SAR-39684-the-neurocircuitry-of-illicit-psychostimulant-addiction--an-_020713.pdf

208211 while still in their relative infancy these

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induced changes in gene expression. 208–211 While still in their relative infancy, these exciting new avenues of research offer a significant expansion of possible biologically based targets for the treatment of psychostimulant addiction. Conclusion Even with over half a century of research directed at understanding the mechanisms and treatment of psychostimulant addiction, this disorder remains a serious socioeconomic problem. Psychostimulants exert their acute rewarding and reinforcing actions primarily via direct and indirect release of extracellular DA in the NAc. DA release in other brain regions, such as the PFC and AMG, play a role in behavioral control and learned associations between environmental stimuli and the subjective rewarding effects. In addition to DA release, psychostimulants also alter other neurotransmitter systems, such as 5-HT, NE, Glu, endocannabinoids, and various neuropeptides. With continued drug use, other regions, such as the DS and CSTC, may mediate such behaviors as action control and habitual or compulsive drug seeking. Chronic drug use leads to persistent adaptive changes within the reward circuitry, including altered receptor and transporter expression, neurotransmitter release, and functional connectivity between brain regions. Ultimately, these adaptive changes are associated with an impaired cognitive state and neuropsychiatric symptoms. While some of the effects of chronic psychostimulant use may dissipate with increasing abstinence, many chronic users are unable to achieve or maintain even a short period of abstinence. The tremendous need for more effective pharmacological treatments for psychostimulant addiction is a mainstay of contemporary addiction research. However, the recent downsizing of many major pharmaceutical companies away from psychiatric indications (including addiction) due to the lack of efficacy of experimental compounds in humans may require a sea change in the translational research approach. 212,213 A new emphasis on larger-scale biomarker, genetic, and epigenetic research focused on the molecular targets of mental disorders has been recently advocated. 212 In addition, the integration of cognitive and behavioral modification of circuit-wide neuroplasticity (ie, computer- based training to enhance executive function) may prove to be an effective adjunct-treatment approach for addiction, particularly when combined with cognitive enhancers. 198,213–216 Furthermore, in order to be effective, all pharmacological or biologically based treatments for addiction need to be integrated into other established forms of addiction rehabilitation, such as cognitive behavioral therapy, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities. Acknowledgment The authors wish to acknowledge the support of NIH grants DA024355 and DA025606.
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