Abstract:
In experimental rodents a prolonged history of alcohol dependence persistently up-regulates voluntary alcohol consumption and behavioral stress responses. While this phenotype is primarily mediated by amygdala hyperactivity, there is emerging evidence for a critical role of the rodent medial prefrontal cortex (mPFC) in the inhibition of addictive behaviours. The underlying neurobiology of altered mPFC function is poorly understood.
A step-wise transcriptome analysis strategy pointed us to the infralimbic projection neurons as a critical point of dependence related neuroplasticity. We identified several candidate genes including transcription factors and the metabotropic glutamate receptor type 2 (Grm2) that are robustly and persistently downregulated during ethanol abstinence. Microdialysis and receptor binding studies demonstrate the importance of these neuroadaptations for glutametergic as well as dopaminergic neurotransmission. To validate the functional role of Grm2 for alcohol seeking behaviour we rescued the receptor deficit in the IL neurons by viral vector gene transfer. Preliminary data show a reversal of increased alcohol seeking in dependent rats, while non-dependent animals were not affected by this treatment.
Together, these data point towards profound alterations in mPFC function, in particular within the infralimbic region, and predict dysfunction of inhibitory control over behaviour in alcohol addiction. We believe that the observed alcohol dependence related pathology within a specific neuronal circuit (infralimbic-accumbal projection) together with our ability to label and to genetically manipulate affected cells in vivo makes this model suitable for neurophysiological and computational investigations aimed to understand the role of glutamate and dopamine signalling in regulating associative and extinction learning.