The Effects of Tyrosine Hydroxylase Blockade in Mice Lacking the Norepinephrine Transporter (NET-KO Mice).

Abstract

In recent years, significant progress has been made in understanding that Parkinson's disease (PD) is associated not only with the dopamine (DA) but also with the norepinephric (NE) system. In order to investigate the potential involvement of NE in the development of the early motor symptoms of PD, we studied the effects of reducing its levels in a norepinephrine transporter knockout mouse (NET-KO). Due to the absence of NET, all the norepinephrine needed must be synthesized de novo. NET-KO mice were injected intraperitoneally with α-methyl-p-tyrosine (AMPT), a blocker of tyrosine hydroxylase, to induce a hyponoradrenergic state. Changes in tissue NE content in the frontal cortex and DA content in the striatum were evaluated using HPLC. We also measured the motor activity parameters of NET-KO mice after AMPT injection. The hyponorepinephric state induced by AMPT administration in NET-KO mice did not lead to severe motor impairments, as occurs in PD models. However, NET-KO mice did exhibit abnormal hindlimb extension, which began three hours after AMPT administration. This symptom may be interpreted as an early symptom preceding PD. These results suggest that the potential involvement of different neurotransmitter systems in motor abnormalities relevant to Parkinson's disease warrants further investigation.