Blockade of the α‐MMT‐induced depletion of rat cortical norepinephrine levels: a method for determining the potency and duration of action of compounds with norepinephrine reuptake inhibition

Abstract

Neurotransmitter transporter inhibitors can prevent the depletion of brain monoamines when the depleting agent requires active uptake into neurons via a transporter. α-Methyl-m-tyrosine (α-MMT), a monoaminergic depleting agent, is β-hydroxylated to metaraminol in vivo and actively transported into noradrenergic neurons, leading to decreased levels of norepinephrine (NE). This depletion of NE by α-MMT is prevented by inhibitors of the neuronal NE transporter, but is dependent upon the dose of α-MMT administered. A 6.25 mg/kg, sc dose of α-MMT produced a 40% to 60% depletion of rat cortical NE 2 to 4 hours after administration that persisted up to 16 hours. Pretreatment with desipramine (DMI) at 10 mg/kg, sc significantly blocked NE depletion produced by a-MMT up to 8 hours regardless of whether measured 2 or 16 hours after a-MMT administration. The α-MMT-induced decrease in brain NE at 2 hours was dose-dependently blocked by a 1 hour pretreatment with DMI and reboxetine (REB) with ED50 doses of <1 and 2.0 mg/kg, sc, respectively. When administered at various times prior to α-MMT, DMI and REB pretreatment significantly blocked the α-MMT-induced depletion of rat cortical NE levels up to 8 hours with no significant effect at 24 hours. This experimental protocol allows for a rapid comparison of the potency and duration of NE reuptake inhibition in rat cortex, which has implications for development of agents effective in the treatment of central nervous system disorders.