Nestler Lab

Laboratory of Molecular Psychiatry

Neurotrophic Mechanisms in Drug Addiction

Over the last few years, we and several other groups have documented that repeated exposure to a drug of abuse causes structural changes in specific neuronal cell types. These effects appear to be achieved in part through drug regulation of neurotrophic mechanisms in brain reward regions. Particular attention has been focused on one neurotrophic factor, BDNF (brain-derived neurotrophic factor), which exerts profound effects on drug reward mechanisms. Increasing evidence supports the importance of BDNF and these morphological adaptations in drug action.

Opiates Shrink the Size of VTA Dopamine Neurons

We have shown that repeated opiate exposure decreases the size of cell bodies of VTA dopamine neurons. This morphological change appears to reflect a downregulation of dopaminergic activity, hence a mechanism of behavioral tolerance, and may contribute to the dysphoria of drug withdrawal states.

Recent work has indicated that this effect of opiates is mediated via the downregulation of one particular BDNF signaling pathway by chronic opiate exposure, including downregulation of IRS2 (insulin receptor substrate 2) and of Akt, a prominent serine/threonine kinase. Viral mediated overexpression of an inhibitor of these proteins mimics opiate action in reducing VTA cell size and the rewarding effects of opiates. We are now exploring the detailed mechanisms underlying this novel mode of regulation.

Stimulants Induce Dendritic Spines on Nucleus Accumbens Neurons In 1997, Terry Robinson and colleagues at the University of Michigan demonstrated that repeated cocaine or amphetamine exposure increases the number of dendritic spines and dendritic branch points of both medium spiny neurons in the nucleus accumbens and of pyramidal neurons in the medial prefrontal cortex (both of which receive dopaminergic inputs). These changes persist for at least several months after the last drug exposure, and are hypothesized to represent a mechanism of drug sensitization. However, a link between such dendritic changes and sensitized behavioral responses remains conjectural.

We have obtained several lines of evidence that this expansion of dendritic arborizations of nucleus accumbens neurons is mediated at least in part via BDNF and the transcription factor ΔFosB and several of its target genes. (See Role of ΔFosB in the Nucleus Accumbens.) In one pathway, ΔFosB induces cyclin-dependent kinase 5 (Cdk5), which then phosphorylates and inhibits another transcription factor called MEF2 (myocyte enhancing factor 2). Repression of MEF2 then stimulates spine growth through regulation of still unidentified targets. In another pathway, ΔFosB induces subunits of the transcription factor, NFkB (nuclear factor kb), which then induces spine growth. We are now studying the specific targets of MEF2 and NFkB which mediate these effects.

The connection to behavior remains complicated. While Cdk5-MEF2 regulation induces dendritic growth of nucleus accumbens neurons, it decreases behavioral responses to cocaine, while NFkB induces spine growth and increases behavioral responses. These findings indicate that the relationship between spine growth and behavior is complex and requires much further investigation.