Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs

• We studied the effects of ethanol in MK genetically deficient mice.
• Acquisition of CPP induced by a low dose of ethanol was enhanced in MK−/− mice.
• MK differentially modulates the behavioural responses to ethanol.
• The anxiolytic effects of a low dose of diazepam are enhanced in MK−/− mice.
• MK could be involved in the sensitivity of GABA(A) receptors to GABA(A) acting drugs.

Midkine (MK) is a cytokine with important functions in dopaminergic neurons that is found upregulated in the prefrontal cortex of alcoholics. We have studied the behavioural effects of ethanol in MK genetically deficient (MK−/−) and wild type (MK+/+) mice. A low dose of ethanol (1.0 g/kg), unable to cause conditioned place preference (CPP) in MK+/+ mice, induced a significant CPP in MK−/− mice, suggesting that MK prevents the rewarding effects of low doses of ethanol. However, this difference between genotypes is lost when a higher, rewarding, dose of ethanol (2.0 g/kg) is used. Accordingly, the anxiolytic effects of 1.0 mg/kg diazepam, other GABA(A) acting drug, were significantly enhanced in MK−/− mice compared to MK+/+ mice; however, 2.0 mg/kg diazepam caused increased anxiolytic effects in MK+/+ mice. In addition, MK−/− mice showed a significant delayed recovery from ethanol (2.0 g/kg)-induced ataxia whereas the sedative effects induced by ethanol (3.6 g/kg), tested in a loss of righting reflex paradigm, were found to be similar in MK−/− and MK+/+ mice. The data indicate that MK differentially regulates the behavioural responses to ethanol. The results suggest that differences in the sensitivity of GABA(A) receptors to GABA(A) acting drugs caused by genetic inactivation of MK could underlie the different behavioural responses to ethanol in MK−/− mice. Overall, these results suggest that MK may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of MK signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.