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In this Review, Lüscher and Lüthi draw some parallels between anxiety and addiction disorders as diseases of the brain's emotional valence system. The authors present an update on the anatomy and heterogeneity of the fear and reward circuitries, analyze our understanding of the synaptic and cellular mechanisms thought to underlie the two conditions and discuss recent studies causally linking the resulting circuit dysfunctions and alterations in behavior. Current models of addiction and anxiety stem from the idea that aberrant function and remodeling of neural circuits cause the pathological behaviors. According to this hypothesis, a disease-defining experience (for example, drug reward or stress) would trigger specific forms of synaptic plasticity, which in susceptible subjects would become persistent and lead to the disease. While the notion of synaptic diseases has received much attention, no candidate disorder has been sufficiently investigated to yield new, rational therapies that could be tested in the clinic. Here we review the arguments in favor of abnormal neuronal plasticity underlying addiction and anxiety disorders, with a focus on the functional diversity of neurons that make up the circuits involved. We argue that future research must strive to obtain a comprehensive description of the relevant functional anatomy. This will allow identification of molecular mechanisms that govern the induction and expression of disease-relevant plasticity in identified neurons. To establish causality, one will have to test whether normalization of function can reverse pathological behavior. With these elements in hand, it will be possible to propose blueprints for manipulations to be tested in translational studies. The challenge is daunting, but new techniques, above all optogenetics, may enable decisive advances.

Compulsion is a cardinal symptom of drug addiction (severe substance use disorder). However, compulsion is observed in only a small proportion of individuals who repeatedly seek and use addictive substances. Here, we integrate accounts of the neuropharmacological mechanisms that underlie the transition to compulsion with overarching learning theories, to outline how compulsion develops in addiction. Importantly, we emphasize the conceptual distinctions between compulsive drug-seeking behaviour and compulsive drug-taking behaviour (that is, use). In the latter, an individual cannot stop using a drug despite major negative consequences, possibly reflecting an imbalance in frontostriatal circuits that encode reward and aversion. By contrast, an individual may compulsively seek drugs (that is, persist in seeking drugs despite the negative consequences of doing so) when the neural systems that underlie habitual behaviour dominate goal-directed behavioural systems, and when executive control over this maladaptive behaviour is diminished. This distinction between different aspects of addiction may help to identify its neural substrates and new treatment strategies.Compulsion is a key symptom of drug addiction. In this Review, Lüscher, Robbins and Everitt integrate the neural and psychological mechanisms that underlie the transition to compulsion within a learning theory framework, highlighting the distinctions between compulsive drug taking and compulsive drug seeking.

Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion 1 – 4 . The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N -methyl- d -aspartic acid (NMDA) receptor (NMDAR) antagonism 5 , 6 . Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability. Experiments in mice show that although ketamine has positive reinforcement properties, which are driven by its action on the dopamine system, it does not induce the synaptic plasticity that is typically observed with addiction.

Circuit remodeling driven by pathological forms of synaptic plasticity underlies several psychiatric diseases, including addiction. Deep brain stimulation (DBS) has been applied to treat a number of neurological and psychiatric conditions, although its effects are transient and mediated by largely unknown mechanisms. Recently, optogenetic protocols that restore normal transmission at identified synapses in mice have provided proof of the idea that cocaine-adaptive behavior can be reversed in vivo. The most efficient protocol relies on the activation of metabotropic glutamate receptors, mGluRs, which depotentiates excitatory synaptic inputs onto dopamine D1 receptor medium-sized spiny neurons and normalizes drug-adaptive behavior. We discovered that acute low-frequency DBS, refined by selective blockade of dopamine D1 receptors, mimics optogenetic mGluR-dependent normalization of synaptic transmission. Consequently, there was a long-lasting abolishment of behavioral sensitization.

Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA ( N -methyl- d -aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders. Information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Cocaine-induced brain changes that lead to relapse Addictive drugs are thought to hijack the neural circuits in integrative brain centres, such as the nucleus accumbens, that send signals to various brain regions to control behavioural responses. Drug-associated cues can become powerful triggers of drug-seeking behaviour because of such manipulations, increasing the chance of relapse after the cessation of drug-taking. Here Christian Lüscher and colleagues identify cocaine-evoked alterations to specific neural pathways in projections from the prefrontal cortex or ventral hippocampus that interact with separate dopaminergic populations in the nucleus accumbens of mice. Manipulation of drug-induced plasticity within both these pathways abolishes drug-seeking behaviour, whereas disrupting plasticity in just one pathway impairs drug-response discrimination or the vigour of cue responses. These findings reveal the plasticity mechanisms underlying information integration at the nucleus accumbens and show how drugs like cocaine can alter this plasticity to permit relapse.

Activation of the mesolimbic dopamine system reinforces goal-directed behaviours. With repetitive stimulation—for example, by chronic drug abuse—the reinforcement may become compulsive and intake continues even in the face of major negative consequences. Here we gave mice the opportunity to optogenetically self-stimulate dopaminergic neurons and observed that only a fraction of mice persevered if they had to endure an electric shock. Compulsive lever pressing was associated with an activity peak in the projection terminals from the orbitofrontal cortex (OFC) to the dorsal striatum. Although brief inhibition of OFC neurons temporarily relieved compulsive reinforcement, we found that transmission from the OFC to the striatum was permanently potentiated in persevering mice. To establish causality, we potentiated these synapses in vivo in mice that stopped optogenetic self-stimulation of dopamine neurons because of punishment; this led to compulsive lever pressing, whereas depotentiation in persevering mice had the converse effect. In summary, synaptic potentiation of transmission from the OFC to the dorsal striatum drives compulsive reinforcement, a defining symptom of addiction. In mice, synaptic potentiation of transmission from the orbitofrontal cortex to the dorsal striatum drives compulsive reinforcement, a defining symptom of addiction.

Drugs of abuse induce long-lasting changes in neural circuits that may underlie core components of addiction. Here we focus on glutamatergic synapses onto dopamine (DA) neurons of the ventral tegmental area (VTA). Using an ' ex vivo ' approach in mice, we show that a single injection of cocaine caused strong rectification and conferred sensitivity to the polyamine Joro spider toxin (JST) of AMPAR-mediated excitatory postsynaptic currents (AMPAR EPSCs), indicating the recruitment of receptors that lack GluR2. This qualitative change in transmission was paralleled by an increase in the AMPAR:NMDAR ratio and was prevented by interfering with the protein interacting with C kinase-1 (PICK1) in vivo . Activation of metabotropic glutamate receptors (mGluR1s) by intraperitoneal injection of a positive modulator depotentiated synapses and abolished rectification in slices of cocaine-treated mice, revealing a mechanism to reverse cocaine-induced synaptic plasticity in vivo .

In mice, cocaine is found to potentiate excitatory transmission in medium-sized spiny neurons expressing the type-1 dopamine receptor; depotentiation reversed cocaine-induced locomotor sensitization, raising the possibility of novel treatments for addiction. Cocaine effects reversible Synaptic plasticity is known to occur in drug addiction, but there is little evidence to link drug-evoked plasticity to the behavioural adaptations seen in drug-addicted animals. Pascoli et al . report that specific potentiation in dopaminergic neurons expressing the type I dopamine receptor causes the locomotor sensitization often observed in animals exposed to cocaine. Specific depotentiation of this pathway using optogenetics both restores normal synaptic transmission and eliminates the behavioural phenotype. These data link synaptic potentiation of D1R-expressing neurons to drug-evoked behaviour, and suggest that therapeutic reversal of cocaine-induced adaptive synaptic changes could lead to behavioural corrections. Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction 1 . Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing 2 and early neuroadaptive effects 3 by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphorylation of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens 4 is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation 5 as well as in several behavioural adaptations 6 , 7 , 8 . A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in D1-receptor-expressing medium-sized spiny neurons (D1R-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in D1R-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation.

Key Points G protein-gated inwardly rectifying K + (GIRK) channels hyperpolarize neurons, reducing membrane excitability. The basal activity of GIRK channels contributes to the resting potential of neurons, whereas activation of different G protein-coupled receptors (GPCRs) controls the excitability of neurons through GIRK-mediated neuronal self-inhibition (that is, the neurotransmitter released by a given neuron leads to inhibition of that neuron), neuron-to-neuron inhibition (that is, through a slow inhibitory postsynaptic potential) and network-level inhibition (that is, volume transmission). High-resolution structures of cytoplasmic domains of GIRK channels provide a new 'toolbox' for investigating the molecular mechanisms underlying the gating and function of GIRK channels. Brain slice electrophysiology provides several examples of plasticity in the slow IPSCs mediated by GIRK channels that are activated by GABA B (γ-aminobutyric acid type B) receptors and D2 dopamine receptors. In addition, activation of GIRK channels by adenosine is implicated in reversing long-term potentiation of glutamatergic transmission (depotentiation). Studies on GIRK-knockout mice suggest GIRK channels are involved in pain perception mediated by endogenous pain modulators such as endorphins and endocannabinoids, and also analgesic drugs. GIRK channels have also been implicated in the response to some drugs of abuse, including morphine, γ-hydroxybutyrate, amphetamines and ethanol, as well as some therapeutic drugs. GIRK channels may contribute to the pathophysiology of several diseases, including epilepsy, addiction, Down's syndrome, ataxia and Parkinson's disease. Loss of GIRK function can lead to excessive neuronal excitability, contributing to epileptic seizures, whereas a gain of GIRK function can substantially reduce neural activity, as is postulated to occur in Down's syndrome. Activation of GIRK channels decreases the excitability of neurons. Lüscher and Slesinger discuss the subunit composition and function of GIRK channels in several brain regions and the possible role of GIRK channel dysfunction in neurological diseases such as epilepsy, Down's syndrome and drug addiction. G protein-gated inwardly rectifying potassium (GIRK) channels hyperpolarize neurons in response to activation of many different G protein-coupled receptors and thus control the excitability of neurons through GIRK-mediated self-inhibition, slow synaptic potentials and volume transmission. GIRK channel function and trafficking are highly dependent on the channel subunit composition. Pharmacological investigations of GIRK channels and studies in animal models suggest that GIRK activity has an important role in physiological responses, including pain perception and memory modulation. Moreover, abnormal GIRK function has been implicated in altering neuronal excitability and cell death, which may be important in the pathophysiology of diseases such as epilepsy, Down's syndrome, Parkinson's disease and drug addiction. GIRK channels may therefore prove to be a valuable new therapeutic target.

The authors show that downregulation of SHANK3 in the VTA induces cell specific changes in DA and GABA neurons that converge to generate social behavioral deficits. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) ameliorates synaptic, circuit and behavioral deficits. Haploinsufficiency of SHANK3 , encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank 3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.