Midbrain dopaminergic neurons project to and modulate multiple highly interconnected modules of the basal ganglia, limbic system, and frontal cortex. Dopamine regulates behaviors associated with action selection in the striatum, reward in the nucleus accumbens (NAc), emotional processing in the amygdala, and executive functioning in the medial prefrontal cortex (mPFC). The multifunctionality of dopamine likely occurs at the individual synapses, with varied levels of phasic dopamine release acting on different receptor populations. This study aimed to characterize specific aspects of stimulation-evoked phasic dopamine transmission, beyond simple dopamine release, using in vivo fixed potential amperometry with carbon fiber recording microelectrodes positioned in either the dorsal striatum, NAc, amygdala, or mPFC of anesthetized mice. To summarize results, the present study found that the striatum and NAc had increased stimulation-evoked phasic dopamine release, faster dopamine uptake (leading to restricted dopamine diffusion), weaker autoreceptor functioning, greater supply levels of available dopamine, and increased dopaminergic responses to DAT blockade compared to the amygdala and mPFC. Overall, these findings indicate that phasic dopamine may have different modes of communication between striatal and corticolimbic regions, with the first being profuse in concentration, rapid, and synaptically confined and the second being more limited in concentration but longer lasting and spatially dispersed. An improved understanding of regional differences in dopamine transmission can lead to more efficient treatments for disorders related to dopamine dysfunction. K E Y W O R D Samperometry, amygdala, autoreceptors, dopamine, nucleus accumbens, phasic, prefrontal cortex, striatum, uptake | INTRODUC TI ONNeural modules involved in emotion, reward, executive functions, and action selection are all regulated by the same chemical signal, bursts of dopamine, which originate from neuronal firing deep within the midbrain (Schultz, 2010). Dopaminergic axons from the midbrain are distributed to multiple brain regions in two independent, parallel circuits, the nigrostriatal and mesocorticolimbic dopamine pathways, each projecting to many highly interconnected modules of the basal ganglia, limbic system, and frontal cortex. The modules and their interconnecting feedback networks make up larger systems termed the motor, motivational, and associative corticostriatal loops, independent neural networks

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed-potential amperometry with carbon-fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections..

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed-potential amperometry with carbon-fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections. (PPT), which projects to and stimulates dopamine cell bodies in the VTA [46,47]. For this reason, the present study stimulated the DN located contralateral to the NAc recording site (left DN stimulation with right NAc recording and vice versa). Lastly, in Experiment 3, we examined the potential cross-hemispheric influence of cerebellar DN on this dopaminergic pathway. During contralateral DN stimulation-evoked dopamine recordings, separate groups of mice received an infusion of either lidocaine or phosphate-buffered saline (PBS; vehicle control) into the ipsilateral DN to determine if communication between each cerebellar DN can influence the contralateral, active pathway being stimulated. (See Figure 1 for a depiction of the experimental configurations.) These experiments are the first to systematically examine the contribution of the cerebellum on lateralized stimulation-evoked phasic dopamine release in the NAc. An improved understanding of cerebello-cortico circuitry may help identify targets for pharmacological interventions in neuropathologies related to dopamine dysfunction.