Targets For Treatment Of Addiction Research Articles

Dorsal Raphe Nucleus 5-HT Neurons: A New Target for Rewarding Regulation and Drug Addiction

In current paper, we reviewed the functional mechanisms of Dorsal Raphe Nucleus (DRN) 5-HT neurons in rewarding regulation and drug addiction in the level of molecular, neuron and neural circuits. Furtherly, we prospected that the DRN 5-HT neurons might be a new drug target for addiction treatment in future.

NBQX attenuates relapse of nicotine seeking but not nicotine and methamphetamine self-administration in rats

Objective Pharmacological manipulations of glutamatergic ionotropic receptors have been suggested as a promising target for addiction treatment. Antagonists of AMPA/kainate receptors were shown to reduce alcohol intake or alcohol-seeking in various animal models. In this study, we evaluated the effect of NBQX, an AMPA/kainate receptor antagonist, on methamphetamine (METH) and nicotine self-administration in rats. Methods Male Wistar rats were trained to self-administer METH (0.08 mg/kg per infusion, session of 90 min) and nicotine (0.03 mg/kg per infusion, session of 60 min) under the fixed ratio 1 schedule of reinforcement. The maintenance training was 2 weeks. During the second week, NBQX was injected subcutaneously at doses of 5 or 10 mg/kg 20 min before the session or intravenously (IV) at doses of 1 and 5 mg/kg 10 min before the session. Following the maintenance training, rats were subjected to forced abstinence for 2 weeks and 1 day of the drug-free relapse-like session with IV NBQX treatment performed as before. Results Although NBQX did not affect nicotine maintenance, it significantly suppressed the drug-paired responding in the relapse session. Regarding METH, NBQX did not exert a significant effect at either phase of the study. Conclusions These findings suggest selective involvement of AMPA/kainate receptors in the relapse of nicotine seeking after a period of forced abstinence.

The Developmental Neuroepigenetics of Substance Abuse

Advances in technology have allowed for the expansion of the field of epigenetics, providing a deeper understanding of gene-environment interactions. Investigations into the neurobiological basis of substance abuse have benefitted from these advances, with findings suggesting that epigenetic mechanisms underlie drug-induced modifications of brain morphology, synaptic plasticity, and behavior. Epigenetic marks likely mediate the long-lasting and potentially transgenerational alterations of neuronal chromatin and subsequent gene expression that may lead to persistent relapse vulnerability and/or offspring vulnerability to addiction. Understanding the epigenetic mechanisms as well as potential sensitive windows for these alterations may provide novel insight into how epigenetics factor into the individual vulnerability and unique time periods for added vulnerability to illicit drug exposure. In the current review, we outline recent literature that provides evidence for early epigenetic changes in several addiction models. We begin the review with an overview of epigenetics as they relate to drug use and abuse, and next focus on findings in the context of prenatal, childhood, and adolescent stages with additional references to adult models of addiction. Further, we also focus on studies that discuss the transgenerational inheritance of epigenetic changes, and how they may affect the individual across development. Lastly, the work presented here and potential future studies focus on demonstrating early disruptions in epigenetic marks following acute or repeated drug exposure that may be of relevance in the broader goal of identifying risk factors and novel targets for addiction treatment.

Thalamic mast cell activity is associated with sign-tracking behavior in rats

Mast cells are resident immune cells in the thalamus that can degranulate and release hundreds of signaling molecules (i.e., monoamines, growth factors, and cytokines) both basally and in response to environmental stimuli. Interestingly, mast cell numbers in the brain show immense individual variation in both rodents and humans. We used a Pavlovian conditioned approach (PCA) procedure to examine whether mast cells are associated with individual variation in the attribution of incentive-motivational value to reward-related cues. During the PCA procedure, a lever response-independently predicts the delivery of a food pellet into a magazine, and over training sessions three conditioned responses (CRs) develop: sign-tracking (lever-directed CRs), goal-tracking (magazine-directed CRs), and an intermediate response (both CRs). In Experiment 1, we measured thalamic mast cell number/activation using toluidine blue and demonstrated that sign-trackers have increased degranulated (activated) but not granulated (inactive) mast cells. In Experiment 2, we infused the mast cell inhibitor, cromolyn (200µg/rat; i.c.v.), immediately before five daily PCA training sessions and demonstrated that mast cell inhibition selectively impairs the acquisition of sign-tracking behavior. Taken together, these results demonstrate that thalamic mast cells contribute to the attribution of incentive-motivational value to reward-related cues and suggest that mast cell inhibition may be a novel target for addiction treatment.

Role of Wnt/β-catenin pathway in the nucleus accumbens in long-term cocaine-induced neuroplasticity: a possible novel target for addiction treatment.

Cocaine addiction is a chronic relapsing disorder characterized by the loss of control over drug-seeking and taking, and continued drug use regardless of adverse consequences. Despite years of research, effective treatments for psycho-stimulant addiction have not been identified. Persistent vulnerability to relapse arises from a number of long-lasting adaptations in the reward circuitry that mediate the enduring response to the drug. Recently, we reported that the activity of the canonical or Wnt/β-catenin pathway in the prefrontal cortex (PFC) is very important in the early stages of cocaine-induced neuroadaptations. In the present work, our main goal was to elucidate the relevance of this pathway in cocaine-induced long-term neuroadaptations that may underlie relapse. We found that a cocaine challenge, after a period of abstinence, induced an increase in the activity of the pathway which is revealed as an increase in the total and nuclear levels of β-catenin (final effector of the pathway) in the nucleus accumbens (NAcc), together with a decrease in the activity of glycogen synthase kinase 3β (GSK3β). Moreover, we found that the pharmacological modulation of the activity of the pathway has long-term effects on the cocaine-induced neuroplasticity at behavioral and molecular levels. All the results imply that changes in the Wnt/β-catenin pathway effectors are long-term neuroadaptations necessary for the behavioral response to cocaine. Even though more research is needed, the present results introduce the Wnt canonical pathway as a possible target to manage cocaine long-term neuroadaptations.

Nucleus Accumbens AMPA Receptors Are Necessary for Morphine-Withdrawal-Induced Negative-Affective States in Rats.

Dependence is a hallmark feature of opiate addiction and is defined by the emergence of somatic and affective withdrawal signs. The nucleus accumbens (NAc) integrates dopaminergic and glutamatergic inputs to mediate rewarding and aversive properties of opiates. Evidence suggests that AMPA glutamate-receptor-dependent synaptic plasticity within the NAc underlies aspects of addiction. However, the degree to which NAc AMPA receptors (AMPARs) contribute to somatic and affective signs of opiate withdrawal is not fully understood. Here, we show that microinjection of the AMPAR antagonist NBQX into the NAc shell of morphine-dependent rats prevented naloxone-induced conditioned place aversions and decreases in sensitivity to brain stimulation reward, but had no effect on somatic withdrawal signs. Using a protein cross-linking approach, we found that the surface/intracellular ratio of NAc GluA1, but not GluA2, increased with morphine treatment, suggesting postsynaptic insertion of GluA2-lacking AMPARs. Consistent with this, 1-naphthylacetyl spermine trihydrochloride (NASPM), an antagonist of GluA2-lacking AMPARs, attenuated naloxone-induced decreases in sensitivity to brain stimulation reward. Naloxone decreased the surface/intracellular ratio and synaptosomal membrane levels of NAc GluA1 in morphine-dependent rats, suggesting a compensatory removal of AMPARs from synaptic zones. Together, these findings indicate that chronic morphine increases synaptic availability of GluA1-containing AMPARs in the NAc, which is necessary for triggering negative-affective states in response to naloxone. This is broadly consistent with the hypothesis that activation of NAc neurons produces acute aversive states and raises the possibility that inhibiting AMPA transmission selectively in the NAc may have therapeutic value in the treatment of addiction. Morphine dependence and withdrawal result in profound negative-affective states that play a major role in the maintenance of addiction. However, the underlying neurobiological mechanisms are not fully understood. We use a rat model of morphine dependence to show that GluA1 subunits of AMPA glutamate receptors in the nucleus accumbens (NAc), a brain region critical for modulating affective states, are necessary for aversive effects of morphine withdrawal. Using biochemical methods in NAc tissue, we show that morphine dependence increases cell surface expression of GluA1, suggesting that neurons in this area are primed for increased AMPA receptor activation upon withdrawal. This work is important because it suggests that targeting AMPA receptor trafficking and activation could provide novel targets for addiction treatment.

Migration and time to first tobacco cigarette after waking

Migration and time to first tobacco cigarette after waking

Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction.

BackgroundAddictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction.ResultsLiterature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling.ConlusionsCancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0167-x) contains supplementary material, which is available to authorized users.

The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys

BackgroundBased on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. MethodsWe first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03–10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. ResultsAZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3–3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. ConclusionsThese results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment.

Characterization of Dopamine D3 receptor‐selective compounds on unconditioned behaviors and food/drug choice in cocaine and methamphetamine self‐administering rhesus monkeys

The dopamine D3 receptor (D3R) continues to be a promising novel treatment target for addiction. Recent studies suggest that the in vivo efficacy of D3R‐preferring compounds is dependent on the behavioral assay and previous exposure to drugs of abuse or diet. The present study examined the effects of a D3 agonist quinpirole (Qp), a selective D3 partial agonist PG 619 (PG) and the D2/D3 antagonist buspirone (Bus), in unconditioned behaviors (agonist‐elicited yawning and hypothermia) and food/drug choice self‐administration (SA) in male rhesus monkeys. In drug‐naïve monkeys, Qp (0.01–0.3 mg/kg, i.m.) elicited yawning in an inverted‐U shaped function with the descending limb characterized by hypothermia. In this assay, PG (0.1–0.3 mg/kg, i.m.) antagonized the ascending limb for yawning without affecting hypothermia, while Bus (0.03–0.056 mg/kg, i.m.) only attenuated hypothermia, suggesting limited activity at the D3R, In food/drug choice SA, Qp (0.03 mg/kg, i.v., 10‐min pretreat) and PG (0.1–0.3 mg/kg, i.v., 10‐min pretreat) robustly attenuated COC and MA SA following 5 days of treatment, but Bus (0.01–0.03 mg/kg, i.v., 10‐min pretreat) did not alter drug SA. Altogether, these findings supporting continued exploration of novel D3R compounds for treatment of COC and MA addiction. DA12460 and NIDA‐IRP