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- Why is Neuroimmunopharmacology crucial for the future of addiction research? [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 11.
A major development in drug addiction research in recent years has been the discovery that immune signaling within the central nervous system contributes significantly to mesolimbic dopamine reward signaling induced by drugs of abuse, and hence is involved in the presentation of reward behaviors. Additionally, in the case of opioids, these hypotheses have advanced through to the discovery of the novel site of opioid action at the innate immune pattern recognition receptor Toll-like receptor 4 as the necessary triggering event that engages this reward facilitating central immune signaling. Thus, the hypothesis of major proinflammatory contributions to drug abuse was born. This review will examine these key discoveries, but also address several key lingering questions of how central immune signaling is able to contribute in this fashion to the pharmacodynamics of drugs of abuse. It is hoped that by combining the collective wisdom of neuroscience, immunology and pharmacology, into Neuroimmunopharmacology, we may more fully understanding the neuronal and immune complexities of how drugs of abuse, such as opioids, create their rewarding and addiction states. Such discoveries will point us in the direction such that one day soon we might successfully intervene to successfully treat drug addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
- Behavioral endophenotypes of drug addiction: Etiological insights from neuroimaging studies. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 10.
This article reviews recent advances in the elucidation of neurobehavioral endophenotypes associated with drug addiction made possible by the translational neuroimaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET). Increasingly, these non-invasive imaging approaches have been the catalyst for advancing our understanding of the etiology of drug addiction as a brain disorder involving complex interactions between pre-disposing behavioral traits, environmental influences and neural perturbations arising from the chronic abuse of licit and illicit drugs. In this article we discuss the causal role of trait markers associated with impulsivity and novelty-/sensation-seeking in speeding the development of compulsive drug administration and in facilitating relapse. We also discuss the striking convergence of imaging findings from these behavioural traits and addiction in rats, monkeys and humans with a focus on biomarkers of dopamine neurotransmission, and highlight areas where further research is needed to disambiguate underlying causal mechanisms. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
- Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in l-DOPA-treated parkinsonian monkeys. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 10.
Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with l-DOPA and developed dyskinesias while those treated with l-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in l-DOPA-treated MPTP monkeys compared to controls but not in those treated with l-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (Bmax) of [(3)H]ABP688 specific binding increased in l-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in l-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in l-DOPA-treated MPTP monkeys compared to controls, saline and l-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.
- Amygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 7.
Complex motivated behavioral processes, such as those that can go awry following substance abuse and other neuropsychiatric disorders, are mediated by a distributive network of neurons that reside throughout the brain. Neural circuits within the amygdala regions, such as the basolateral amygdala (BLA), and downstream targets such as the bed nucleus of the stria terminalis (BNST), are critical neuroanatomical structures for orchestrating emotional behavioral responses that may influence motivated actions such as the reinstatement of drug seeking behavior. Here, we review the functional neurocircuitry of the BLA and the BNST, and discuss how these circuits may guide maladaptive behavioral processes such as those seen in addiction. Thus, further study of the functional connectivity within these brain regions and others may provide insight for the development of new treatment strategies for substance use disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
- Transition from 'model-based' to 'model-free' behavioral control in addiction: Involvement of the orbitofrontal cortex and dorsolateral striatum. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 8.
Cocaine addiction is a complex and multidimensional process involving a number of behavioral and neural forms of plasticity. The behavioral transition from voluntary drug use to compulsive drug taking may be explained at the neural level by drug-induced changes in function or interaction between a flexible planning system, associated with prefrontal cortical regions, and a rigid habit system, associated with the striatum. The dichotomy between these two systems is operationalized in computational theory by positing model-based and model-free learning mechanisms, the former relying on an "internal model" of the environment and the latter on pre-computed or cached values to control behavior. In this review, we will suggest that model-free and model-based learning mechanisms appear to be differentially affected, at least in the case of psychostimulants such as cocaine, with the former being enhanced while the latter are disrupted. As a result, the behavior of long-term drug users becomes less flexible and responsive to the desirability of expected outcomes and more habitual, based on the long history of reinforcement. To support our specific proposal, we will review recent neural and behavioral evidence on the effect of psychostimulant exposure on orbitofrontal and dorsolateral striatum structure and function. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
- Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 8.
Neurotrophins are essential for multiple aspects of neuronal development and function. Especially BDNF (brain-derived-neurotrophic-factor) has been shown to play an important role in neuronal survival and in the maintenance of several neuronal systems. In addition, BDNF has been implicated in numerous processes of functional and structural synaptic plasticity. In this review we would like to summarize what is known regarding the cellular mechanism mediating the activity of BDNF during functional and/or structural changes at neurons in order to promote synaptic plasticity. In addition, we address open questions and conflicting results.
- mTORC1 dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 8.
Administration of N-methyl-d-aspartate receptors (NMDAR) antagonists initiates a rapid anti-depressant response requiring mammalian Target of Rapamycin Complex 1 (mTORC1) kinase; however the molecular mechanism is unknown. We have determined that upon NMDAR blockade, dendritic γ-amino-butyric acid B receptors (GABABR) facilitate dendritic calcium entry. The GABABR mediated increase in calcium signal requires the availability of dendritic L-type calcium channels. Moreover, GABABR can activate mTOR and increase mTOR dependent expression of BDNF under the same NMDAR blocked conditions. In vivo, blocking GABABR prevents the fast-acting, anti-depressant effect of the NR2B antagonist, Ro-25-6891, decreases active mTORC1 kinase, and reduces expression of BDNF and the AMPA receptor subunit GluA1. These findings propose a novel role for GABABRs in the anti-depressant action of NR2B antagonists and as an initiator/regulator of mTORC1-mediated translation.
- Monocyte Chemoattractant Protein-1 upregulates GABA-induced current: Evidence of modified GABAA subunit composition in cortical neurons from the G93A mouse model of Amyotrophic Lateral Sclerosis. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 8.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons. Previous evidence has indicated that excitotoxic cell death in ALS may remarkably depend on Cl(-) ion influx through the GABAA receptors. In this study we have analysed the effect of Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) and compared with wild type SOD1 (SOD1) and their corresponding non transgenic littermates (Control). By performing electrophysiological experiments we have observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of GABA-evoked currents that was significantly higher in G93A neurons compared to controls. The effect of MCP-1 was not dependent on the activation of its receptor CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. Analysis of GABAA receptor subunit composition has indicated an altered subunit expression level in G93A cortical neurons compared to controls. Instead, in cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked currents, also through the benzodiazepine sites, indicating a region-specific mechanism of action. However, no differences were observed in the current reduction between the three neuronal populations. These findings provide the first evidence that MCP-1, acting on benzodiazepine sites, can modulate the GABA-evoked currents, depending on the subunit composition of GABAA receptor. In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is exacerbated in the mutated neurons. It is reasonable to assume that the higher Cl(-) influx through GABAA receptors in the presence of MCP-1 in mutated cortical neurons may induce an excitotoxicity acceleration. Agents able to block the MCP-1 production may then prove useful for ALS treatment.
- Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 7.
Tobacco smoking continues to be a major global health hazard despite significant public awareness of its harmful consequences. Although several treatment options are currently available for smoking cessation, these medications are effective in only a small subset of smokers, and relapse rates continue to be high. Therefore, a better understanding of the neurobiological mechanisms that mediate tobacco dependence is essential for the development of effective smoking cessation medications. Nicotine is the primary psychoactive component of tobacco that drives the harmful tobacco smoking habit. Nicotine binds to nicotinic acetylcholine receptors (nAChRs) in the brain, resulting in the release of a wide range of neurotransmitters, including glutamate and γ-aminobutyric acid (GABA). This review article focuses on the role of the excitatory glutamate system and inhibitory GABA system in nicotine dependence. Accumulating evidence suggests that blockade of glutamatergic transmission or facilitation of GABAergic transmission attenuates the positive reinforcing and incentive motivational aspects of nicotine, inhibits the reward-enhancing and conditioned rewarding effects of nicotine, and blocks nicotine-seeking behavior. Chronic nicotine exposure produced long-term neuroadaptations that contribute to nicotine withdrawal, but the role of GABA and glutamate transmission in nicotine withdrawal is less understood. Overall, the findings presented in this review provide strong converging evidence for the potential effectiveness of glutamatergic and GABAergic medications in nicotine dependence and potentially nicotine withdrawal. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
- A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to d-amfetamine, methylphenidate and modafinil. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 6.
Lisdexamfetamine dimesylate, which consists of l-lysine covalently bound to d-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield d-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include d-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, d-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5-1.5 mg/kg [d-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its d-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0-10 mg/kg, p.o.) and d-amfetamine (0.1-1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal d-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as d-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and d-amfetamine by 3.4× and 2.2×, respectively. Modafinil (50-200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self-administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [d-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to d-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics.