Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism

BELLO, EP; CASAS CORDERO, R; GALIÑANES, G; CASEY, E; BELLUSCIO, M; RODRÍGUEZ, V; NOAÍN, D; MURER, GM; RUBINSTEIN, M

MOLECULAR PSYCHIATRY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2017 vol. 22 p. 595 - 604

1359-4184

Motor execution and planning are tightly regulated bydopamine D1 and D2 receptors present in basal ganglia circuits. Althoughstimulation of D1 receptors is known to enhance motor function, the globaleffect of D2 receptor (D2R) stimulation or blockade remains highlycontroversial with studies showing increasing, decreasing or no changes inmotor activity. Moreover, pharmacological and genetic attempts to block oreliminate D2R have led to controversial results that questioned the importanceof D2R in motor function. In this study, we generated an inducible Drd2null-allele mouse strain that circumvented developmental compensations found inconstitutive Drd2-/- mice and allowed us to directly evaluate the participationof D2R in spontaneous activity, the acquisition of novel motor skills andduring the performance of previously learned motor routines. We have found thatloss of D2R during adulthood causes severe motor impairments, includinghypolocomotion, deficits in motor coordination, impaired learning of new motorroutines and spontaneous catatonia. Moreover, severe motor impairment, restingtremor and abnormal gait and posture, phenotypes reminiscent of Parkinson?sdisease, were evident when the mutation was induced in aged mice. Altogether,the conditional Drd2 knockout model studied here revealed the overallfundamental contribution of D2R in motor functions and explains some of theside effects elicited by D2R blockers when used in neurological and psychiatricconditions including schizophrenia, bipolar disorder, Tourette?s syndrome,dementia, alcohol-induced delusions, and obsessive-compulsive disorder.