SUMMARY 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.

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems.

Sensitivity to reinforcement from methamphetamine (MA) likely influences risk for MA addiction, and genetic differences are one source of individual variation. Generation of two sets of selectively bred mouse lines for high and low MA drinking has shown that genetic factors influence MA intake, and pronounced differences in sensitivity to rewarding and aversive effects of MA play a significant role. Further validation of these lines as a unique genetic model relevant to MA addiction was obtained using operant methods to study MA reinforcement. High and low MA drinking line mice were used to test the hypotheses that: 1) oral and intracerebroventricular (ICV) MA serve as behavioral reinforcers, and 2) MA exhibits greater reinforcing efficacy in high than low MA drinking mice. Operant responses resulted in access to an MA or non-MA drinking tube or intracranial delivery of MA. Behavioral activation consequent to orally consumed MA was determined. MA available for consumption maintained higher levels of reinforced instrumental responding in high than low MA drinking line mice, and MA intake in the oral operant procedure was greater in high than low MA drinking line mice. Behavioral activation was associated with amount of MA consumed during operant sessions. High line mice delivered more MA via ICV infusion than did low line mice across a range of doses. Thus, genetic risk factors play a critical role in the reinforcing efficacy of MA and the oral self-administration procedure is suitable for delineating genetic contributions to MA reinforcement.

Background: The c-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol).Methods: In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABA A receptor agonist muscimol, and the GABA B receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined.Results: NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response.Conclusions: These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABA A receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABA B receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABA B receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders.

Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum. The mechanisms driving this vulnerability are poorly understood. In this study, we found that downregulating D2R expression selectively in striatal indirect-pathway neurons triggers a multitude of changes in D1 receptor (D1R)-expressing direct-pathway neurons, which comprise the other main subpopulation of striatal projection neurons. These changes include a leftward shift in the dose-response to a D1-like agonist that indicates a behavioral D1R hypersensitivity, a shift from PKA to ERK intracellular signaling cascades upon D1R activation, and a reduction in the density of bridging collaterals from D1R-expressing neurons to pallidal areas. We hypothesize that the D1R hypersensitivity underlies abuse vulnerability by facilitating the behavioral responses to repeated cocaine, such as locomotor sensitization and drug self-administration. We found evidence that littermate control mice develop D1R hypersensitivity after they are sensitized to cocaine. Indeed, D1-like agonist and cocaine cross-sensitize in control littermates and this effect was potentiated in mice lacking striatal D2Rs from indirect-pathway neurons. To our surprise, mice with low striatal D2Rs acquired cocaine self-administration similarly to littermate controls and showed no significant change in motivation to take cocaine but lower seeking. These findings indicate that downregulation of striatal D2Rs triggers D1R hypersensitivity to facilitate cocaine locomotor sensitization, which by itself was not associated with greater cocaine taking or seeking under the conditions tested.

Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well‐suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit‐wide restructuring of local and long‐range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine‐dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place.

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Bipolar disorder is associated with very high rates of substance abuse. However, few clinical trials are reported in this population. Naltrexone is effective for alcohol dependence, but its safety and efficacy are not established in patients with bipolar disorder and alcohol dependence. A 16-week, open-label, add-on pilot study of naltrexone was conducted in 34 outpatients with bipolar disorder and alcohol dependence. Assessments included the 17-item Hamilton Rating Scale for Depression (HRSD-17), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and an alcohol craving scale. Alcohol use was quantified. Significant improvement was observed in the HRSD-17 and YMRS, and days of alcohol use and craving decreased significantly. Naltrexone was well tolerated. Controlled trials are warranted.