Ethanol impairment of spontaneous alternation behaviour and associated changes in medial prefrontal glutamatergic gene expression precede putative markers of dependence

Chris Pickering; Johan Alsiö; Julia Morud; Mia Ericson; Trevor W Robbins; Bo Söderpalm

doi:10.1016/j.pbb.2015.02.021

Ethanol impairment of spontaneous alternation behaviour and associated changes in medial prefrontal glutamatergic gene expression precede putative markers of dependence

Pharmacol Biochem Behav. 2015 May:132:63-70. doi: 10.1016/j.pbb.2015.02.021. Epub 2015 Mar 2.

Authors

Chris Pickering¹, Johan Alsiö², Julia Morud³, Mia Ericson³, Trevor W Robbins⁴, Bo Söderpalm⁵

Affiliations

¹ University of Gothenburg, Institute of Neuroscience and Physiology at the Sahlgrenska Academy, Department of Psychiatry and Neurochemistry, Addiction Biology Unit, Gothenburg, Sweden. Electronic address: christopher.pickering@gu.se.
² Uppsala University, Department of Neuroscience, Unit of Functional Neurobiology, Uppsala, Sweden; University of Cambridge, Department of Psychology and the Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
³ University of Gothenburg, Institute of Neuroscience and Physiology at the Sahlgrenska Academy, Department of Psychiatry and Neurochemistry, Addiction Biology Unit, Gothenburg, Sweden.
⁴ University of Cambridge, Department of Psychology and the Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
⁵ University of Gothenburg, Institute of Neuroscience and Physiology at the Sahlgrenska Academy, Department of Psychiatry and Neurochemistry, Addiction Biology Unit, Gothenburg, Sweden; Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden.

PMID: 25743187
DOI: 10.1016/j.pbb.2015.02.021

Abstract

Cognitive impairments are observable in over half of cases with alcoholism, deficits in spatial working memory being particularly common. Previously we observed that rats make more alternation errors in a Y-maze test of spontaneous alternation behaviour/spatial working memory after 5-day intermittent ethanol. Here we used qPCR to quantify changes in gene expression accompanying this behavioural impairment. Male Wistar rats were treated with either saline or ethanol (1 or 2.5g/kg) for 5days followed by 2 drug-free days. Brains were dissected after Y-maze analysis and RNA was extracted from the medial prefrontal cortex, hippocampus and nucleus accumbens. Using the Qiagen GABA & Glutamate PCR array we measured changes in these two neurotransmitter systems. A dose of 1g/kg ethanol did not affect spontaneous alternation behaviour or any other behavioural variable. 2.5g/kg significantly decreased % correct alternations (p=0.028) without affecting total distance (p=0.54) and increased time in the choice area (p=0.023) at the Y-maze centre, indicating a possible impairment in decision-making. In the medial prefrontal cortex, 2.5g/kg ethanol decreased mRNA expression of brain-derived neurotrophic factor, NMDA NR2A subunit, mGluR8 receptor, Homer1, the glutamate transporters SLC1a1 and SLC1a6 and Srr. In the nucleus accumbens this dose did not affect mRNA expression of the dopamine D1 or D2 receptors but did upregulate the GABA transporter GAT-3. Even if only correlational, these data suggest that gene expression changes in the medial prefrontal cortex and associated cognitive impairment occur before adaptation of the dopaminergic system and, presumably, drug dependence.

Keywords: Alcoholism; Cognitive impairment; Dopamine; GABA; qPCR.