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Description:
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Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum, part of the brain’s reward circuitry. However, the specific mechanisms driving this vulnerability are poorly understood. Further, D2Rs are expressed ubiquitously throughout the striatum in several cell types and axonal projections, thus the particular subpopulation of D2Rs important for generating vulnerability toward cocaine abuse is unclear. Within the striatum, indirect pathway medium spiny neurons (iMSNs) express D2Rs and form inhibitory, GABAergic synapses on neighboring striatal neurons through axon collaterals. In the current study, we uncovered a novel synaptic mechanism through which cocaine exerts its stimulant effect on locomotion. By using transgenic mice with targeted deletion of D2Rs from iMSNs in combination with ex vivo slice electrophysiology, behavioral pharmacology, and chemogenetic rescue experiments, we characterized how D2Rs gate this striatal synaptic mechanism to promote cocaine’s canonical locomotor stimulant response. Subsequent experiments investigated how this selective D2R downregulation triggers alterations in striatal dopamine D1 receptors and also adressed whether low levels of these D2Rs potentiates cocaine seeking and taking use a mouse model of cocaine self-administration. Our data indicate that low levels of striatal D2Rs induce profound adaptations in striatal circuit functioning and suggest that these adaptations may be important in regulating the behavioral responses to repeated cocaine administration.
WebEx information
Meeting number (access code): 623 767 978
Host key: 454097
Meeting password: PzDdxgkS
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Series Name:
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Neurobiology Interest Group Seminar Series
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Videocast:
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Event will not be videocast
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