Real-time monitoring of stimulated dopamine release in mice with different ␣-synuclein expression was used to study the role of ␣-synuclein in presynaptic dopamine recruitment. Repeated electrical stimulations of ascending dopaminergic pathways decreased the capacity of the readily releasable pool (RRP) and temporarily increased its refilling rate, significantly slowing the rate of dopamine decline in mice with normally expressed ␣-synuclein. Mice with ␣-synuclein null mutation demonstrated a permanent increase of the refilling rate. This increase maintained stable dopamine release during stimulation (which induced dopamine decline in other animals) and served as an adaptation to altered dopamine compartmentalization. Mice without ␣-synuclein and with overexpression of human A30P mutated ␣-synuclein had a lower capacity of the dopamine storage pool than other animals. Reducing capacity of the storage pool in transgenic A30P mice led to paradoxical effects of L-dopa, which elevated dopamine release in response to single stimulation but decreased the refilling rate of the RRP.

Accumulating evidence from clinical and preclinical studies shows that catechol-O-methyltransferase (COMT) plays a significant role in dopamine metabolism in the prefrontal cortex, but not in the striatum. However, to what extent dopamine overflow in the prefrontal cortex and striatum is controlled by enzymatic degradation versus reuptake is unknown. We used COMT deficient mice to investigate the role of COMT in these two brain regions with in vivo voltammetry. A real-time analysis of evoked dopamine overflow showed that removal of dopamine was twofold slower in the prefrontal cortex of mice lacking COMT than in wild-type mice, indicating that half of the dopamine decline in this brain region results from COMT-mediated enzymatic degradation. Lack of COMT did not influence dopamine overflow/decline in the dorsal striatum. COMT-deficient mice demonstrated a small (20 -25%) but consistent increase in evoked dopamine release in the prefrontal cortex, but not in the dorsal striatum. Cocaine affected equally dopaminergic neurotransmission in the prefrontal cortex in both genotypes by prolonging 3-4 times dopamine elimination from extracellular space. Paradoxically, this happened without increase of the peak levels of evoked dopamine release. The present findings represent the first demonstration of the significant contribution of COMT in modulating the dynamics of dopamine overflow in the prefrontal cortex and underscore the therapeutic potential of manipulating COMT activity to alter dopaminergic neurotransmission in the prefrontal cortex.

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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.