M-1 and M-3 muscarinic receptors may play a role in the neurotoxicity of anhydroecgonine methyl ester, a cocaine pyrolysis product

Author(s):Show less -

Tamborelli Garcia, Raphael Caio ^{[1, 2, 3, 4]} ; Munhoz Dati, Livia Mendonca ^[1] ; Torres, Larissa Helena ^[1] ; Alencar da Silva, Mariana Aguilera ^[1] ; Berto Udo, Mariana Sayuri ^[1] ; Francis Abdalla, Fernando Mauricio ^[5] ; da Costa, Jose Luiz ^[6] ; Gorjao, Renata ^[7] ; Afeche, Solange Castro ^[5] ; Yonamine, Mauricio ^[1] ; Niswender, Colleen M. ^{[3, 4]} ; Conn, P. Jeffrey ^{[3, 4]} ; Camarini, Rosana ^[8] ; Lopes Sandoval, Maria Regina ^[5] ; Marcourakis, Tania ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09913030 Diadema, SP - Brazil

^[3] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37212 - USA

^[4] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 - USA

^[5] Butantan Inst, Lab Pharmacol, BR-05503900 Sao Paulo, SP - Brazil

^[6] Criminalist Inst Sao Paulo, BR-05507060 Sao Paulo, SP - Brazil

^[7] Univ Cruzeiro Sul, Postgrad Program Human Movement Sci, Inst Phys Act Sci & Sports, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 5, DEC 2 2015.
• Web of Science Citations: 4

Abstract

The smoke of crack cocaine contains cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). AEME possesses greater neurotoxic potential than cocaine and an additive effect when they are combined. Since atropine prevented AEME-induced neurotoxicity, it has been suggested that its toxic effects may involve the muscarinic cholinergic receptors (mAChRs). Our aim is to understand the interaction between AEME and mAChRs and how it can lead to neuronal death. Using a rat primary hippocampal cell culture, AEME was shown to cause a concentration-dependent increase on both total {[}H-3]inositol phosphate and intracellular calcium, and to induce DNA fragmentation after 24 hours of exposure, in line with the activation of caspase-3 previously shown. Additionally, we assessed AEME activity at rat mAChR subtypes 1-5 heterologously expressed in Chinese Hamster Ovary cells. l-{[}N-methyl-H-3]scopolamine competition binding showed a preference of AEME for the M-2 subtype; calcium mobilization tests revealed partial agonist effects at M-1 and M-3 and antagonist activity at the remaining subtypes. The selective M-1 and M-3 antagonists and the phospholipase C inhibitor, were able to prevent AEME-induced neurotoxicity, suggesting that the toxicity is due to the partial agonist effect at M-1 and M-3 mAChRs, leading to DNA fragmentation and neuronal death by apoptosis. (AU)

• FAPESP's process: 11/02734-6 - Neuronal death pathway induced by methylecgonidine, cocaine pyrolysis product, and its involvement in addiction
• Grantee: Tania Marcourakis
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/11149-0 - Caracterization of death pathway, induced by metilecgonidine, product by cocaine pirolise.
• Grantee: Lívia Mendonça Munhoz Dati
• Support Opportunities: Scholarships in Brazil - Master