Official websites use. Share sensitive information only on official, secure websites. The use of haloperidol in the original DNC test to challenge dopamine neurons was less than ideal, as it may cause extrapyramidal motor symptoms. Here we report an improved DNC Test, in which the original challenging agents, haloperidol and methylphenidate, are replaced by a single challenging agent, a dopamine autoreceptor preferring antagonist AJ76 or UH We show that the improved DNC Test can achieve the same level of sensitivity and selectivity in detecting early PD in a mouse model without causing motor side effects.
These findings significantly improve the practicality of using the DNC Test as a screening or diagnostic test for detecting early-stage PD in the high-risk population in humans. The most pronounced neuropathological feature is the progressive loss of dopamine neurons DANs in the substantia nigra pars compacta SNc Lima et al.
Since the loss of DANs is irreversible, an early diagnosis of the disease is critical for an early start of interventions Chan et al. It could also reveal the hypodopaminergic state at an ultra-early stage when MitoPark mice did not show detectable loss of DANs Zhou et al. One reasonable concern with the original DNC Test is the use of haloperidol as a challenging agent.
Haloperidol is known to have the risk of causing extrapyramidal symptoms in elderly adults by blocking postsynaptic D2Rs Sanberg, Figure 1. Blockade of postsynaptic D2 receptors by haloperidol leads to Parkinsonian symptoms. Haloperidol is a nonselective DR2 antagonist blocking both pre- autoreceptors and postsynaptic D2Rs Garau et al. Since its DAN challenging effect is mediated by blocking dopamine autoreceptors, and its motor side effects are mediated by blocking the postsynaptic D2Rs Sanberg, , we hypothesize that replacing haloperidol with a dopamine autoreceptor preferring antagonist Sotnikova et al.
In the current study, we explored whether dopamine autoreceptor antagonists AJ76 Johansson et al. Either AJ76 or UH was injected intraperitoneally i. Viral vectors were micro-injected into the left and right dorsal striatum by standard stereotaxic procedures with animals under isoflurane anesthesia Cui et al. A total volume of 1. The needle was left in place for ten more minutes before withdrawal. The volume ratio of viral vectors in the mixtures for injections was for dLight1. Another pair of bur holes for anchoring screws were drilled bilaterally above the parietal lobes.
