The dorsal striatum plays an important role in the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using a novel approach that relies on the viral-mediated expression of an engineered GPCR (hM4D), we demonstrated that activation of hM4D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM4D receptors were selectively expressed in either direct or indirect pathway neurons in rats, CNO did not change acute locomotor responses to amphetamine but altered behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behaviors such as sensitization.

Addiction is a chronic relapsing disorder characterized by the loss of control over drug intake, high motivation to obtain drug, and a persistent craving for the drug. Accumulating evidence implicates cellular and molecular alterations within cortico-basal ganglia-thalamic circuitry in the development and persistence of this disease. The striatum is a heterogeneous structure that sits at the interface of this circuit, receiving input from a variety of brain regions (e.g., prefrontal cortex, ventral tegmental area) to guide behavioral output, including motor planning, decision-making, motivation and reward. However, the vast interconnectivity of this circuit has made it difficult to isolate how individual projections and cellular subtypes within this circuit modulate each of the facets of addiction. Here, we review the use of new technologies, including optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), in unraveling the role of the striatum in addiction. In particular, we focus on the role of striatal cell populations (i.e., direct and indirect pathway medium spiny neurons) and striatal dopaminergic and glutamatergic afferents in addiction-related plasticity and behaviors.

Substance use disorder (SUD) is a chronic, relapsing disease with a highly multifaceted pathology that includes (but is not limited to) sensitivity to drug-associated cues, negative affect, and motivation to maintain drug consumption. SUDs are highly prevalent, with 35 million people meeting criteria for SUD. While drug use and addiction are highly studied, most investigations of SUDs examine drug use in isolation, rather than in the more prevalent context of comorbid substance histories. Indeed, 11.3% of individuals diagnosed with a SUD have concurrent alcohol and illicit drug use disorders. Furthermore, having a SUD with one substance increases susceptibility to developing dependence on additional substances. For example, the increased risk of developing heroin dependence is twofold for alcohol misusers, threefold for cannabis users, 15fold for cocaine users, and 40-fold for prescription misusers. Given the prevalence and risk associated with polysubstance use and current public health crises, examining these disorders through the lens of co-use is essential for translatability and improved treatment efficacy. The escalating economic and social costs and continued rise in drug use has spurred interest in developing preclinical models that effectively model this phenomenon. Here, we review the current state of the field in understanding the behavioral and neural circuitry in the context of co-use with common pairings of alcohol, nicotine, cannabis, and other addictive substances. Moreover, we outline key considerations when developing polysubstance models, including challenges to developing preclinical models to provide insights and improve treatment outcomes.

These data validate gaps in primary care practices in obtaining family history of cancer, as well as lack of confidence in explaining genetic test results and in tailoring recommendations based on the tests.

The lateral habenula (LHb) is part of the habenula complex of the dorsal thalamus. Recent studies of the LHb have focused on its projections to the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg), which contain GABAergic neurons that mediate reward prediction error via inhibition of dopaminergic activity. However, older studies in the rat have also identified LHb outputs to the lateral and posterior hypothalamus, median raphe, dorsal raphe, and dorsal tegmentum. Although these studies have shown that the medial and lateral divisions of the LHb have somewhat distinct projections, the topographic specificity of LHb efferents is not completely understood, and the relative extent of these projections to brainstem targets is unknown. Here we have used anterograde tracing with adeno-associated virus mediated expression of green fluorescent protein, combined with serial two-photon tomography, to map the efferents of the LHb on a standard coordinate system for the entire mouse brain, and reconstruct the efferent pathways of the LHb in three dimensions. Using automated quantitation of fiber density, we show that in addition to the RMTg, the median raphe, caudal dorsal raphe, and pontine central gray are major recipients of LHb efferents. Using retrograde tract tracing with cholera toxin subunit B, we show that LHb neurons projecting to the hypothalamus, VTA, median raphe, and caudal dorsal raphe, and pontine central gray reside in characteristic, but sometimes overlapping regions of the LHb. Together these results provide the anatomical basis for systematic studies of LHb function in neural circuits and behavior in mice.

The rapid delivery of drugs of abuse to the brain is thought to promote addiction, but why this occurs is unknown. In the present study, we characterized the influence of rate of intravenous cocaine infusion (5-100 sec) on three effects thought to contribute to its addiction liability: its ability to block dopamine (DA) uptake, to activate immediate early gene expression, and to produce psychomotor sensitization. Rapid infusions potentiated the ability of cocaine to block DA reuptake, to induce c-fos and arc mRNA expression, especially in mesocorticolimbic regions, and to produce psychomotor sensitization. Thus, the rate at which cocaine is delivered influences both its neurobiological impact and its ability to induce a form of drug experience-dependent plasticity implicated in addiction. We propose that rapidly delivered cocaine may be more addictive, in part, because this more readily induces forms of neurobehavioral plasticity that lead to the compulsive pursuit of drugs.

The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.

Whether serotonin-1B (5-HT(1B)) receptor activation enhances or diminishes the reinforcing properties of psychostimulants remains unclear. We have previously shown that increased expression of 5-HT(1B) receptors in nucleus accumbens (NAcc) shell neurons sensitized rats to the locomotor-stimulating and rewarding properties of cocaine. In this study we further examined the contribution of 5-HT(1B) receptors on the effect of cocaine under conditions intended to selectively influence either conditioned place preference or avoidance (CPP or CPA, respectively). Viral-mediated gene transfer techniques were used to overexpress 5-HT(1B) receptors in medial NAcc shell medium spiny neurons projecting to the ventral tegmental area. Animals were then conditioned to associate place cues with the effects of either a low (5 mg/kg) or moderately high (20 mg/kg) dosage of cocaine immediately or 45 min after intraperitoneal cocaine administration. Animals with increased 5-HT(1B) expression showed cocaine-induced CPP immediately after administration of the low 5 mg/kg dose of cocaine, but a CPA 45 min after administration of the high 20 mg/kg dose. Control animals showed no preference at the 5 mg/kg dose and a significant preference at 20 mg/kg. Given this, we believe that increased 5-HT(1B) receptor activation in NAcc shell projection neurons intensifies both the rewarding and negative properties of cocaine use.