Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteraction by co-administration with local anesthetics

Abstract

Alterations of norepinephrine transporter (NET) function by chronic inhibition of NET in relation to sensitization to seizures induce by cocaine and local anesthetics were studied in mice. Daily administration of desipramine, an inhibitor of the NET, for 5 days decreased [(3)H]norepinephrine uptake in the P2 fractions of hippocampus but not cortex, striatum or amygdalae. Co-administration of lidocaine, bupivacaine or tricaine with desipramine reversed this effect. Daily treatment of cocaine increased [(3)H]norepinephrine uptake into the hippocampus. Daily administration of desipramine increased the incidence of appearance of lidocaine-induced convulsions and decreased that of cocaine-induced convulsions. Co-administration of lidocaine with desipramine reversed the changes of convulsive activity of lidocaine and cocaine induced by repeated administration of desipramine. These results suggest that down-regulation of hippocampal NET induced by chronic administration of desipramine may be relevant to desipramine-induced sensitization of lidocaine convulsions. Inhibition of Na(+) channels by local anesthetics may regulate desipramine-induced down-regulation of NET function. Repeated administration of cocaine induces up-regulation of hippocampal NET function. Desipramine-induced sensitization of lidocaine seizures may have a mechanism distinct from kindling resulting from repeated administration of cocaine.

Insulin Reveals Akt Signaling as a Novel Regulator of Norepinephrine Transporter Trafficking and Norepinephrine Homeostasis

“…In addition, chronic antidepressant treatment in both mice and humans results in enhanced levels of phosphorylated Akt (Krishnan et al, 2008) which our studies correlate with decreased surface NET. Interestingly, chronic antidepressant treatment has also been shown to result in a down regulation of NET (Kitayama et al, 2006; Song et al, 2008; Jeannotte et al, 2009b; Jeannotte et al, 2009a). Whether this antidepressant-stimulated decrease in surface NET is Akt dependent, however remains to be determined.…”

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

“…6), arguably offsetting any lesion-induced increase (Chotibut et al, 2012). Chronic DMI can reduce NET expression in other CNS regions such as amygdala, striatum (Jeannotte et al, 2009), and hippocampus (Kitayama et al, 2006). We also point out that the serotonin terminals or transporter (SERT) can affect LID severity in preclinical models Eskow et al, 2007;Bishop et al, 2012).…”

Regulated interactions of the norepineprhine transporter by the actin and microtubule cytoskeletons

“…Its activity underlies arousal, attention, and sleep, and a variety of disorders, such as depression, attention deficit disorders, drug addiction and Parkinson's disease (Jellinger 1991;Miller and Gold 1993;Klimek et al 1997;Aston-Jones et al 2000;Gesi et al 2000;Zahniser and Doolen 2001;Marien et al 2004;Aston-Jones and Cohen 2005;Bonisch and Bruss 2006;Kim et al 2006). Many modes of regulating NET have been identified including transient activation of kinases and phosphatases Apparsundaram et al 2001;Holton et al 2005;Jayanthi et al 2004Jayanthi et al , 2006Sung and Blakely 2007;Yang and Raizada 1999) and chronic regulation via drugs (Benmansour et al 2004;Dipace et al 2007;Frazer 2001;Galli et al 1995;Hebert et al 2001;Heikkila et al 1975;Kantor et al 2004;Kitayama et al 2006;Mash et al 2005;Miller and Gold 1993;Pacholczyk et al 1991;Xu et al 2000;Zhu et al, 1998), yet a clear mechanism of regulation that is both longterm and endogenous remains elusive.…”