Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

Abstract

The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

Inhibition of Monoamine Neurotransmitter Transporters and Central Nervous System Stimulation Induced by Synthetic Local Anesthetics and Cocaine: A Comparative Review-Update

“…Therefore, it is suggested that chronic inhibition of MAT is closely related to the development of local anesthetic-induced kindling. This is further supported by the facilitation of the development of lidocaine-kindling by repeated administration of specific inhibitors of DAT, NET or SERT [45]. Daily treatment with desipramine and maprotiline for 5 days remarkably increased the incidence of lidocaine-induced convulsions, intensified the symptoms of convulsions as shown by an increased score, and reduced the convulsive threshold for lidocaine.…”

“…Comparing the ability of daily treatment with a subconvulsive dose of the following 3 local anesthetics with different properties; cocaine with a potent inhibitory action on MAT, meprylcaine with a relatively potent inhibitory action on MAT and lidocaine lacking an inhibitory effect on MAT [1], clearly showed that the two former local anesthetics produced kindling seizures within 5 days, while lidocaine did not. These results indicate that the chronic administration of local anesthetics that inhibit MAT can facilitate convulsive activity, while that of lidocaine, which lacks this property, does not [45]. Therefore, it is suggested that chronic inhibition of MAT is closely related to the development of local anesthetic-induced kindling.…”

The 3′ Part of the Dopamine Transporter Gene DAT1/SLC6A3 Is Associated With Withdrawal Seizures in Patients With Alcohol Dependence

“…Several drugs have pro‐convulsive effects, such as cocaine (Post, 2004) or bupropion (Foley et al., 2006). This effect is probably linked to their common effect of inhibition of the DAT function (Arai et al., 2003) and can be in part facilitated by the stimulation of dopamine D1 receptors (Witkin et al., 1993). DAT1 plays a physiological role in prolactin gene expression and secretion (Demaria et al., 2000).…”

Seizures, illicit drugs, and ethanol

“…In mice, cocaine sensitization (to itself as well as to seizures induced by other local anesthetics) depends critically on its actions at norepinephrine transporters, less so on its actions at dopamine transporters, and not at all on actions at serotonin transporters [ 14 ]. In other animal studies, dopamine release in the nucleus accumbens and cocaine actions at sigma receptors appeared to be involved in cocaine-induced seizures [ 15 ].…”