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The Anterior Insular Cortex→Central Amygdala Glutamatergic Pathway Is Critical to Relapse after Contingency Management.
Neuron. 2017 Oct 11;96(2):414-427.e8. doi: 10.1016/j.neuron.2017.09.024.

Venniro M, Caprioli D, Zhang M, Whitaker LR, Zhang S, Warren BL, Cifani C, Marchant NJ, Yizhar O, Bossert JM, Chiamulera C, Morales M, Shaham Y.

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist. Here we used a novel rat model, in which the availability of a mutually exclusive palatable food maintains prolonged voluntary abstinence from intravenous methamphetamine self-administration, to demonstrate that the activation of monosynaptic glutamatergic projections from anterior insular cortex to central amygdala is critical to relapse after the cessation of contingency management. We identified the anterior insular cortex-to-central amygdala projection as a new addiction- and motivation-related projection and a potential target for relapse prevention.

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Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia
Neuron. 2017 Jul 19;95(2):341-356.e6. doi: 10.1016/j.neuron.2017.06.020. Epub 2017 Jul 6.

De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, Zhang HY, Liu QR, Shen H, Xi ZX, Goldman D, Bonci A.

Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei. Region-specific phenotypes of BG microglia emerged during the second postnatal week and were re-established following genetic or pharmacological microglial ablation and repopulation in the adult, indicating that local cues play an ongoing role in shaping microglial diversity. These findings demonstrate that microglia in the healthy brain exhibit a spectrum of distinct functional states and provide a critical foundation for defining microglial contributions to BG circuit function.

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Chemogenetics revealed: DREADD occupancy and activation via converted clozapine
Science. 2017 Aug 4;357(6350):503-507. doi: 10.1126/science.aan2475.

Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, Ellis RJ, Richie CT, Harvey BK, Dannals RF, Pomper MG, Bonci A, Michaelides M.

Designer receptors exclusively activated by designer drugs (DREADDs) constitute a powerful chemogenetic strategy that can modulate nerve cell activity in freely moving animal preparations. NIDA scientists used radioligand receptor occupancy measurements and in vivo positron emission tomography to show that DREADDs expressed in the brain are not activated by the designer compound CNO. Instead, they are activated by the CNO metabolite clozapine, a drug with multiple endogenous targets. This may have important implications for the interpretation of results obtained with this popular technology.

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Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial.
JAMA Psychiatry. 2017 Jun 1;74(6):632-640. doi: 10.1001/jamapsychiatry.2017.0400.

Lesage E, Aronson SE, Sutherland MT, Ross TJ, Salmeron BJ, Stein EA.

In this paper, NIDA scientists wanted to answer the question : ”How are reward sensitivity, in brain regions thought to be involved in drug abuse, and cognitive flexibility affected by acute abstinence and stimulation of the nicotinic acetylcholine receptors in dependent smokers?” In this placebo-controlled crossover study they found a “double dissociation” between decreased neural signatures of reward sensitivity, which are associated with severity of nicotine dependence but not with the acute effects of nicotine or varenicline tartrate (the drug Chantix), and behavioral and neural signatures of cognitive flexibility, which were impaired in the abstinent state but restored with stimulation of the nicotinic acetylcholine receptors. This means that currently available drug therapies appear to alleviate abstinent smokers’ impaired cognitive flexibility but not reward sensitivity.

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Dopamine transients are sufficient and necessary for
acquisition of model-based associations
Nat Neurosci. 2017 Apr 3. doi: 10.1038/nn.4538. [Epub ahead of print]

Melissa J Sharpe, Chun Yun Chang, Melissa A Liu, Hannah M Batchelor, Lauren E Mueller, Joshua L Jones, Yael Niv & Geoffrey Schoenbaum

Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

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Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior
Nat Neurosci. 2017 Mar;20(3):438-448. doi: 10.1038/nn.4482. Epub 2017 Jan 23.

Edwards NJ, Tejeda HA, Pignatelli M, Zhang S, McDevitt RA, Wu J, Bass CE, Bettler B, Morales M, Bonci A.

Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABAB receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.

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Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning.
Neuron. 2017 Jan 18;93(2):425-440.

Pignatelli M, Umanah GK, Ribeiro SP, Chen R, Karuppagounder SS, Yau HJ, Eacker S, Dawson VL, Dawson TM, Bonci A.

Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT+ neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT+ neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning.

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Pathway- and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity.
Neuron. 2017 Jan 4;93(1):147-163.

Tejeda HA, Wu J, Kornspun AR, Pignatelli M, Kashtelyan V, Krashes MJ, Lowell BB, Carlezon WA Jr, Bonci A

Endogenous dynorphin signaling via the kappa-opioid receptor (KOR) in the nucleus accumbens (NAcc) powerfully mediates negative affective states and stress reactivity. Excitatory inputs from the hippocampus and amygdala play a fundamental role in shaping the activity of both NAcc D1 and D2 MSNs, which encode positive and negative motivational valences, respectively. However, a circuit-based mechanism by which KOR modulation of excitation-inhibition balance modifies D1 and D2 MSN activity is lacking. Here, we provide a comprehensive synaptic framework wherein presynaptic KOR inhibition decreases the excitatory drive of D1 MSN activity by the amygdala, but not the hippocampus. Conversely, presynaptic inhibition by KORs of inhibitory synapses on D2 MSNs enhances integration of excitatory drive by the amygdala and hippocampus. In conclusion, we describe a circuit-based mechanism showing differential gating of afferent control of D1 and D2 MSN activity by KORs in a pathway-specific manner.

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Spatially Compact Neural Clusters in the Dorsal Striatum Encode Locomotion Relevant Information

Neuron. 2016 Oct 5;92(1):202-213. Epub 2016 Sep 22.

Barbera G, Liang B, Zhang L, Gerfen CR, Culurciello E, Chen R, Li Y, Lin DT.

An influential striatal model postulates that neural activities in the striatal direct and indirect pathways promote and inhibit movement, respectively. Normal behavior requires coordinated activity in the direct pathway to facilitate intended locomotion and indirect pathway to inhibit unwanted locomotion. In this striatal model, neuronal population activity is assumed to encode locomotion relevant information. Here, we propose a novel encoding mechanism for the dorsal striatum. We identified spatially compact neural clusters in both the direct and indirect pathways. Detailed characterization revealed similar cluster organization between the direct and indirect pathways, and cluster activities from both pathways were correlated with mouse locomotion velocities. Using machine-learning algorithms, cluster activities could be used to decode locomotion relevant behavioral states and locomotion velocity. We propose that neural clusters in the dorsal striatum encode locomotion relevant information and that coordinated activities of direct and indirect pathway neural clusters are required for normal striatal controlled behavior.

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Constituents and functional implications of the rat default mode network

Proc Natl Acad Sci U.S.A. 2016 Aug 2;113(31):E4541-7. Epub 2016 Jul 20.

Li-Ming Hsu, Xia Liang, Hong Gu, Julia K. Brynildsen, Jennifer A. Stark, Jessica A. Ash, Ching-Po Lin, Hanbing Lu, Peter R. Rapp, Elliot A. Stein, and Yihong Yang

The default mode network (DMN) has been suggested to support a variety of self-referential functions in humans and has been fractionated into subsystems based on distinct responses to cognitive tasks and functional connectivity architecture. Such subsystems are thought to reflect functional hierarchy and segregation within the network. Because preclinical models can inform translational studies of neuropsychiatric disorders, partitioning of the DMN in nonhuman species, which has previously not been reported, may inform both physiology and pathophysiology of the human DMN. In this study, we sought to identify constituents of the rat DMN using resting-state functional MRI (rs-fMRI) and diffusion tensor imaging. After identifying DMN using a group-level independent-component analysis on the rs-fMRI data, modularity analyses fractionated the DMN into an anterior and a posterior subsystem, which were further segregated into five modules. Diffusion tensor imaging tractography demonstrates a close relationship between fiber density and the functional connectivity between DMN regions, and provides anatomical evidence to support the detected DMN subsystems. Finally, distinct modulation was seen within and between these DMN subcomponents using a neurocognitive aging model. Taken together, these results suggest that, like the human DMN, the rat DMN can be partitioned into several subcomponents that may support distinct functions. These data encourage further investigation into the neurobiological mechanisms of DMN processing in preclinical models of both normal and disease states.

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Temporal Specificity of Reward Prediction Errors Signaled by Putative Dopamine Neurons in Rat VTA Depends on Ventral Striatum

Neuron. Volume 91, Issue 1, p182–193, 6 July 2016

Yuji K. Takahashi, Angela J. Langdon,Yael Niv, and Geoffrey Schoenbaum

Dopamine neurons signal reward prediction errors. This requires accurate reward predictions. It has been suggested that the ventral striatum provides these predictions. Here we tested this hypothesis by recording from putative dopamine neurons in the VTA of rats performing a task in which prediction errors were induced by shifting reward timing or number. In controls, the neurons exhibited error signals in response to both manipulations. However, dopamine neurons in rats with ipsilateral ventral striatal lesions exhibited errors only to changes in number and failed to respond to changes in timing of reward. These results, supported by computational modeling, indicate that predictions about the temporal specificity and the number of expected reward are dissociable and that dopaminergic prediction- error signals rely on the ventral striatum for the former but not the latter.

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Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

Mol Psychiatry. 2016 Apr 5. doi: 10.1038/mp.2016.48

Cadet JL, Brannock C, Krasnova IN, Jayanthi S, Ladenheim B, McCoy MT, Walther D, Godino A, Pirooznia M, Lee RS

Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)- and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage- and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

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The nutrient sensor OGT in PVN neurons regulates feeding

Science. 2016 Mar 18;351(6279):1293-6

Olof Lagerlöf, Julia E. Slocomb, Ingie Hong, Yeka Aponte, Seth Blackshaw, Gerald W. Hart, Richard L. Huganir

Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from aCaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGTwas associated with impaired satiety. These results identify O-GlcNAcylation in aCaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior.

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VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons

Nat Neurosci. 2016 Mar 28. doi: 10.1038/nn.4281. [Epub ahead of print]

Jia Qi, Shiliang Zhang, Hui-Ling Wang, David J Barker, Jorge Miranda-Barrientos & Marisela Morales

The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens glutamatergic pathway remains unknown. Here we report that nAcc photoactivation of mesoaccumbens glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens glutamatergic fibers lack GABA, the aversion evoked by their photoactivation depended on glutamate- and GABA-receptor signaling, and not on dopamine-receptor signaling. We found that mesoaccumbens glutamatergic fibers established multiple asymmetric synapses on single parvalbumin GABAergic interneurons and that nAcc photoactivation of these fibers drove AMPA-mediated cellular firing of parvalbumin GABAergic interneurons. These parvalbumin GABAergic interneurons in turn inhibited nAcc medium spiny output neurons, thereby controlling inhibitory neurotransmission in nAcc. To our knowledge, the mesoaccumbens glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin GABAergic interneurons.

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Aggregated single-walled carbon nanotubes attenuate the behavioural and neurochemical effects of methamphetamine in mice

Nat Nanotechnol. 2016 Mar 14. doi: 10.1038/nnano.2016.23. [Epub ahead of print]

Xue Xue, Jing-Yu Yang, Yi He, Li-Rong Wang, Ping Liu, Li-Sha Yu, Guo-Hua Bi, Ming-Ming Zhu, Yue-Yang Liu, Rong-Wu Xiang, Xiao-Ting Yang, Xin-Yu Fan, Xiao-Min Wang, Jia Qi, Hong-Jie Zhang, Tuo Wei, Wei Cui, Guang-Lu Ge, Zheng-Xiong Xi, Chun-FuWu, and Xing-Jie Liang

Methamphetamine (METH) abuse is a serious social and health problem worldwide. At present, there are no effective medications to treat METH addiction1. Here, we report that aggregated single-walled carbon nanotubes (aSWNTs) significantly inhibited METH self-administration, METH-induced conditioned place preference and METH- or cue-induced relapse to drugseeking behaviour in mice. The use of aSWNTs alone did not significantly alter the mesolimbic dopamine system, whereas pretreatment with aSWNTs attenuated METH-induced increases in extracellular dopamine in the ventral striatum. Electrochemical assays suggest that aSWNTs facilitated dopamine oxidation. In addition, aSWNTs attenuated METH-induced increases in tyrosine hydroxylase or synaptic protein expression. These findings suggest that aSWNTs may have therapeutic effects for treatment of METH addiction by oxidation of METH-enhanced extracellular dopamine in the striatum.

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Brief optogenetic inhibition of dopamine neurons mimics endogenous negative reward prediction errors

Nat Neurosci. 2015 Dec 7. doi: 10.1038/nn.4191.

Chun Yun Chang, Guillem R Esber, Yasmin Marrero-Garcia, Hau-Jie Yau, Antonello Bonci & Geoffrey Schoenbaum

Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. Although there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors. In the absence of such evidence, the effect of increases in firing could reflect novelty or salience, variables also correlated with dopamine activity. Here we provide evidence in support of the proposed linkage, showing in a modified Pavlovian over-expectation task that brief pauses in the firing of dopamine neurons in rat ventral tegmental area at the time of reward are sufficient to mimic the effects of endogenous negative prediction errors. These results support the proposal that brief changes in the firing of dopamine neurons serve as full-fledged bidirectional prediction error signals.

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Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatinremodeling factors at the nuclear envelope

Proc Natl Acad Sci USA. 2015 Nov 9. pii: 201518894. [Epub ahead of print]

Shang-Yi A. Tsai, Jian-Ying Chuang, Meng-Shan Tsia, Xiao-fei Wang, Zheng-Xiong Xi, Jan-Jong Hung, Wen-Chang Chang, Antonello Bonci, and Tsung-Ping Su

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER–mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of theMAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest theMAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

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Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer

PNAS June 22, 2015, doi: 10.1073/pnas.1507704112

Jordi Bonaventura, Gemma Navarro, Verònica Casadó-Anguera, Karima Azdad, William Rea, Estefanía Moreno, Marc Brugarolas, Josefa Mallol, Enric I. Canela, Carme Lluís, Antoni Cortés, Nora D. Volkow, Serge N. Schiffmann, Sergi Ferré, and Vicent Casadó

Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.

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Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

PNAS May 11, 2015, doi: 10.1073/pnas.1422001112

Shang-Yi A. Tsai, Michael J. Pokrass, Neal R. Klauer, Hiroshi Nohara, and Tsung-Ping Su

Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor’s interaction with myristic acid. In Sig-1R–KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R–KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R–KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.

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Mesopontine median raphe regulates hippocampal ripple oscillation and memory consolidation

Nat Neurosci. 2015 Apr 13. doi: 10.1038/nn.3998. [Epub ahead of print]

Dong V Wang, Hau-Jie Yau, Carl J Broker, Jen-Hui Tsou, Antonello Bonci, and Satoshi Ikemoto

Sharp wave-associated field oscillations (~200 Hz) of the hippocampus, referred to as ripples, are believed to be important for consolidation of explicit memory. Little is known about how ripples are regulated by other brain regions. We found that the median raphe region (MnR) is important for regulating hippocampal ripple activity and memory consolidation. We performed in vivo simultaneous recording in the MnR and hippocampus of mice and found that, when a group of MnR neurons was active, ripples were absent. Consistently, optogenetic stimulation of MnR neurons suppressed ripple activity and inhibition of these neurons increased ripple activity. Notably, using a fear conditioning procedure, we found that photostimulation of MnR neurons interfered with memory consolidation. Our results demonstrate a critical role of the MnR in regulating ripples and memory consolidation.

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Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment

Am J Psychiatry. 2015 Mar 17:appiajp201414081014. [Epub ahead of print]

Kowalczyk WJ, Phillips KA, Jobes ML, Kennedy AP, Ghitza UE, Agage DA, Schmittner JP, Epstein DH, Preston KL.

Objective: Theauthors testedwhetherclonidineblocks stressinduced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients’ stress to test hypotheses about clonidine’s behavioral mechanism of action.

Method: The authors conducted a randomized double-blind placebo-controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5–6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo(N=57) for 14weeks....

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Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons

Nature Neuroscience Published online 09 February 2015

Shiliang Zhang, Jia Qi, Xueping Li, Hui-Ling Wang, Jonathan P Britt, Alexander F Hoffman, Antonello Bonci, Carl R Lupica & Marisela Morales

Mesoaccumbens fibers are thought to co-release dopamine and glutamate. However, the mechanism is unclear, and co-release by mesoaccumbens fibers has not been documented. Using electron microcopy, we found that some mesoaccumbens fibers have vesicular transporters for dopamine (VMAT2) in axon segments that are continuous with axon terminals that lack VMAT2, but contain vesicular glutamate transporters type 2 (VGluT2). In vivo overexpression of VMAT2 did not change the segregation of the two vesicular types, suggesting the existence of highly regulated mechanisms for maintaining this segregation. The mesoaccumbens axon terminals containing VGluT2 vesicles make asymmetric synapses, commonly associated with excitatory signaling. Using optogenetics, we found that dopamine and glutamate were released from the same mesoaccumbens fibers. These findings reveal a complex type of signaling by mesoaccumbens fibers in which dopamine and glutamate can be released from the same axons, but are not normally released at the same site or from the same synaptic vesicles.

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Serotonergic versus Nonserotonergic Dorsal Raphe Projection Neurons: Differential Participation in Reward Circuitry

Cell Reports Volume 8, Issue 6, p1857–1869, 25 September 20143

Ross A. McDevitt, Alix Tiran-Cappello, Hui Shen, Israela Balderas, Jonathan P. Britt, Rosa A.M. Marino, Stephanie L. Chung, Christopher T. Richie, Brandon K. Harvey, and Antonello Bonci

The dorsal raphe nucleus (DRN) contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and nonserotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via nonserotonergic neurons, for which the main projection target is the ventral tegmental area (VTA). Furthermore, these nonserotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.

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Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice.

PNAS 2014 Nov 3. pii: 201413210. [Epub ahead of print]

Hai-Ying Zhang, Ming Gao, Qing-Rong Liu, Guo-Hua Bi, Xia Li, Hong-Ju Yang, Eliot L. Gardner, Jie Wu, and Zheng-Xiong Xi

Cannabinoid CB2 receptors (CB2Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB2Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB2 mRNA and CB2R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB2Rs by JWH133 or other CB2R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed inWT or CB1 -/- mice are blocked by CB2R antagonist and absent in CB2 -/- mice. These data suggest that CB2R-mediated reduction of VTA DA neuronal activity may underlie JWH133’s modulation of DA-regulated behaviors.

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A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons

Nature Communications 5, Article number: 5390

Jia Qi, Shiliang Zhang, Hui-Ling Wang, Huikun Wang, Jose de Jesus Aceves Buendia, Alexander F. Hoffman, Carl R. Lupica, Rebecca P. Seal, and Marisela Morales

Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibres of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibres have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release in nucleus accumbens. Activation also reinforces instrumental behaviour and establishes conditioned place preferences. These findings indicate that the DR–VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR—one of the most sensitive reward sites in the brain—to VTA dopaminergic neurons.

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Single rodent mesohabenular axons release glutamate and GABA

Nature Neuroscience (2014) doi:10.1038/nn.3823

David H Root, Carlos A Mejias-Aponte, Shiliang Zhang, Hui-Ling Wang, Alexander F Hoffman, Carl R Lupica, & Marisela Morales

The lateral habenula (LHb) is involved in reward, aversion, addiction and depression through descending interactions with several brain structures, including the ventral tegmental area (VTA). The VTA provides reciprocal inputs to LHb, but their actions are unclear. Here we show that the majority of rat and mouse VTA neurons innervating LHb coexpress markers for both glutamate signaling (vesicular glutamate transporter 2; VGluT2) and GABA signaling (glutamic acid decarboxylase; GAD, and vesicular GABA transporter; VGaT). A single axon from these mesohabenular neurons coexpresses VGluT2 protein and VGaT protein and, surprisingly, establishes symmetric and asymmetric synapses on LHb neurons. In LHb slices, light activation of mesohabenular fibers expressing channelrhodopsin2 driven by VGluT2 (Slc17a6) or VGaT (Slc32a1) promoters elicits release of both glutamate and GABA onto single LHb neurons. In vivo light activation of mesohabenular terminals inhibits or excites LHb neurons. Our findings reveal an unanticipated type of VTA neuron that cotransmits glutamate and GABA and provides the majority of mesohabenular inputs.

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Orbitofrontal activation restores insight lost after cocaine use

Nature Neuroscience (2014) doi:10.1038/nn.3763

Federica Lucantonio, Yuji K Takahashi, Alexander F Hoffman, Chun Chang, Sheena Bali-Chaudhary, Yavin Shaham, Carl R Lupica, & Geoffrey Schoenbaum

Addiction is characterized by a lack of insight into the likely outcomes of one’s behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

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Orbitofrontal neurons infer the value and identity of predicted outcomes

Nature Communications 5:3926 | DOI: 10.1038/ncomms4926

Thomas A. Stalnaker, Nisha K. Cooch, Michael A. McDannald, Tzu-Lan Liu, Heather Wied, & Geoffrey Schoenbaum

The best way to respond flexibly to changes in the environment is to anticipate them. Such anticipation often benefits us if we can infer that a change has occurred, before we have actually experienced the effects of that change. Here we test for neural correlates of this process by recording single-unit activity in the orbitofrontal cortex in rats performing a choice task in which the available rewards changed across blocks of trials. Consistent with the proposal that orbitofrontal cortex signals inferred information, firing changes at the start of each new block as if predicting the not-yet-experienced reward. This change occurs whether the new reward is different in number of drops, requiring signalling of a new value, or in flavour, requiring signalling of a new sensory feature. These results show that orbitofrontal neurons provide a behaviourally relevant signal that reflects inferences about both value-relevant and value-neutral information about impending outcomes....

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Critical Role of Peripheral Vasoconstriction in Fatal Brain Hyperthermia Induced by MDMA (Ecstasy) under Conditions That Mimic Human Drug Use

J. Neurosci June 4, 2014 - 34(23):7754–7762

Eugene A. Kiyatkin, Albert H. Kim, Ken T. Wakabayashi, Michael H. Baumann, and Yavin Shaham

MDMA(Ecstasy) is an illicit drug used by young adults at hot, crowed “rave” parties, yet the data on potential health hazards of its abuse remain controversial. Here, we examined the effect of MDMA on temperature homeostasis in male rats under standard laboratory conditions and under conditions that simulate drug use in humans.Wechronically implanted thermocouple microsensors in the nucleus accumbens (a brain reward area), temporal muscle, and facial skin to measure temperature continuously from freely moving rats....

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Large-Scale Brain Network Coupling Predicts Acute Nicotine Abstinence Effects on Craving and Cognitive Function

JAMA Psychiatry 2014;():. doi:10.1001/jamapsychiatry.2013.4109.

Caryn Lerman, Hong Gu, James Loughead, Kosha Ruparel, Yihong Yang, & Elliot A. Stein

IMPORTANCE Interactions of large-scale brain networks may underlie cognitive dysfunctions in psychiatric and addictive disorders.

OBJECTIVES To test the hypothesis that the strength of coupling among 3 large-scale brain networks—salience, executive control, and default mode—will reflect the state of nicotine withdrawal (vs smoking satiety) and will predict abstinence-induced craving and cognitive deficits and to develop a resource allocation index (RAI) that reflects the combined strength of interactions among the 3 large-scale networks....

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Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Nature Neuroscience 17, 232–239 (2014)

Wei Xiong, Shao-Rui Chen, Liming He, Kejun Cheng, Yi-Lin Zhao, Hong Chen, De-Pei Li, Gregg E Homanics, John Peever, Kenner C Rice, Ling-gang Wu, Hui-Lin Pan & Li Zhang

Although postsynaptic glycine receptors (GlyRs) as αβ heteromers attract considerable research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing point mutations in α1 GlyRs that are responsible for a hereditary startle-hyperekplexia disease....

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Neural Estimates of Imagined Outcomes in the Orbitofrontal Cortex Drive Behavior and Learning

Neuron Volume 80, Issue 2, 507-518, 16 October 2013

Yuji K. Takahashi, Chun Yun Chang, Federica Lucantonio, Richard Z. Haney, Benjamin A. Berg, Hau-Jie Yau, Antonello Bonci, and Geoffrey Schoenbaum

Imagination, defined as the ability to interpret reality in ways that diverge from past experience, is fundamental to adaptive behavior. This can be seen at a simple level in our capacity to predict novel outcomes in new situations. The ability to anticipate outcomes never before received can also influence learning if those imagined outcomes are not received....

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Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

Nature Neuroscience published online 13 October 2013; doi:10.1038/nn.3540

Zuzana Justinova, Paola Mascia, Hui-Qiu Wu, Maria E Secci, Godfrey H Redhi, Leigh V Panlilio, Maria Scherma, Chanel Barnes, Alexandra Parashos, Tamara Zara, Walter Fratta, Marcello Solinas, Marco Pistis, Jack Bergman, Brian D Kangas, Sergi Ferré, Gianluigi Tanda, Robert Schwarcz, and Steven R Goldberg

In the reward circuitry of the brain, a-7-nicotinic acetylcholine receptors (a7nAChRs) modulate effects of Δ9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of a7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels....

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Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake

Nature Neuroscience 16, 1094–1100 (2013) doi:10.1038/nn.3445

Taban Seif, Shao-Ju Chang, Jeffrey A Simms, Stuart L Gibb, Jahan Dadgar, Billy T Chen, Brandon K Harvey, Dorit Ron, Robert O Messing, Antonello Bonci, & F Woodward Hopf

Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats....

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Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking

Nature 496, 359 362 (18 April 2013) doi:10.1038/nature12024

Billy T. Chen, Hau-Jie Yau, Christina Hatch, Ikue Kusumoto-Yoshida, Saemi L. Cho, F. Woodward Hopf, and Antonello Bonci

Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking....

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NIH Director's Blog Highlights this Paper (off-site link to NIH)

Risk-Responsive Orbitofrontal Neurons Track Acquired Salience

Neuron 2013 Jan 23; Volume 77, Issue 2, 251-258

Masaaki Ogawa, Matthijs A.A. van der Meer, Guillem R. Esber, Domenic H. Cerri, Thomas A. Stalnaker, and Geoffrey Schoenbaum

Decision making is impacted by uncertainty and risk (i.e., variance). Activity in the orbitofrontal cortex, an area implicated in decision making, covaries with these quantities. However, this activity could reflect the heightened salience of situations in which multiple outcomes reward and reward omission  are expected. To resolve these accounts, rats were trained to respond to cues predicting 100%, 67%, 33%, or 0% reward. Consistent with prior reports, some orbitofrontal neurons fired differently in anticipation of uncertain (33% and 67%) versus certain (100% and 0%) reward....

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Dynamic Interaction between Sigma-1 Receptor and Kv1.2 Shapes Neuronal and Behavioral Responses to Cocaine

Cell 2013 Jan 17;152(1-2):236-47. doi: 10.1016/j.cell.2012.12.004.

Kourrich S, Hayashi T, Chuang JY, Tsai SY, Su TP, Bonci A.

The sigma-1 receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an interorganelle signaling modulator that potentially plays a role in drug-seeking behaviors. However, the brain site of action and underlying cellular mechanisms remain unidentified. We found that cocaine exposure triggers a Sig-1R-dependent upregulation of D-type K+ current in the nucleus accumbens (NAc) that results in neuronal hypoactivity and thereby enhances behavioral cocaine response....

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Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens.

Neuron 2012 Nov 21;76(4):790-803. doi: 10.1016/j.neuron.2012.09.040.

Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A.

Excitatory afferents to the nucleus accumbens (NAc) are thought to facilitate reward seeking by encoding reward-associated cues. Selective activation of different glutamatergic inputs to the NAc can produce divergent physiological and behavioral responses, but mechanistic explanations for these pathway-specific effects are lacking. Here, we compared the innervation patterns and synaptic properties of ventral hippocampus, basolateral amygdala, and prefrontal cortex input to the NAc. Ventral hippocampal input was found to be uniquely localized to the medial NAc shell, where it was predominant and selectively potentiated after cocaine exposure....

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Orbitofrontal Cortex Supports Behavior and Learning Using Inferred But Not Cached Values

SCIENCE 16 November 2012: Vol. 338 no. 6109 pp. 953-956

Joshua L. Jones, Guillem R. Esber, Michael A. McDannald, Aaron J. Gruber, Alex Hernandez, Aaron Mirenzi, Geoffrey Schoenbaum

Computational and learning theory models propose that behavioral control reflects value that is both cached (computed and stored during previous experience) and inferred (estimated on the fly on the basis of knowledge of the causal structure of the environment). The latter is thought to depend on the orbitofrontal cortex. Yet some accounts propose that the orbitofrontal cortex contributes to behavior by signaling economic  value, regardless of the associative basis of the information. We found that the orbitofrontal cortex is critical for both value-based behavior and learning when value must be inferred but not when a cached value is sufficient. The orbitofrontal cortex is thus fundamental for accessing model-based representations of the environment to compute value rather than for signaling value per se....

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Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization

NATURE NEUROSCIENCE 2012 Sep 30. doi: 10.1038/nn.3232. [Epub ahead of print]

Eisuke Koya, Fabio C Cruz, Robert Ator, Sam A Golden, Alexander F Hoffman, Carl R Lupica, & Bruce T Hope

Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved....

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Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors

Nature Neuroscience advance online publication 30 October 2011; doi: 10.1038/nn.2940

Elena E Bagley, Jennifer Hacker, Vladimir I Chefer, Christophe Mallet, Gavan P McNally, Billy C H Chieng, Julie Perroud, Toni S Shippenberg, MacDonald J Christie

Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations....

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Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain

Molecular Psychiatry advance online publication 16 August 2011; doi: 10.1038/mp.2011.93

S González, C Rangel-Barajas, M Peper, R Lorenzo, E Moreno, F Ciruela, J Borycz, J Ortiz, C Lluís, R Franco, PJ McCormick, ND Volkow, M Rubinstein, B Floran, & S Ferre

Polymorphic variants of the dopamine D4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D4.4) and the 2-repeat (D4.2) variants form functional heteromers with the short isoform of the dopamine D2 receptor (D2S), the 7-repeat risk allele (D4.7) does not....

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Brain cannabinoid CB2 receptors modulate cocaine's actions in mice

NATURE NEUROSCIENCE doi:10.1038/nn.2874

Zheng-Xiong Xi, Xiao-Qing Peng, Xia Li, Rui Song, Hai-Ying Zhang, Qing-Rong Liu, Hong-Ju Yang, Guo-Hua Bi, Jie Li & Eliot L Gardner

The presence and function of cannabinoid CB2 receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB1-/-, also known as Cnr1-/-) mice, but not in CB2-/- (Cnr2-/-) mice....

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Linking Context with Reward: A Functional Circuit from Hippocampal CA3 to Ventral Tegmental Area

SCIENCE 10.1126/science.1204622

Alice H. Luo, Pouya Tahsili-Fahadan, Roy A. Wise, Carl R. Lupica, Gary Aston-Jones

Reward-motivated behavior is strongly influenced by the learned significance of contextual stimuli in the environment. However, the neural pathways that mediate context-reward relations are not well understood. We have identified a circuit from area CA3 of dorsal hippocampus to ventral tegmental area (VTA) that uses lateral septum (LS) as a relay. Theta frequency stimulation of CA3 excited VTA dopamine (DA) neurons and inhibited non-DA neurons. DA neuron excitation was likely mediated by disinhibition because local antagonism of g-aminobutyric acid receptors blocked responses to CA3 stimulation....

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