Dopamine transporter–mediated conductances increase excitability of midbrain dopamine neurons

10.1038/nn920 ◽  
2002 ◽  
Vol 5 (10) ◽  
pp. 971-978 ◽  
Author(s):  
Susan L. Ingram ◽  
Balakrishna M. Prasad ◽  
Susan G. Amara
Keyword(s):  
Dopamine Transporter ◽  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

scholarly journals The effect of dopamine transporter blockade on optical self-stimulation: behavioral and computational evidence for parallel processing in brain reward circuitry

2019 ◽  
Author(s):  
Ivan Trujillo-Pisanty ◽  
Kent Conover ◽  
Pavel Solis ◽  
Daniel Palacios ◽  
Peter Shizgal
Keyword(s):  
Dopamine Transporter ◽  
Time Allocation ◽  
Opportunity Cost ◽  
Dopamine Neurons ◽  
Reward Circuitry ◽  
Reward Seeking ◽  
Brain Reward ◽  
Midbrain Dopamine ◽  
The Brain ◽  
Midbrain Dopamine Neurons

AbstractThe neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the “reward mountain”). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.Author summaryTo succeed in the struggle for survival and reproductive success, animals must make wise choices about which goals to pursue and how much to pay to attain them. How does the brain make such decisions and adjust behaviour accordingly? An animal model that has long served to address this question entails delivery of rewarding brain stimulation. When the probe is positioned appropriately in the brain, rats will work indefatigably to trigger such stimulation. Dopamine neurons play a crucial role in this phenomenon. The dominant model of the brain circuitry responsible for the reward-seeking behavior treats these cells as a gateway through which the reward-generating brain signals must pass. Here, we challenge this idea on the basis of an experiment in which the dopamine neurons were activated selectively and directly. Mathematical modeling of the results argues for a new view of the structure of brain reward circuitry. On this view, the pathway(s) in which the dopamine neurons are embedded is one of a set of parallel channels that process reward signals in the brain. To achieve a full understanding of how goals are evaluated, selected and pursued, the full set of channels must be identified and investigated.

scholarly journals Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kauê Machado Costa ◽  
Daniela Schenkel ◽  
Jochen Roeper
Keyword(s):  
Dopamine Transporter ◽  
Marked Reduction ◽  
Dopamine Neurons ◽  
Novelty Preference ◽  
Male And Female ◽  
Behavioral Variables ◽  
Midbrain Dopamine ◽  
Calming Effect ◽  
Transporter Expression ◽  
Midbrain Dopamine Neurons

AbstractHeterozygous mice that express Cre-recombinase under the dopamine transporter promoter (DAT-Cre knock in mice, or KI) are widely used for targeting midbrain dopamine neurons, under the assumption that their constitutive physiology is not affected. We report here that these mice display striking sex-dependent behavioral and molecular differences in relation to wildtypes (WT). Male and female KI mice were constitutively hyperactive, and male KI mice showed attenuated hyperlocomotor responses to amphetamine. In contrast, female KIs displayed a marked reduction in locomotion (“calming” effect) in response to the same dose of amphetamine. Furthermore, male and female DAT-Cre KI mice showed opposing differences in reinforcement learning, with females showing faster conditioning and males showing slower extinction. Other behavioral variables, including working memory and novelty preference, were not changed compared to WT. These effects were paralleled by differences in striatal DAT expression that disproportionately affected female KI mice. Our findings reveal clear limitations of the DAT-Cre line that must be considered when using this model.

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