Is There a Common Molecular Pathway for Addiction?

Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9070, USA.
Nature Neuroscience (Impact Factor: 16.1). 12/2005; 8(11):1445-9. DOI: 10.1038/nn1578
Source: PubMed


Drugs of abuse have very different acute mechanisms of action but converge on the brain's reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.

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    • "Self-administration of cocaine, ethanol, and nicotine, which greatly differ with respect to their pharmacodynamics, was reduced by similar levels of mGluR5 negative allosteric modulation. This finding indicates that mGluR5 NAMs act on a molecular final common pathway affected by these substances of abuse (Everitt and Robbins, 2005;Nestler, 2005;Koob and Volkow, 2010), rather than at their primary binding sites. According to the glutamate homeostasis hypothesis (Kalivas, 2009;Kalivas and Volkow, 2011), synaptic glutamate overflow activating mGluR5 drives together with reduced function of mGluR2/3 and glutamate/cysteine transporter pathological neuroplastic changes in the ventral striatum in addiction. "
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    ABSTRACT: Background: Abundant evidence at the anatomical, electrophysiological, and molecular level implicates metabotropic glutamate receptors subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential which can be translated to the clinic.
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    • "For example, as a result of chronic and/or excessive SU, the rewarding effects of a substance and related stimuli (e.g. persons, places, thoughts or feelings associated with SU, drug paraphernalia) become overvalued at the expense of other rewards (Nestler, 2005; Hyman et al., 2005). Robinson & Berridge (2008) have called this 'incentive salience' or cognitive biases, meaning they seem attractive, 'grab attention' and elicit approach behaviour. "
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    ABSTRACT: Background: Substance use disorders (SUD) are associated with several neurobiological disruptions, including biases in attention and approach/avoidance behaviour. The aims of this study were to compare the strength of cognitive biases between light and problematic drinkers, to explore the role of IQ on the cognitive biases and to study the psychometric qualities of the measures. Method: Participants (N = 130) were divided into four groups based on IQ and severity of alcohol use-related problems: light (n = 28) and problematic drinkers (n = 25) with (sub)average IQ and light (n = 33) and problematic drinkers (n = 44) with mild to borderline intellectual disability (MBID). All participants performed the visual dot probe task and the approach avoidance task to measure the strength of cognitive biases. Results: In contrast with the hypothesis, no cognitive biases were found in problematic drinkers. Full scale IQ nor level of craving influenced the strength of the cognitive biases in light and problematic drinkers, although IQ did influence task performance (i.e. large intra-individual, trial-to-trial variation in reaction time). The internal consistency of the visual dot probe task was good, whereas the internal consistency of the approach avoidance task was poor. Conclusion: Cognitive biases seem to vary within the group of problematic drinkers as a whole. The psychometric qualities of the measures are problematic, especially in relation to the intra-individual variability in reaction time found in participants with MBID. Until the implications of this variability on the validity of implicit measures and establishing bias scores are more clear, the use of these measures in individuals with MBID calls for scrutiny.
    No preview · Article · Dec 2015 · Journal of Intellectual Disability Research
    • "The reactive system is sensitive to reward and generates impulses following dopaminergic stimulation of the NAc whereas the reflective system operates glutamatergic control over impulses generated in the striatum (Bechara 2005; Faure et al. 2010; Kalivas and Volkow 2005). All drugs of abuse increase dopamine transmission in the NAc (Nestler 2005) which is essential for acute drug reward (Dagher and Robbins 2009; Kalivas and Volkow 2011; Volkow et al. 2011) and may be very relevant for progressively shaping drug use into drug seeking behavior (Kalivas 2009) by reducing inhibitory control over the reactive system (D'Amour-Horvat and Leyton 2014). Vulnerability to drug addiction and loss of inhibitory control may be affected by inter-individual variations in genetic expression and tonic dopamine levels in the limbic circuit (Koob 1998; Kreek et al. 2005; Volkow et al. 2007, 2011). "
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    ABSTRACT: The dopamine β-hydroxylase (DβH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic 'reward' circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 μg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.
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