Dopamine D2 receptors: key regulators of dopaminergic transmission
Anzalone, Andrea (2011) Dopamine D2 receptors: key regulators of dopaminergic transmission. [Tesi di dottorato] (Inedito)
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Dopamine (DA) is an important neuromodulator of the central nervous system; an accurate control of DA levels and the resulting interaction with DA receptors is important for a correct brain functioning. Several human neurological disorders such as Parkinson’s disease and psychiatry disorders are characterized by DArgic dysfunctions. DA D2 receptor (D2R) occupies a privileged position in the dopaminergic transmission. D2Rs are widely expressed in the brain; importantly, they are expressed presynaptically on dopaminergic neurons as well as postsynaptically on neurons targeted by dopaminergic neurons. To date it has been impossible to discern pre- from post-synaptic D2R-mediated functions. Genetically engineered mice, thus, represent important tools to address this question and identify D2R functions in vivo. Presynaptically, D2Rs (also named autoreceptors) regulate DA synthesis and release from dopaminergic neurons; thereby, their activation (i.e. by agonists/antagonists) affects mice motor behavior and can be used as readout of autoreceptor functions. Importantly, we have recently generated mutants lacking D2Rs either from dopaminergic neurons or from striatal medium spiny neurons (MSNs). D2 autoreceptor mutants present hyperactivity in a novel environment and an increased motor response to cocaine. Unexpectedly, we observed that in the absence of these receptors, the postsynaptic D2Rs (heteroreceptors) exert an inhibitory control on dopaminergic neurons thus affecting the release and the synthesis of DA, a function previously thought to be controlled only by D2 autoreceptors. Conversely, mice lacking D2Rs on the MSNs present a strong impairment of movements and an altered response to drugs such as cocaine, showing their importance in the regulation of the initiation of movement.
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