The role of the mesolimbic dopamine system in interferon-α mediated anhedonia

Abstract

SAMMUT, S. The role of the mesolimbic dopamine system in Interferon-a mediated anhedonia

Changes in sucrose intake were used as a measure of anhedonia. Non-drug manipulations confirmed that the differences observed in the sucrose concentration-intake curve between the single-bottle and three-bottle were not due to aversion or satiety but more likely attributable to an effort to regulate reward to an optimal level. In the single-bottle test increasing hours of deprivation prior to sucrose tests, nonspecifically altered sucrose intake, while increasing the response-force requirement to access the sucrose solutions decreased the consumption of the 1 % solution and increased the intake of the 32% solution, effectively shifting the bell-shaped response reward curve to the right. This effect was attributed to the motivational drive associated with the perceived reward value of the sucrose solution on offer. Sucrose intake is subject to modulation by several neurotransmitters including DAergic as evident by the effects of raclopride (RAC), a D2/D3/D4 receptor antagonist, glutamatergic (MK-801, non-competitive NMDA receptor antagonist) and GABAergic (muscimol and b acI of en , GABAA and GABAB receptor agonists respectively) systems which showed a similar intake pattern to those of increased response force requirement (i.e. decreased consumption at the 1 % sucrose solution and increased consumption at the 32% solution). Administration of chlordiazepoxide (CDP, a benzodiazepine anxiolytic) however, produced a non-specific increase at all concentrations of sucrose. These results indicate a close interaction between DA, GABA and glutamate in sucrose reward and anhedonia.

rHIFN-α is a cytokine used in the treatment of various viral illnesses. A major limiting factor in the therapy is depression. Acute administration of rHIFN-α decreased sucrose intake in a three-bottle test at all concentrations of sucrose, although the effect was greater at 1 % solution. Chronic administration of rHIFN-α decreased sucrose intake at the 1 % and increased that at the 32%. The increase in consumption of the 32% solution was reversed by the chronic administration of a tricyclic and selective serotonin reuptake inhibitor antidepressant. rHIFN-α however failed to alter locomotor activity or amphetamine (AMP)-induced sensitisation.

Using in vitro voltammetry in brain slices, it was shown that peripheral pretreatment with AMP led to increased levels of DA in the nucleus accumbens (NAcb) core relative to the rats that had been treated with vehicle. rHlFN- α, reduced evoked DA release in the NAcb core at all frequencies of stimulation. The administration of anti-human lFN-cx, antibody (mHlFNAb) reversed the decrease in sucrose intake at the 32% solution produced by the acute administration of rHlFN-cx,. This strongly suggests that the behavioural effects produced by lFN- α, may be related to these central dopaminergic changes. These findings are discussed in relation to a behavioural model for rHINF-α,-induced depression and relative to furthering our understanding into the possible mechanisms through which rHIFN-α, may produce depression in patients and possible therapeutic strategies to alleviate such.