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

Abstract

Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2 mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.

Behavioral control by striatal adenosine A2A‐dopamine D2 receptor heteromers

“…D 2 R −/− mice demonstrated a significant ( P < .05) but relatively small reduction in spontaneous locomotor activity (Figure A,B), as previously reported in the D 2 R −/− C57BL/6 mouse . This is in contrast with the pronounced akinesia and catalepsy that characterizes pharmacological D 2 R blockade, which may be associated with neuroadaptations counteracting the loss of a D 2 R‐mediated tonic stimulatory effect on psychomotor activity (see Reference ). Likewise, the spontaneous locomotor activity of A 2A R −/− mice was significantly reduced ( P < .01) (Figure A,B), as also previously reported in the A 2A R C57BL/6 mouse .…”

Opioid and nondopamine reward circuitry and state‐dependent mechanisms

“…However, a compensatory response in dopamine‐deficient mice may result in the supersensitivity of dopamine signaling, in which dopamine‐deficient mice have low levels of dopamine beginning in the neonatal stage. Indeed, compensatory responses that are caused by long‐term low dopamine tone have been reported in several studies other than those that have employed mouse models of dopamine deficiency . However, dopamine‐deficient mouse could be used as a good model to understand phenotypes when dopamine is depleted.…”

Finasteride inhibited brain dopaminergic system and open‐field behaviors in adolescent male rats

“…35 Ablation of dopamine D2 receptor or age-related reduction of the brain dopaminergic activity was involved in motor dysfunction. 36,37 Thus, the present finding that finasteride treatment inhibited brain dopaminergic system, implies finasteride as a potential therapeutic option for neuropsychiatric disorders with hyperactivities of dopaminergic system and androgen.…”

“…The doses of finasteride were determined based on the previous reports. [20][21][22] Rats in finasteride group were repeatedly administrated with finasteride dissolved in sesame oil and ethanol (5% v/v) by subcutaneous injection on the back of rats once a day for 14 days from postnatal day [35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Rats in control group were administrated with vehicle (sesame oil) as the same protocol to those in finasteride group.…”