SYNAPTIC PLASTICITY IN DRUG ABUSE DISORDERS: STUDIES OF THE HUMAN POST-MORTEM BRAIN

Drug addiction is a chronic disorder characterized by craving and compulsive drug use despite adverse consequences and high rates of relapse during periods of abstinence. Therapeutic interventions for most addiction disorders are limited today, partly because the underlying neurobiology is still unknown. A growing body of evidence indicates that synaptic plasticity contributes to the development and persistence of addiction, however, most research have focused on rodent animal models and very limited knowledge exists about the effects of drugs of abuse on the glutamatergic system in the human brain. The aim of this thesis was therefore to gain deeper insight into the neurobiology of drugs of abuse, including alcohol, heroin and cocaine directly in the human brain relevant to synaptic plasticity in key neuronal circuits relevant for the development and persistence of addiction. In the first study we examined the gene expression profile of sixteen endogenous control genes in the prefrontal and motor cortex of alcoholics. The results demonstrated differences in gene expression stability between the prefrontal and motor cortex as well as region-specific-alterations in several genes normally used as reference genes between alcoholic and controls. These observations implicate the importance of selecting proper genes for normalization when performing gene expression studies. Next we investigated whether the NF-! B system was altered in the prefrontal and motor cortex of alcoholics. The results revealed a reduced DNA-binding activity of the NF-! B and p50 homodimer in the prefrontal cortex of alcoholics that was coupled to a reduction in RELA mRNA levels. NF-! B has been implicated in synaptic plasticity and memory consolidation, thus it is tempting to speculate that decreased NF-! B function could lead to a disruption of learning and memory formation, or effect alcoholinduced associative memory reconsolidation often linked to relapse. Third, we examined the effect of alcohol consumption on modulators of synaptic strength (synaptophysin) and executors of glutamate release in the prefrontal and motor cortex. We observed increased synaptophysin I levels in the prefrontal cortex of alcoholics compared to controls, while levels of predominant members of the synaptic vesicular machinery important for glutamate release were unaltered. These results suggest a role for synaptophysin in the alcohol dependence–associated enduring neuroplasticity in the prefrontal cortical glutamate circuitry. Finally, we evaluated glutamatergic receptors and their associated scaffolding proteins in the amygdala and striatum of heroin, cocaine and polysubstance (heroin/cocaine) abusers. The findings revealed region-specific disturbances in glutamatergic systems tightly coupled to PSD-95 and Homer in human drug abusers indicting an abberant regulation of glutamatergic signaling and function. In conclusion, we have demonstrated disturbances in several key mechanisms underlying synaptic plasticity/function in the human brain of drug abusers that are in line with research findings from animal models. Altogether these findings emphasize pathology of neuroplasticity as a common feature in addiction disorders. LIST OF PUBLICATIONS I. Johansson S. , Fuchs A. , Ökvist A. , Karimi M. , Harper C. , Garrick T. , Sheedy D. , Hurd Y. , Bakalkin G. , Ekström T.J., Validation of endogenous controls for quantitative gene expression analysis: Application on brain cortices of human chronic alcoholics. Brain Research, 2007, 1132(1): 20-28. II. Ökvist A. , Johansson S. , Kuzmin A. , Bazov I. , Merino-Martinez R. , Ponomarev I. , Mayfield D. , Harris R.A. , Sheedy D. , Garrick T. , Harper C. , Hurd Y.L. , Terenius L. , Ekström T.J., Bakalkin G. , Yakovleva T. Neuroadaptations in Human Chronic Alcoholics: Dysregulation of the NF! B – system. PLoS ONE, 2007, 9: e930. III. Henriksson R. , Kuzmin A. , Ökvist A. , Harper C. , Sheedy D. , Garrick T. , Yakovleva T. , Bakalkin G. , Elevated Synaptophysin I in the Prefrontal Cortex of Human Chronic Alcoholics. Synapse, 2008, 62: 829–833 IV. Ökvist A. , Fagergren P., Garcia A. , Drakenberg K. , Bannon M. , Horvath M. , Keller E. , Hurd Y.L. Dysregulation of the synaptic machinery in the striatum and amygdala of human drug abusers. Manuscript