The Role of Adult Neurogenesis in Cocaine Addiction

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2009-01-14

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Abstract

New neurons are born in the adult hippocampus in a region known as the subgranular zone (SGZ). This process is dynamically regulated and new neurons are thought to be important for certain types of spatial learning and memory. Proliferation of SGZ neural progenitors is decreased by drugs of abuse, yet it is not clear how the type and amount of drug as well as the pattern of administration changes long-term effects on neurogenesis. In addition, it is unclear what role if any SGZ neurogenesis plays in initiating drug-taking or relapse behaviors, or whether changes in neurogenesis are merely side effects of drug-taking. I first examined effects of chronic cocaine self-administration and withdrawal on the different stages of neurogenesis. I found an early deficit in proliferation of neural progenitors, as well as a 4 week delayed increase in doublecortin-positive (DCX+) immature neurons which were common to both rats in withdrawal or those continuing to self-administer cocaine. I next asked the question of the functional consequence of changes in adult hippocampal neurogenesis to the acquisition and maintenance of drug-taking, as well as relapse to drug-taking. I found that reduced adult neurogenesis via cranial irradiation prior to cocaine-taking was associated with increased acquisition of drug-taking and increased motivation for cocaine, but not sucrose, while reduced adult neurogenesis after rats have acquired cocaine self-administration was associated with increased resistance to extinction of drug-seeking behavior. Finally, I asked if formation of drug-context associations would be altered in rodents with reduced neurogenesis in a passive drug exposure paradigm. I found that a transgenic mouse with reduced adult neurogenesis has impaired long-term drug-context memory in the cocaine conditioned place preference paradigm (CPP). Together these findings suggest that reduced adult hippocampal neurogenesis is a risk factor for drug addiction, that decreased proliferation after chronic drug intake likely contributes to drug-taking and drug-seeking behaviors, and that the delayed increase in immature neurons after drug-taking is likely protective against relapse. In sum, increases in adult hippocampal neurogenesis are beneficial both to the naïve and addicted brain, and therapeutics specifically increasing adult neurogenesis could aid in preventing initial addiction as well preventing future relapse.

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