Microarray Studies of Psychostimulant-Induced Changes in Gene Expression

Abstract

Alterations in the expression of multiple genes in many brain regions are likely to contribute to psychostimulant-induced behaviours. Microarray technology provides a powerful tool for the simultaneous interrogation of gene expression levels of a large number of genes. Several recent experimental studies, reviewed here, demonstrate the power, limitations and progress of microarray technology in the field of psychostimulant addiction. These studies vary in the paradigms of cocaine or amphetamine administration, drug doses, route and also mode of administration, duration of treatment, animal species, brain regions studied and time of tissue collection after final drug administration. The studies also utilize different microarray platforms and statistical techniques for analysis of differentially expressed genes. These variables influence substantially the results of these studies. It is clear that current microarray techniques cannot detect small changes reliably in gene expression of genes with low expression levels, including functionally significant changes in components of major neurotransmission systems such as glutamate, dopamine, opioid and GABA receptors, especially those that may occur after chronic drug administration or drug withdrawal. However, the microarray studies reviewed here showed cocaine- or amphetamine-induced alterations in the expression of numerous genes involved in the modulation of neuronal growth, cytoskeletal structures, synaptogenesis, signal transduction, apoptosis and cell metabolism. Application of laser capture microdissection and single-cell cDNA amplification may greatly enhance microarray studies of gene expression profiling. The combination of rapidly evolving microarray technology with established methods of neuroscience, molecular biology and genetics, as well as appropriate behavioural models of drug reinforcement, may provide a productive approach for delineating the neurobiological underpinnings of drug responses that lead to addiction.

Differential Regulation of Immediate-Early Gene Expression in the Prefrontal Cortex of Rats with a High vs Low Behavioral Response to Methamphetamine

“…In this regard, Gsk-3a was differentially expressed in HR vs LR and has previously been reported to be downregulated after stimulant administration (Yuferov et al, 2005). The downregulation of Gsk-3a in HR but not LR ( Figure 5) could represent a compensatory adaptation to differences in these pathways in these two groups of rats.…”

“…Measurement of gene expression in rat brain provides a powerful means to address the molecular mechanisms underlying individual responsiveness to stimulants and there is a large literature on stimulant-induced gene expression changes in rodent brain (reviewed by Harlan and Garcia, 1998;Yuferov et al, 2005). However, for the most part, these studies have not addressed individual differences.…”

Involvement of the AMPA Receptor GluR-C Subunit in Alcohol-Seeking Behavior and Relapse

“…In recent years, it has been suggested that a specific AMPA receptor subunit composition provides a fine-tuning in neuroadaptive processes derived from chronic drug exposure, including those that presumably control craving and relapse behavior (Lu et al, 2003;Tang et al, 2004;Yuferov et al, 2005). However, the contribution of different AMPA receptor subunits in this respect is less clear.…”

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims

“…7,8,19 In addition to the cocaine-induced NAc plasticity, studies in rodent models indicate persistent or even permanent biochemical alterations in regions associated with the mesolimbic dopamine pathway including upregulation of the cyclic AMP (cAMP) pathway, [20][21][22][23][24][25][26] activator protein 1 family members [27][28][29][30][31][32] as well as glutamate, dopamine, gaminobutyric acid (GABA) and opiate receptors, growth factors, cytoskeletal elements and cell metabolism. [33][34][35][36][37][38][39][40][41] Genomic analyses in human post-mortem tissue of cocaine overdose (COD) victims have confirmed the findings of studies employing rodent models and have revealed novel mechanisms of drug-induced neuronal and non-neuronal dysregulation in human post-mortem brain tissue. [42][43][44][45] For example, Bannon and co-workers 42 examined gene expression in the NAc of post-mortem brain tissue of human cocaine abusers and controls and found significant alterations in several novel functional classes and transcripts including signal transduction, transcriptional and translational processing, neurotransmission and synaptic function, glia, structural and cell adhesion, receptors/transporters/ion channels, cell cycle and growth and lipid and protein processing.…”