Lobeline Attenuates Methamphetamine-Induced Changes in Vesicular Monoamine Transporter 2 Immunoreactivity and Monoamine Depletions in the Striatum

Abstract

L-Lobeline is an alkaloid that inhibits the behavioral effects of methamphetamine (METH) in rats. No studies have examined the effects of lobeline on the acute and long-term neurochemical changes produced by neurotoxic doses of METH. The effects of lobeline on METH-induced dopamine release, alterations in vesicular monoamine transporter 2 (VMAT-2) distribution, and long-term depletions of dopamine and serotonin (5-HT) content in the rat striatum were examined. METH increased body temperature and dopamine release, decreased VMAT-2 immunoreactivity at 1 and 24 h after METH, and decreased dopamine and 5-hydroxytryptamine (5-HT) content in striatum when examined 7 days later. Prevention of METH-induced hyperthermia attenuated the decrease in VMAT-2 as well as dopamine and 5-HT content. Lobeline pretreatment did not affect METH-induced dopamine release but attenuated the decreases in VMAT-2 after METH and the long-term decreases in striatal dopamine and 5-HT content. These effects of lobeline were due partly to the attenuation of METH-induced hyperthermia. The maintenance of hyperthermia during lobeline ϩ METH exposure restored the effects of METH on decreases in VMAT-2 as well as dopamine and 5-HT content. To examine the effects of lobeline independent of its effects on METHinduced hyperthermia, lobeline was administered after METH when body temperature returned to normal. Lobeline treatment at 5 and 7 h after METH attenuated the METH-induced decreases in synaptosomal, membrane-associated, and vesicular VMAT-2 24 h after METH, as well as the METH-induced decreases in dopamine and 5-HT content 7 days later. Therefore, lobeline has both temperature-dependent and -independent neuroprotective effects against METH toxicity.Methamphetamine (METH, ice, crystal) is an amphetamine derivative whose use has increased exponentially in the United States. METH is a significant health concern because of its abuse liability and potential neurotoxic effects, which include long-term monoamine depletions, degradation of both dopamine and serotonin (5-HT) striatal terminals in rodents and primates (Wagner et al., 1980;Gibb et al., 1987;Ricaurte and McCann, 1992), decreases in tyrosine hydroxylase activity (Gibb and Kogan, 1979), and loss of dopamine and serotonin transporters (Wagner et al., 1980). Despite these observed changes, the mechanisms underlying the toxic effects of METH remain to be elucidated.METH also affects the vesicular monoamine transporter 2 (VMAT-2), the protein that regulates the sequestration of monoamines into vesicles for subsequent release. Repeated administrations of high doses of METH cause a loss of VMAT protein on the vesicular membrane 1 h after a repeated high-dose regimen of METH (Riddle et al., 2002) and a decrease in VMAT-2 function 1 and 24 h after the last METH administration (Brown et al., 2000). Although the transient effects of METH on VMAT-2 function have been examined, it is unknown if the distribution of VMAT-2 protein is altered 24 h after METH and how this relates to the long-term effe...

Chronic stress enhances methamphetamine‐induced extracellular glutamate and excitotoxicity in the rat striatum

“…In contrast to previously published observations using the acute toxic dosing model (i.e., four injections of METH every 2 h; Daberkow et al, 2005;Eyerman and Yamamoto, 2005;Friedman et al, 1998;Ricaurte et al 1982;Straiko et al, 2007;Wallace et al, 2001), METH administration to rats not exposed to CUS did not produce depletions in 5-HT tissue content (Fig. 3B).…”

Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

“…For example, multiple high-dose administrations of METH rapidly (within 1 h) decrease VMAT2 activity (Brown et al, 2000), an effect that may be caused by a rapid redistribution of VMAT2 to a location that is not retained in the preparation of synaptosomes (Riddle et al, 2002) and oxidation of VMAT2 (Eyerman and Yamamoto, 2007). The decrease in VMAT2 function and a loss of VMAT2 immunoreactivity persist 24 h after treatment (Eyerman and Yamamoto, 2005;Chu et al, 2008). The present studies extend this work by demonstrating that the loss of VMAT2 immunoreactivity after 24 h is attenuated by pretreatment with the D2 receptor antagonist eticlopride.…”

Prior Exposure to Chronic Stress and MDMA Potentiates Mesoaccumbens Dopamine Release Mediated by the 5-HT1B Receptor

“…It can be speculated that one contributory factor may be a stressinduced reduction in the vesicular monoamine transporter-2 (VMAT-2) (Zucker et al, 2005) resulting in decreased filling of 5-HT vesicles (Pothos et al, 2000;Fon et al, 1997). This reduction of VMAT-2 and 5-HT quantal size may decrease basal release to a greater degree in neurons previously compromised by MDMA, particularly since neurotoxic amphetamines have also been shown to reduce VMAT-2 (Hansen et al, 2002;Eyerman and Yamamoto, 2005;Frey et al, 1997). Regardless, further studies are necessary to examine the impact of stress and MDMA on VMAT-2 as one of several mechanisms that are likely contributors to the observed decrease in basal 5-HT.…”