Inhibition of CREB activity in the dorsal portion of the striatum potentiates behavioral responses to drugs of abuse

Stefania Fasano

doi:10.3389/neuro.08.029.2009

Abstract

The striatum participates in multiple forms of behavioral adaptation, including habit formation, other forms of procedural memory, and short- and long-term responses to drugs of abuse. The cyclic-AMP response element binding protein (CREB) family of transcription factors has been implicated in various forms of behavioral plasticity, but its role in the dorsal portion of the striatum-has been little explored. We previously showed that in transgenic mice in which CREB function is inhibited in the dorsal striatum, bidirectional synaptic plasticity and certain forms of long-term procedural memory are impaired. Here we show, in startling contrast, that inhibition of striatal CREB facilitates cocaine- and morphine-place conditioning and enhances locomotor sensitization to cocaine. These findings propose CREB as a positive regulator of dorsal striatum-dependent procedural learning but a negative regulator of drug-related learning.

Highlights

By comparing str-KCREB and control mice we confirmed a significant increase in the number of cyclic-AMP response element binding protein (CREB) positive cells associated to the dorsal portion of the striatum in the transgenic mice, with no changes of immunoreactivity in the nucleus accumbens (NAc) (Figures 1A–D)
Our earlier observations indicate that synaptic plasticity is lost in the dorsal portion of the striatum, in marked contrasts with normal responses in both the hippocampus and the NAc and that may impact on the observed loss of long-term memory in instrumental learning (Pittenger et al, 2006)
We have previously shown that disruption of striatal CREB-regulated transcription results in impairments of corticostriatal LTP and LTD in the dorsal striatum and of several striatum-dependent memory tasks (Pittenger et al, 2006)

Summary

Introduction

Transcription factors of the cyclic-AMP response element binding protein (CREB) family, and the signaling cascades that regulate them, have been shown to importantly contribute to memory formation and long-term synaptic plasticity both in invertebrate systems and in several areas of the mammalian brain (Dash et al, 1990; Bourtchuladze et al, 1994; Yin et al, 1994; Bartsch et al, 1998; Ahn et al, 1999; Josselyn et al, 2001, 2004; Barco et al, 2002, 2005; Kida et al, 2002; Pittenger et al, 2002, 2006; Han et al, 2007, 2009; Lopez de Armentia et al, 2007; Lee et al, 2008; Jancic et al, 2009; Mamiya et al, 2009; Viosca et al, 2009a,b). The cognitive basis of this transition has been linked to the formation of maladaptive habits, in which aberrant stimulus-response associations, normally acquired through multiple repetitions of goal directed learning processes, become independent of the reinforcing properties of the drug in question (Everitt and Robbins, 2005; Belin et al, 2009)

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Conclusion