Less Addictive and Smarter with PSD-95

Abstract

It has been thought that changes that occur in the brain in response to psychostimulants are similar to those that are critical for learning and memory. Drug addiction has been linked to adaptive changes in the striatum, the reward center of the brain, where dopaminergic and glutamatergic inputs converge. But the molecular details of drug sensitization are still being uncovered. Yao et al. studied the striatal response of both normal and transgenic mice that have increased sensitivity to dopamine agonists to chronic treatment with cocaine. Using a microarray-genomics approach, the study compared more than 36,000 genes and identified six that had significantly altered expression compared with those of normal mice. One of the genes encodes postsynaptic density-95 (PSD-95), a protein not previously linked to addiction. PSD-95 is a scaffolding protein at excitatory glutamatergic synapses that organizes a postsynaptic network of signaling molecules and strengthens synapses and cognitive abilities in mice. Mice with decreased PSD-95 expression not only have learning and memory deficits but now also appear to be more sensitive to cocaine. In normal mice, the decrease in PSD-95 in response to cocaine lasted for more than 2 months, which represents long-lasting molecular adaptation. Neurons from the brains of either transgenic mice lacking functional PSD-95 or mice supersensitive to cocaine exhibited increased response to electrical stimulation compared with neurons from control mice. These mice also showed heightened locomotive behavior compared with controls. The authors propose that dysregulation of PSD-95 may alter the synaptic signaling circuit of the brain reward system, possibly through interaction with dopamine receptors or perhaps by altering the interplay of glutamatergic and dopaminergic axons on postsynaptic dendritic spines in a way that contributes to behavioral sensitization. W.-D. Yao, R. R. Gainetdinov, M. I. Arbuckle, T. D. Sotnikova, M. Cyr, J.-M. Beaulieu, G. E. Torres, S. G. N. Grant, M. G. Caron, Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41 , 625-638 (2004). [Online Journal]