Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology

Abstract

Once thought to produce global, nonspecific brain injury, drugs of abuse are now known to produce selective neuro-adaptations in particular brain regions. These neuro-adaptations are being closely examined for clues to the development, maintenance, and treatment of addiction. The hippocampus is an area of particular interest, as it is central to many aspects of the addictive process, including relapse to drug taking. A recently appreciated hippocampal neuro-adaptation produced by drugs as diverse as opiates and psychostimulants is decreased neurogenesis in the sub-granular zone (SGZ). While the role of adult-generated neurons is not clear, their functional integration into hippocampal circuitry raises the possibility that decreased adult SGZ neurogenesis may alter hippocampal function in such a way as to maintain addictive behavior or contribute to relapse. Here, we review the impact of opiates and psychostimulants on the different stages of cell development in the adult brain, as well as the different stages of the addictive process. We discuss how examination of drug-induced alterations of adult neurogenesis advances our understanding of the complex mechanisms by which opiates and psychostimulants affect brain function while also opening avenues for novel ways of assessing the functional role of adult-generated neurons. In addition, we highlight key discrepancies in the field and underscore the necessity to move "beyond BrdU"--beyond merely counting new hippocampal cells labeled with the S phase marker bromodeoxyuridine--so as to probe mechanistic questions about how drug-induced alterations in adult hippocampal neurogenesis occur and what the functional ramifications of alterations in neurogenesis are for addiction.

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

“…Besides being toxic to neurons, drugs of abuse have been also shown to induce a decrease in hippocampal neurogenesis (reviewed by Eisch and Harburg, 2006), compromising the capacity of the brain to generate new neurons. In the adult mammalian brain there are two main neurogenic regions, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus (reviewed by Gage, 2002).…”

“…Cocaine (Yamaguchi et al, 2004;Mackowiak al., 2005) and methamphetamine (Teuchert-Noodt et al, 2000) were also reported to decrease hippocampal neurogenesis. Repeated or chronic exposure seems to be required to observe the inhibition in adult hippocampal neurogenesis induced by opiates or psychostimulants (Eisch and Harburg, 2006).…”

“…Although the mechanisms involved in the decrease in neurogenesis induced by drugs of abuse are just starting to be investigated, they may be related with alteration of the proliferative environment, direct action of the drugs of abuse in the progenitor cells and/or alteration of the cell cycle of SGZ (Eisch and Harburg, 2006).…”

Glial-restricted precursors: Patterns of expression of opioid receptors and relationship to human immunodeficiency virus-1 Tat and morphine susceptibility in vitro

“…The particular effects seen for each receptor type are contextual and differ among cell types and at different stages of development. Immature neurons Eisch and Harburg, 2006;Narita et al, 2006a), astrocytes (Stiene-Martin and Hauser, 1990;Eriksson et al, 1990;Eriksson et al, 1991;Stiene-Martin and Hauser, 1991;Hauser et al, 1996;Stiene-Martin et al, 1998;Belcheva et al, 2005), oligodendrocytes (Knapp et al, 1998;Stiene-Martin et al, 2001), and their precursors (Persson et al, 2003a;Persson et al, 2003b;Persson et al, 2006;Kim et al, 2006) can respond uniquely to opioids. For example, MOR receptor activation can inhibit proliferation in immature astroglia, while activation of the same receptor type in immature oligodendroglia increases proliferation (Knapp et al, 1998).…”

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

“…Lesion of the DG blocks cocaine-induced conditioned place preference (CPP) (Meyers et al 2006;Hernandez-Rabaza et al 2008). Moreover, the DG is one of the few regions in the adult brain where neurogenesis continues to take place (Christie and Cameron 2006;Aimons et al 2010) and neurogenesis is thought to play an important role in the formation of addictive memory (Eisch and Harburg 2006;Canales 2007Canales , 2010Noona et al 2010). Finally, the DG is a brain region that is highly sensitive to nicotine and significantly affects synaptic plasticity.…”