Regulation of Glutamate Release by α7 Nicotinic Receptors: Differential Role in Methamphetamine-Induced Damage to Dopaminergic and Serotonergic Terminals

Abstract

Regulation of glutamate release is an important underlying mechanism in mediating excitotoxic events such as damage to dopamine (DA) and serotonin (5-HT) neurons observed after exposure to methamphetamine (Meth). One way to regulate glutamate release may be through the modulation of ␣7 nicotinic acetylcholine (nACh) receptors. Meth administration is known to increase acetylcholine release; however, it is unknown whether Meth increases glutamate release and causes long-term damage to both DA and 5-HT terminals through the activation of ␣7 nACh receptors. To test this hypothesis, the ␣7 nACh receptor antagonist, methyllycaconitine (MLA), was administered before the administration of repeated doses of Meth while simultaneously monitoring extracellular striatal glutamate with in vivo microdialysis. In addition, the subsequent longterm decreases in markers of dopaminergic and serotonergic terminals, including DA reuptake transporter (DAT), serotonin reuptake transporter (SERT), vesicular monoamine transporter-2, vesicular DA, and vesicular 5-HT content in the rat striatum, were measured. The results show that MLA pretreatment prevented Meth-induced increases in striatal glutamate and protected against the subsequent long-term decreases in striatal DAT and vesicular DA content without affecting the hyperthermia produced by Meth. In contrast, the Meth-induced decreases in striatal SERT immunoreactivity and vesicular 5-HT content were not affected by MLA. This suggests that the ␣7 nACh receptor differentially mediates glutamate-dependent damage to DA but not 5-HT terminals in a manner that is independent of hyperthermia. Furthermore, antagonism of ␣7 nACh receptors may be a possible therapeutic strategy for decreasing extracellular glutamate and preventing the excitotoxic damage observed in other DA-related neurodegenerative disorders.

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

“…These data extend past studies indicating a role for a7 nAChRs in contributing to the neurotoxic effects of METH (Northrop et al, 2011), by implicating a4b2 nAChRs as contributing to this phenomenon. The lack of a6b2 nAChRs, owing to a shift in balance with a4b2 nAChRs, may also affect this phenomenon.…”

Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine

“…The prostaglandin EP1R is associated with excitotoxic damage and activation of the EP1R potentiates NMDA-induced neurotoxicity, whereas antagonism of the receptor protects neurons against NMDA-induced cell death (Kawano et al, 2006). Because Meth increases extracellular concentrations of glutamate (Nash and Yamamoto, 1992; Northrop et al, 2011) and stress enhances Meth-induced glutamate release and excitotoxicity (Raudensky and Yamamoto, 2007; Tata and Yamamoto, 2008), the effects of the EP1R antagonist, SC-51089, on Stress+Meth-induced monoaminergic depletions were studied. Contrary to our expectations, antagonism of the EP1R during Meth treatment did not attenuate hippocampal or striatal monoaminergic depletions induced by the combination of stress and Meth (Fig 7).…”

Neuroimmune Basis of Methamphetamine Toxicity

“…In the rat, 6-hydroxydopamine model of Parkinson’s disease, the α7 receptor agonist, 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride, reduces 6-hydroxydopamine-induced cell loss and the elevation of markers of neurotoxicity (Suzuki et al, 2013). The possibility that α7 receptors play a similar role in methamphetamine-induced neurotoxicity is supported by evidence that the α7 antagonist methyllycaconitine (MLA) prevents methamphetamine-induced neurotoxic events including decreases in cellular dopamine and in dopamine transporter expression, and methamphetamine-induced glutamate release (Northrop, Smith, Yamamoto, & Eyerman, 2011). The effect may be mediated by ROS, since MLA blocks methamphetamine-induced ROS production (Escubedo, Camarasa, Chipana, García-Ratés, & Pubill, 2009; Escubedo, Chipana, Pérez-Sánchez, Camarasa, & Pubill, 2005; Pubill et al, 2005).…”