. The observations of Russell et al. (2016) Vekovischeva et al., 2001). Is a similar (2016) found that NASPM, a selective in- significantly advance our understanding of mechanism also at work in the regulation of hibitor of GluA2-lacking AMPA receptors, the molecular underpinnings of negative- affective components of withdrawal? had effects similar to those of NBQX: affective states associated with chronic To assess AMPA receptor subunit com- NASPM significantly attenuated naloxone- morphine use and withdrawal (Fig. 1). It re- position on the cell surface of NAc neurons, induced increases in brain stimulation mains to be seen whether similar mecha- Russell et al. (2016) used BS 3 to covalently thresholds in ICSS, although no such nisms apply to other addictive substances. cross-link cell surface proteins while leaving changes were observed in nondependent In addition, the extent to which the mode of intracellular molecules intact. Morphine- rats (Russell et al., 2016, their Fig. 8C). This drug delivery influences these adaptations dependent rats indeed exhibited signifi- is in line with previous observations that the should be investigated. Although subcuta- cantly higher surface GluA1 levels as well as surface expression of GluA2-lacking AMPA neous implantation of morphine pellets, as higher surface/intracellular ratio of GluA1 receptors is significantly increased during performed by Russell et al. (2016), reliably but not GluA2 subunits (Russell et al., 2016, withdrawal in cocaine self-administering achieves morphine dependence, animals do their Fig. 5). Interestingly, this increase in animals (Conrad et al., 2008). not actually engage in drug-seeking behav- surface GluA1 was reversed during nalox- The changes identified by Russell et al. ior in this paradigm. Drug self-administra- one-precipitated withdrawal. In addition, (2016) outline a molecular mechanism for tion remains the gold standard in the naloxone significantly decreased GluA1 morphine-related postsynaptic potentia- addiction field (Howell and Fantegrossi, protein levels in synaptosomal membranes tion of glutamatergic inputs to the NAc. 2009) as it is more directly translatable to the in morphine-dependent rats, an effect that Increased surface levels of GluA2-lacking human condition and allows investigation Egervari • Journal Club J. Neurosci., October 12, 2016 • 36(41):10505–10507 • 10507 of multiple aspects of substance use (initia- ing. Nat Neurosci 11:344–353. CrossRef essary for heroin seeking. J Neurosci 28:3170– tion, maintenance, withdrawal/abstinence, Medline 3177. CrossRef Medline reinstatement/drug-seeking). 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