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• W2388891674 abstract "•Synchronized activation of GABA transmission from multiple iMSNs inhibits APs in dMSNs•Cocaine suppresses lateral inhibition via D2Rs in iMSNs to disinhibit dMSNs•D2R agonist show higher efficacy at axon collaterals than at projections to VP•D2Rs in iMSNs are required for the stimulant effect of cocaine on locomotion Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine’s ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJmYjc0NGY2NmQyZDZhOGU2MDIzODU3NDllZTQwMWYyZCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDM2NDkwfQ.JH2gnLXnfJWLsm3s3Ox3PrqtaVlUIrSfRBOATh3GC1WLC1sDiadzvDeUxL9RpV503c2s1Tvceny0O0lXkEGVpXzmREyR00jgWeBYWbXj8m1dMyLojDu3g7meZ2JnOpCCiz6_Muw3O21Z_kEnxrqUVXWmp8qyaLP8gs2xuIt8eJTmqvegIrltY-KnhbX5ZkiUQzwsQ1g6tovmWy5FwuAzKGVwuedexM9SCsMY14TNfhhN6c2Av1VebWA-jV9sZycg2KwEfUEX3XnkRw1U3sC5xs_7CJTPjEQuDAGZ5CZFIfjD2oq9mMBnydnE2ekPJWzHamrZq47KbDGRY87xI1tbgg(mp4, (48.32 MB) Download video Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine’s ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. MSNs form the two main outputs of the striatum: the direct pathway formed by long-range axonal projections from dMSNs to the internal segment of the globus pallidus and the substantia nigra pars reticulata, and the indirect pathway formed by long-range axonal projections from iMSNs, but also dMSNs in the NAc region specially, to the globus pallidum/ventral pallidum (Gerfen and Surmeier, 2011Gerfen C.R. Surmeier D.J. Modulation of striatal projection systems by dopamine.Annu. Rev. Neurosci. 2011; 34: 441-466Crossref PubMed Scopus (1041) Google Scholar; and see also Kupchik et al., 2015Kupchik Y.M. Brown R.M. Heinsbroek J.A. Lobo M.K. Schwartz D.J. Kalivas P.W. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.Nat. Neurosci. 2015; 18: 1230-1232Crossref PubMed Scopus (263) Google Scholar). Previous studies provided functional evidence that these two pathways exert opposing effects on basal ganglia-mediated behaviors. Activation of the direct pathway facilitates locomotion, reward, and reinforcement, while activation of the indirect pathway suppresses these behaviors (Freeze et al., 2013Freeze B.S. Kravitz A.V. Hammack N. Berke J.D. Kreitzer A.C. Control of basal ganglia output by direct and indirect pathway projection neurons.J. Neurosci. 2013; 33: 18531-18539Crossref PubMed Scopus (248) Google Scholar, Kravitz et al., 2010Kravitz A.V. Freeze B.S. Parker P.R. Kay K. Thwin M.T. Deisseroth K. Kreitzer A.C. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.Nature. 2010; 466: 622-626Crossref PubMed Scopus (1224) Google Scholar, Kravitz et al., 2012Kravitz A.V. Tye L.D. Kreitzer A.C. Distinct roles for direct and indirect pathway striatal neurons in reinforcement.Nat. Neurosci. 2012; 15: 816-818Crossref PubMed Scopus (638) Google Scholar, Lobo et al., 2010Lobo M.K. Covington 3rd, H.E. Chaudhury D. Friedman A.K. Sun H. Damez-Werno D. Dietz D.M. Zaman S. Koo J.W. Kennedy P.J. et al.Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.Science. 2010; 330: 385-390Crossref PubMed Scopus (612) Google Scholar). It has been assumed that the long-range connectivity is mainly responsible for this functionally dichotomy. However, in addition to the long-range projections, MSNs extend short-range axonal projections within the striatum to form an extensive collateral plexus. The collateral transmission remains an underappreciated aspect of the striatal circuit and its contribution to regulating the behavioral output of the basal ganglia is unclear. Initial reports of the anatomical evidence for collateral transmission between MSNs in the dorsal striatum and the NAc appeared decades ago (Chang and Kitai, 1986Chang H.T. Kitai S.T. Intracellular recordings from rat nucleus accumbens neurons in vitro.Brain Res. 1986; 366: 392-396Crossref PubMed Scopus (31) Google Scholar, Pennartz et al., 1991Pennartz C.M. Boeijinga P.H. Kitai S.T. Lopes da Silva F.H. Contribution of NMDA receptors to postsynaptic potentials and paired-pulse facilitation in identified neurons of the rat nucleus accumbens in vitro.Exp. Brain Res. 1991; 86: 190-198Crossref PubMed Scopus (67) Google Scholar, Preston et al., 1980Preston R.J. Bishop G.A. Kitai S.T. Medium spiny neuron projection from the rat striatum: an intracellular horseradish peroxidase study.Brain Res. 1980; 183: 253-263Crossref PubMed Scopus (257) Google Scholar, Wilson and Groves, 1980Wilson C.J. Groves P.M. Fine structure and synaptic connections of the common spiny neuron of the rat neostriatum: a study employing intracellular inject of horseradish peroxidase.J. Comp. Neurol. 1980; 194: 599-615Crossref PubMed Scopus (394) Google Scholar). However, the electrophysiological confirmation of functional inhibitory synapses between MSNs has only recently been shown (Lalchandani et al., 2013Lalchandani R.R. van der Goes M.S. Partridge J.G. Vicini S. Dopamine D2 receptors regulate collateral inhibition between striatal medium spiny neurons.J. Neurosci. 2013; 33: 14075-14086Crossref PubMed Scopus (35) Google Scholar, Tunstall et al., 2002Tunstall M.J. Oorschot D.E. Kean A. Wickens J.R. Inhibitory interactions between spiny projection neurons in the rat striatum.J. Neurophysiol. 2002; 88: 1263-1269PubMed Google Scholar). Using paired recordings of unidentified MSNs, the rate of connectivity was found to be variable and low (10%–25%). This is likely explained by the highly asymmetrical connectivity observed between the two subclasses of MSNs (Taverna et al., 2008Taverna S. Ilijic E. Surmeier D.J. Recurrent collateral connections of striatal medium spiny neurons are disrupted in models of Parkinson’s disease.J. Neurosci. 2008; 28: 5504-5512Crossref PubMed Scopus (279) Google Scholar, Tepper et al., 2004Tepper J.M. Koós T. Wilson C.J. GABAergic microcircuits in the neostriatum.Trends Neurosci. 2004; 27: 662-669Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). Each iMSN forms functional synapses with approximately one-third of neighboring dMSNs (iMSN→dMSN) and one-third of neighboring iMSNs (iMSN→iMSN), while dMSN collateral connectivity is mainly restricted to other dMSNs and rarely observed with iMSNs (Taverna et al., 2008Taverna S. Ilijic E. Surmeier D.J. Recurrent collateral connections of striatal medium spiny neurons are disrupted in models of Parkinson’s disease.J. Neurosci. 2008; 28: 5504-5512Crossref PubMed Scopus (279) Google Scholar, Tecuapetla et al., 2009Tecuapetla F. Koós T. Tepper J.M. Kabbani N. Yeckel M.F. Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals.J. Neurosci. 2009; 29: 8977-8990Crossref PubMed Scopus (66) Google Scholar). Further, it was estimated that each iMSN makes only a few GABA synapses (2–5) with their target neurons (Taverna et al., 2008Taverna S. Ilijic E. Surmeier D.J. Recurrent collateral connections of striatal medium spiny neurons are disrupted in models of Parkinson’s disease.J. Neurosci. 2008; 28: 5504-5512Crossref PubMed Scopus (279) Google Scholar, Tecuapetla et al., 2009Tecuapetla F. Koós T. Tepper J.M. Kabbani N. Yeckel M.F. Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals.J. Neurosci. 2009; 29: 8977-8990Crossref PubMed Scopus (66) Google Scholar). Thus, the functional relevance of this lateral inhibition to striatal output was considered to be minimal, relative to feedforward inhibition from local interneurons, and has been largely overlooked. Here, we use optogenetic stimulation to synchronously activate the widespread collateral plexus from iMSNs in order to test its effect on the excitability of neighboring dMSNs and its modulation by dopamine (DA) and cocaine. Cocaine is an addictive stimulant drug that induces transient increases in locomotion in humans and other mammal species (Julien, 2001Julien R.M. A Primer of Drug Action: A Concise Nontechnical Guide to the Actions, Uses, and side Effects of Psychoactive Drugs.Ninth Edition. Worth Publishers, 2001Google Scholar). The mechanisms that mediate the locomotor response are not well understood, despite this being one of the most well-characterized cocaine behavioral responses. It is known that cocaine is a high-affinity blocker of the monoamine transporters, including the DA transporter, and that acute administration of cocaine causes a rapid increase in DA concentration in the NAc, which is reliably observed both in vivo and in vitro within minutes following drug administration (Adrover et al., 2014Adrover M.F. Shin J.H. Alvarez V.A. Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine.J. Neurosci. 2014; 34: 3183-3192Crossref PubMed Scopus (51) Google Scholar, Fowler et al., 2001Fowler J.S. Volkow N.D. Wang G.J. Gatley S.J. Logan J. [(11)]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy.Nucl. Med. Biol. 2001; 28: 561-572Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, Zombeck et al., 2009Zombeck J.A. Gupta T. Rhodes J.S. Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice.Psychopharmacology (Berl.). 2009; 201: 589-599Crossref PubMed Scopus (54) Google Scholar). There is solid evidence that the DA increase in the NAc is required for the cocaine-induced locomotion (Kelly and Iversen, 1976Kelly P.H. Iversen S.D. Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats.Eur. J. Pharmacol. 1976; 40: 45-56Crossref PubMed Scopus (618) Google Scholar, Longo, 1973Longo V.G. Central effects of 6-hydroxydopamine.Behav. Biol. 1973; 9: 397-420Crossref PubMed Scopus (19) Google Scholar, Ziegler et al., 1972Ziegler H. Del Basso P. Longo V.G. Influence of 6-hydroxydopamine and of -methyl-p-tyrosine on the effects of some centrally acting agents.Physiol. Behav. 1972; 8: 391-396Crossref PubMed Scopus (9) Google Scholar), but the synaptic mechanisms downstream of DA elevation that mediate this acute behavioral response in the NAc are still under debate. DA Gi-coupled D2Rs are mainly expressed in iMSNs and are considered critical for cocaine-induced locomotion (Kita et al., 1999Kita K. Shiratani T. Takenouchi K. Fukuzako H. Takigawa M. Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats.Eur. Neuropsychopharmacol. 1999; 9: 1-7Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Ushijima et al., 1995Ushijima I. Carino M.A. Horita A. Involvement of D1 and D2 dopamine systems in the behavioral effects of cocaine in rats.Pharmacol. Biochem. Behav. 1995; 52: 737-741Crossref PubMed Scopus (68) Google Scholar). D2R activation in iMSNs produces well-described changes in intracellular signaling, biochemical pathway, and gene expression (Girault and Greengard, 2004Girault J.A. Greengard P. The neurobiology of dopamine signaling.Arch. Neurol. 2004; 61: 641-644Crossref PubMed Scopus (297) Google Scholar, Tritsch and Sabatini, 2012Tritsch N.X. Sabatini B.L. Dopaminergic modulation of synaptic transmission in cortex and striatum.Neuron. 2012; 76: 33-50Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, Walker et al., 2015Walker D.M. Cates H.M. Heller E.A. Nestler E.J. Regulation of chromatin states by drugs of abuse.Curr. Opin. Neurobiol. 2015; 30: 112-121Crossref PubMed Scopus (69) Google Scholar). The electrophysiological consequences of D2R activation, however, are still controversial (Gaval-Cruz et al., 2016Gaval-Cruz M. Goertz R.B. Puttick D.J. Bowles D.E. Meyer R.C. Hall R.A. Ko D. Paladini C.A. Weinshenker D. Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.Addict. Biol. 2016; 21: 35-48Crossref PubMed Scopus (9) Google Scholar, Hernandez-Lopez et al., 2000Hernandez-Lopez S. Tkatch T. Perez-Garci E. Galarraga E. Bargas J. Hamm H. Surmeier D.J. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade.J. Neurosci. 2000; 20: 8987-8995Crossref PubMed Google Scholar, Lemos et al., 2016Lemos J.C. Friend D.M. Kaplan A.R. Shin J.H. Rubinstein M. Kravitz A.V. Alvarez V.A. Striatal D2 receptors constrain local inhibitory transmission to set in vivo firing and spontaneous basal movement.Neuron. 2016; (Published online May 18, 2016)https://doi.org/10.1016/j.neuron.2016.04.040Abstract Full Text Full Text PDF Scopus (84) Google Scholar, Nicola et al., 1996Nicola S.M. Kombian S.B. Malenka R.C. Psychostimulants depress excitatory synaptic transmission in the nucleus accumbens via presynaptic D1-like dopamine receptors.J. Neurosci. 1996; 16: 1591-1604PubMed Google Scholar) in part because MSNs lack the G protein inward-rectifying potassium (GIRK) channels that are responsible for generating the D2R-mediated currents in other neurons such as midbrain DA neurons (Beckstead et al., 2004Beckstead M.J. Grandy D.K. Wickman K. Williams J.T. Vesicular dopamine release elicits an inhibitory postsynaptic current in midbrain dopamine neurons.Neuron. 2004; 42: 939-946Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). Adding to the complexity is the diverse expression pattern of D2Rs in the striatum, which has limited the interpretation of experiments relying on pharmacology to characterize the effect of D2R activation in iMSNs because D2Rs are also expressed in cholinergic interneurons (Maurice et al., 2004Maurice N. Mercer J. Chan C.S. Hernandez-Lopez S. Held J. Tkatch T. Surmeier D.J. D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons.J. Neurosci. 2004; 24: 10289-10301Crossref PubMed Scopus (172) Google Scholar, Zhang et al., 2009Zhang T. Zhang L. Liang Y. Siapas A.G. Zhou F.M. Dani J.A. Dopamine signaling differences in the nucleus accumbens and dorsal striatum exploited by nicotine.J. Neurosci. 2009; 29: 4035-4043Crossref PubMed Scopus (119) Google Scholar), and in presynaptic terminals from midbrain DA neurons (Adrover et al., 2014Adrover M.F. Shin J.H. Alvarez V.A. Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine.J. Neurosci. 2014; 34: 3183-3192Crossref PubMed Scopus (51) Google Scholar, Ford, 2014Ford C.P. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission.Neuroscience. 2014; 282C: 13-22Crossref PubMed Scopus (299) Google Scholar) and corticostriatal glutamatergic neurons (Bamford et al., 2004aBamford N.S. Robinson S. Palmiter R.D. Joyce J.A. Moore C. Meshul C.K. Dopamine modulates release from corticostriatal terminals.J. Neurosci. 2004; 24: 9541-9552Crossref PubMed Scopus (181) Google Scholar, Bamford et al., 2004bBamford N.S. Zhang H. Schmitz Y. Wu N.P. Cepeda C. Levine M.S. Schmauss C. Zakharenko S.S. Zablow L. Sulzer D. Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals.Neuron. 2004; 42: 653-663Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). This study takes advantage of a recently developed mouse model with targeted deletion of D2Rs to iMSNs to uncover a novel synaptic mechanism through which cocaine, and dopamine, regulates intra-striatal connectivity to facilitate locomotion. Adora2a-Cre mice were used in this study to target iMSNs. Cre-positive neurons in these mice show >80% co-localization with met-enkephalin, another iMSNs marker, and form projection patterns that are consistent with the indirect pathway (Figure S1; Supplemental Experimental Procedures) (Lemos et al., 2016Lemos J.C. Friend D.M. Kaplan A.R. Shin J.H. Rubinstein M. Kravitz A.V. Alvarez V.A. Striatal D2 receptors constrain local inhibitory transmission to set in vivo firing and spontaneous basal movement.Neuron. 2016; (Published online May 18, 2016)https://doi.org/10.1016/j.neuron.2016.04.040Abstract Full Text Full Text PDF Scopus (84) Google Scholar). Channelrodopsin-2 (ChR2) tagged with a fluorophore was expressed in iMSNs in the NAc using stereotaxic injection of a Cre-dependent viral vector (Figure 1A). This approach allows for selective stimulation of axonal collaterals from iMSNs within the NAc region in order to evaluate the efficacy of the lateral inhibition in regulating the excitability of neighboring MSNs. Whole-cell current-clamp recordings were performed from MSNs that were negative for ChR2 and are defined here as putative dMSNs (see Experimental Procedures for details). Current steps were delivered to the putative dMSNs to elicit action potentials (APs) in the presence and absence of optogenetic stimulation of collateral transmission (Figures 1B and 1C). Before stimulation (laser OFF), each current step (267 ± 18 pA, 800 ms) elicited 10.5 ± 1 APs with a mean latency to fire the first AP of 198 ± 29 ms (n = 6). Optogenetic stimulation (laser ON, 20 pulses of 1–5 ms duration at 16 Hz) applied concurrently with the current step significantly decreased AP firing to 6.8 ± 1 APs (36% ± 5%; 2WRM ANOVA; drug × laser: F1,5 = 21.66, p < 0.01; post hoc: p < 0.01 ON versus OFF at baseline) and increased the latency to 239 ± 33 ms (24% ± 8%; 2WRM ANOVA drug × laser: F1,5 = 13.25, p < 0.05; post hoc: p < 0.05 ON versus OFF at baseline). Application of the GABAA receptor blocker gabazine (5 μM) increased the number of APs evoked by the current step and decreased the latency during laser OFF, revealing a tonic GABAA-mediated inhibition of AP firing under baseline conditions (APs: from 10.5 ± 1 to 14 ± 1.3; latency: from 198 ± 9 to 157 ± 21 ms after gabazine; post hoc: APs: p < 0.01; latency: p < 0.05 baseline versus gabazine during OFF; Figure 1D). Importantly, gabazine blocked the optical inhibition of AP firing and blocked the increase in latency induced by optogenetic stimulation of iMSNs (post hoc: APs: p < 0.0001; latency: p < 0.0001 baseline versus gabazine during ON). The GABAA receptor antagonist abolished the collateral inhibition (from 35.5% ± 4.7% to −2.1% ± 5.2%; paired t test: t5 = 6.4, p < 0.01; Figure 1E), demonstrating that GABAergic transmission and GABAA receptor activation are required for the inhibition of dMSN excitability by iMSN stimulation. Altogether, these results show that inhibitory GABAergic collateral transmission by iMSNs can inhibit dMSN excitability. Direct measurement of iMSN→dMSN short-range collateral GABA transmission was performed in voltage-clamp recordings from dMSNs in the NAc core (Figure 2A). Optogenetic stimulation of iMSNs reliably evoked inhibitory postsynaptic currents (oIPSCs) in neighboring putative dMSNs, which were blocked by 5 μM gabazine (97% ± 0.4% inhibition, n = 37). In agreement with previous reports (Lalchandani et al., 2013Lalchandani R.R. van der Goes M.S. Partridge J.G. Vicini S. Dopamine D2 receptors regulate collateral inhibition between striatal medium spiny neurons.J. Neurosci. 2013; 33: 14075-14086Crossref PubMed Scopus (35) Google Scholar, Tecuapetla et al., 2009Tecuapetla F. Koós T. Tepper J.M. Kabbani N. Yeckel M.F. Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals.J. Neurosci. 2009; 29: 8977-8990Crossref PubMed Scopus (66) Google Scholar), the D2-like agonist quinpirole (1 μM) inhibited oIPSC amplitude by 59% ± 6% (n = 6; Figures 2B–2D). Quinpirole showed a trend to increase the paired-pulse ratio (baseline: 1.1 ± 0.1, quinpirole: 1.7 ± 0.3; paired t test, t5 = 2.17, p = 0.08), which was reversed by sulpiride (1.1 ± 0.1), suggesting that quinpirole’s actions are mediated by presynaptic mechanisms that could involve inhibition of GABA release. In parallel experiments under the same conditions, we tested the effect of quinpirole on long-range axonal projections to the VP (iMSN→VP synapses). Optogenetic stimulation of iMSN fibers reliably evoked gabazine-sensitive oIPSCs in VP neurons. Quinpirole inhibition was less reliable and smaller in VP neurons compared to dMSNs in the NAc (19% ± 4%, n = 11). Sulpiride reversed the quinpirole inhibition in VP and dMSNs (1 μM; VP: −3% ± 7%; dMSNs: 10% ± 8%). Conversely, the GABAB receptor agonist baclofen (1–5 μM) potently inhibited oIPSC amplitude to a similar extent in dMSNs and VP neurons (62% ± 2% and 73% ± 8% for dMSNs and VP, respectively; n = 6–8; 2WRM ANOVA; site × drug: F1,12 = 5.31, p < 0.05; post hoc: p = NS; Figures 2C and 2E). Thus, while modulation by Gi-coupled GABAB receptors is similar at both terminals, the magnitude of the D2-like agonist inhibition was significantly greater in short-range collaterals than long-range projections to the VP (2WRM ANOVA; site × drug: F1,15 = 6.33, p < 0.05; post hoc: p < 0.001, VP versus dMSNs in quinpirole). These results indicate differential inhibition by a GABAA antagonist and a D2-like receptor on oIPSC amplitude in the VP. While surprising, these results are consistent with the relatively weak DA fiber innervation of the VP compared to the dense innervation of the NAc from midbrain DA neurons (fluorescent fiber density: 67 ± 4.6 and 31 ± 3.5 a.u. for NAc core and VP, respectively; paired t test: t4 = 13.8, p < 0.001, n = 5; Figures 2F and 2G). Quinpirole’s effects on the intrinsic excitability of iMSNs could contribute to the inhibition of synaptic transmission and account for its greater efficacy at short-range collaterals versus long-range projections. Using cell-attached recordings and in the presence of synaptic transmission blockers, we tested the effect of quinpirole on the intrinsic excitability of iMSNs by eliciting APs via optogenetic stimulation at different frequencies and under similar conditions as the oIPSC recordings (Figure 3A). The minimum light pulse duration to elicit 100% fidelity in AP firing was used and delivered at 4 and 16 Hz (4 Hz: 20.1 ± 0.03 APs; 16 Hz: 20 ± 0 APs, n = 8; Figures 3A–3C). Neither quinpirole (1 μM) nor sulpiride (1 μM) affected AP firing at either frequency (2WRM ANOVA: p values = NS, n = 5–8), indicating that quinpirole inhibits synaptic collateral GABA transmission downstream of changes in iMSNs excitability. D2-like receptor agonists have poor selectivity between D2Rs and D3Rs, which are both expressed in the NAc. Moreover, due to the complex expression pattern of D2Rs, it is extremely difficult to determine where the D2Rs implicated in this modulation are expressed. To determine whether D2Rs expressed specifically in iMSNs mediate the quinpirole regulation of collateral transmission, we took advantage of a mouse line with a targeted deletion of D2Rs from iMSNs (iMSN-Drd2KO mice; Lemos et al., 2016Lemos J.C. Friend D.M. Kaplan A.R. Shin J.H. Rubinstein M. Kravitz A.V. Alvarez V.A. Striatal D2 receptors constrain local inhibitory transmission to set in vivo firing and spontaneous basal movement.Neuron. 2016; (Published online May 18, 2016)https://doi.org/10.1016/j.neuron.2016.04.040Abstract Full Text Full Text PDF Scopus (84) Google Scholar). In iMSN-Drd2KO mice, quinpirole did not inhibit oIPSC amplitude (2% ± 6%, n = 11; Figures 3D and 3E). This was in contrast to the robust quinpirole-mediated inhibition of oIPSC amplitude in Adora2a-Cre controls (53% ± 7%; n = 9; 2WRM ANOVA; genotype × quinpirole: F1,18 = 30.86, p < 0.0001, post hoc: Adora2a-Cre: p < 0.0001, iMSN-Drd2KO: p = NS, baseline versus quinpirole). Conversely, baclofen inhibited oIPSC amplitude by 52% ± 6% in iMSN-Drd2KO mice, which was similar to the baclofen effect Adora2a-Cre mice (n = 13; 2WRM ANOVA; baclofen: F1,22 = 257, p < 0.0001). These experiments demonstrate that the loss of quinpirole inhibition is not due to a general disruption in Gi/o-mediated inhibition of GABA release from these terminals and that D2Rs in iMSNs, possibly localized to presynaptic terminals, are required for the suppression of iMSN→dMSN collateral transmission. We hypothesized that suppression of short range collateral transmission by D2Rs could disinhibit dMSNs and that this effect would be lost in iMSN-Drd2KO mice. These hypotheses were tested using a similar experimental configuration as in Figure 1. In control Adora2a-Cre mice, optogenetic stimulation of iMSN→dMSN collateral transmission inhibited dMSN firing by 46% ± 7% (OFF: 10.4 ± 0.8 APs; ON: 5.9 ± 0.9 APs, n = 11; 2WRM ANOVA; laser: F1,11 = 30.36, p < 0.001; Figures 3F and 3G). In the presence of quinpirole, the optogenetic-mediated inhibition of firing was significantly reduced to 26% ± 8% (paired t test: t11 = 4.01, p < 0.01; OFF: 9.8 ± 1 APs and ON: 7.4 ± 1.1 APs; n = 12; 2WRM ANOVA; laser × quinpirole: F1,11 = 11.46, p = 0.01; post hoc: p < 0.05 baseline ON versus quinpirole ON). Similarly, in iMSN-Drd2KO mice, optogenetic stimulation of iMSN→dMSN collateral transmission inhibited dMSN firing (36% ± 6%; OFF: 9.5 ± 1.2 APs; ON: 6 ± 1.1 APs, n = 11; 2WRM ANOVA; ON: F1,10 = 20.52, p = 0.01). In agreement with the lack of a quinpirole effect on oIPSC amplitude, quinpirole also did not affect the optogenetic-mediated inhibition of firing in iMSN-Drd2KO mice (34% ± 10%; paired t test: p = NS; OFF: 9.5 ± 1.2 APs and ON: 6.3 ± 1.1 APs; n = 11; no effect or interaction; Figures 3F and 3G). Cocaine increases extracellular DA concentration in the NAc by blocking DA transporters (DATs) (Kiyatkin and Stein, 1995Kiyatkin E.A. Stein E.A. Fluctuations in nucleus accumbens dopamine during cocaine self-administration behavior: an in vivo electrochemical study.Neuroscience. 1995; 64: 599-617Crossref PubMed Scopus (75) Google Scholar, Rice and Cragg, 2008Rice M.E. Cragg S.J. Dopamine spillover after quantal release: rethinking dopamine transmission in the nigrostriatal pathway.Brain Res. Brain Res. Rev. 2008; 58: 303-313Crossref PubMed Scopus (246) Google Scholar, Stuber et al., 2005Stuber G.D. Roitman M.F. Phillips P.E. Carelli R.M. Wightman R.M. Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration.Neuropsychopharmacology. 2005; 30: 853-863Crossref PubMed Scopus (176) Google Scholar). While this is a very robust, acute effect of cocaine, there are very few reports of other acute cocaine actions in the NAc (Harvey and Lacey, 1996Harvey J. Lacey M.G. Endogenous and exogenous dopamine depress EPSCs in rat nucleus accumbens in vitro via D1 receptors activation.J. Physiol. 1996; 492: 143-154Crossref PubMed Scopus (99) Google Scholar, Nicola et al., 1996Nicola S.M. Kombian S.B. Malenka R.C. Psychostimulants depress excitatory synaptic transmission in the nucleus accumbens via presynaptic D1-like dopamine receptors.J. Neurosci. 1996; 16: 1591-1604PubMed Google Scholar). Based on our findings, we hypothesized that cocaine would affect iMSN→dMSN collateral transmission. Indeed, cocaine (10 μM) inhibited oIPSC amplitude recorded in putative dMSNs by 40% ± 8% in control Adora2a-Cre mice (n = 6; 2WRM ANOVA; cocaine × genotype: F1,12 = 10.3, p < 0.01; post hoc: p < 0.01 baseline versus cocaine; Figures 4A and 4B ). Interestingly, cocaine had no effect on oIPSCs in iMSN-Drd2KO mice (0.2% ± 10% inhibition; n = 8; p = NS), indicating that D2Rs in iMSNs mediate the cocaine suppression of iMSN→dMSN collateral transmission. In experiments similar to those performed with quinpirole, cocaine suppressed lateral inhibition and enhanced the excitability of dMSNs. Optogenetic stimulation of iMSNs significantly inhibited dMSN baseline firing from 13." @default.
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• W2388891674 title "Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine" @default.
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