Dynamic regulation of dopamine and serotonin responses to salient stimuli during chronic haloperidol treatment

Antipsychotic drugs are the clinical standard for the treatment of schizophrenia. Although these drugs work initially, many compliant patients relapse due to treatment failure. The known biomarkers can not sufficiently explain antipsychotic treatment failure. We, therefore, enquired how the dynamic responses of the neurotransmitters, dopamine and serotonin, change in relation to treatment action and failure. Rats received either short-term (2-6 d) or long-term (12-14 d) treatment with haloperidol, which resembled human D2 receptor occupancy, using osmotic mini-pumps. Dopamine and serotonin basal levels and responses to novelty, appetitive food, and to an aversive tail pinch were measured in the prefrontal cortex, nucleus accumbens and caudate putamen using in-vivo microdialysis, and the behaviour was recorded. Subsequently, we used in-vivo voltammetry to measure dopamine overflow in the nucleus accumbens. Haloperidol decreased dopamine, but not serotonin baseline levels in a time-dependent way. Salient stimuli induced dopamine and serotonin responses. Short-term haloperidol treatment attenuated the mesolimbic dopamine responses to aversive stimulation, while the responses to appetitive stimulation were largely preserved. After long-term treatment, the initial response adaptations were reversed. Similar changes were also observed at the behavioural level. In-vivo voltammetry showed that nucleus accumbens dopamine adaptations and their reversal were mediated by changes in extracellular dopamine release. Chronic haloperidol treatment, which resembles human D2 receptor occupancy, modulates dopamine and behavioural responses to aversive and appetitive stimulation depending on the duration of treatment. Specific changes in dopamine response dynamics and their reversal may be a functional substrate of antipsychotic action and failure respectively.