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

159161 unlike with vmat2 increased duration of

Info icon This preview shows pages 9–10. Sign up to view the full content.

View Full Document Right Arrow Icon
159–161 Unlike with VMAT2, increased duration of abstinence was associated with increased striatal DAT density. 162 Note on inflammatory effects Repeated use of high doses of METH results in neurotoxicity in preclinical models, particularly in the striatum (for review, see Krasnova and Cadet). 163 While the mechanism underlying METH-induced neurotoxicity has not been fully elucidated, it is likely due to repeated, high levels of extracellular DA leading to production of quinones and free radicals such as reactive oxygen species. 164,165 Studies in humans have investigated the role of inflammatory mediators in METH- induced neurotoxicity, due to the fact that microglial activation has been associated with METH neurotoxicity in animal models. 166 Interestingly, the number of microglia but not activation of glial cells in the postmortem striatum of METH users was significantly increased. 145 A follow-up study confirmed and extended these results in non-abstinent METH users, finding that METH use results in significantly increased striatal microglia in the absence of reactive gliosis. 167 However, in abstinent METH abusers, a PET study found a significant increase in binding of a radiotracer (PK11195) for activated microglia in all brain regions. 168 In adults in remission from METH dependence, immune- system dysregulation was found, in addition to significant cognitive impairments, which encompassed learning, memory, and attentional/informational processing. 169 In the same study, impaired global cognition was significantly and positively correlated with plasma levels of the cytokine alpha- interferon. 169 In addition, a decrease in the anti-inflammatory marker interleukin 10 and increased proinflammatory tumor necrosis factor alpha in response to stress exposure has been found in cocaine abusers (compared to social drinkers), potentially indicating an elevated inflammatory state. 170 Interestingly, postmortem brain studies suggest that cocaine addiction is not associated with increased activation of markers of apoptotic cell-death pathways. 47,171 Together, these initial studies indicate dysregulated inflammatory processes following chronic psychostimulant use in humans and provide evidence to support the need for further investigations. Implications for the treatment of substance abuse At present, no pharmacological therapy has been approved by the FDA to treat psychostimulant addiction. Many drugs have been tested, but none have shown conclusive efficacy with tolerable side effects in humans. 172 These drugs have included DA-receptor ligands, such as DA receptor agonists, partial agonists, and antagonists, as well as DA-reuptake inhibitors. 173,174 One newer dopaminergic drug that has shown some promise is the antipsychotic medication aripiprazole, a partial agonist at D 2 -like receptors, which is currently approved for the treatment of schizophrenia, depression, and bipolar disorder.
Image of page 9

Info icon This preview has intentionally blurred sections. Sign up to view the full version.

View Full Document Right Arrow Icon
Image of page 10
This is the end of the preview. Sign up to access the rest of the document.

{[ snackBarMessage ]}

What students are saying

  • Left Quote Icon

    As a current student on this bumpy collegiate pathway, I stumbled upon Course Hero, where I can find study resources for nearly all my courses, get online help from tutors 24/7, and even share my old projects, papers, and lecture notes with other students.

    Student Picture

    Kiran Temple University Fox School of Business ‘17, Course Hero Intern

  • Left Quote Icon

    I cannot even describe how much Course Hero helped me this summer. It’s truly become something I can always rely on and help me. In the end, I was not only able to survive summer classes, but I was able to thrive thanks to Course Hero.

    Student Picture

    Dana University of Pennsylvania ‘17, Course Hero Intern

  • Left Quote Icon

    The ability to access any university’s resources through Course Hero proved invaluable in my case. I was behind on Tulane coursework and actually used UCLA’s materials to help me move forward and get everything together on time.

    Student Picture

    Jill Tulane University ‘16, Course Hero Intern