Neuroprotective Effects of Selegiline Agent Methamphetamine‑Prompted Mood‑Related Behavior Disorder Mediated Via 5‑HT2 and D2 Receptors

Mina Gholami, Neda Kaviani, Majid Motaghinejad, Luis Ulloa


Background: Many previous studies demonstrated that methamphetamine (METH) abuses can cause mood‑related behavioral changes. Previous studies indicated neuroprotective effects of Selegiline. Methods: Seventy male Wistar rats were randomly divided into eight groups (10 rats in each group). Group 1 and Group 2 received normal saline and methamphetamine (10 mg/kg) for 21 days, respectively. Groups 3, 4, and 5 were treated simultaneously with methamphetamine and Selegiline with doses of 10, 15, and 20 mg/kg for 21 days. Groups 6 and 7 are methamphetamine‑dependent groups which received 15 mg/kg of Selegiline with haloperidol (as D2 receptor antagonist) and trazodone (as 5‑HT2 receptor antagonist) for 21 days, respectively. In days 23 and 24, elevated plus maze (EPM) and open‑field test (OFT) were conducted to assess motor activity and mood (anxiety and depression) levels. Results: METH as 10 mg/kg causes reduction of rearing number, ambulation distances, time spent in central square and also number of central square entries in OFT. Also METH administration causes decreases of time spent in open arm and number of open arm entries and increases of time spent in closed arm and number of closed arm entries in EPM. In contrast, Selegiline (of 10, 15, and 20 mg/kg) inhibited behavioral effects of methamphetamine in both OFT and EPM. Also administration of haloperidol and trazodone inhibited these behavioral protective effects of Selegiline and caused decrease of OFT behaviors (rearing number, ambulation distances, time spent in central square, and also number of central square entries) and also caused decreases of spend times in open arm, number of open arm entries, and also increased closed arm time spending and number of entries in closed arm in EPM. Conclusions: Current research showed that Selegiline via mediation of D2 and 5‑HT2 receptors inhibits METH‑induced neurobehavioral changes, mood‑related behavior, and motor activity disturbances.


D2 and 5‑HT2 receptors; methamphetamine; neurobehavioral; Selegiline


Chomchai C, Chomchai S, Global patterns of methamphetamine

use. Curr Opin Psychiatry 2015;28:269‑74.

Keshavarzi S, Kermanshahi S, Karami L, Motaghinejad M,

Motevalian M, Sadr S. Protective role of metformin

against methamphetamine induced anxiety, depression,

cognition impairment and neurodegeneration in rat: The

role of CREB/BDNF and Akt/GSK3 signaling pathways.

Neurotoxicology 2019;72:74‑84.

Mozaffari S, Yasuj SR, Motaghinejad M, Motevalian M,

Kheiri R. Crocin acting as a neuroprotective agent against

methamphetamine‑induced neurodegeneration via CREB‑BDNF

signaling pathway. Iran J Pharm Res 2019;18:745‑58.

Mehrafza S, Kermanshahi S, Mostafidi S, Motaghinejad M,

Motevalian M, Fatima S. Pharmacological evidence

for lithium‑induced neuroprotection against

methamphetamine‑induced neurodegeneration via Akt‑1/GSK3

and CREB‑BDNF signaling pathways. Iran J Basic Med Sci


Borumand MR, Motaghinejad M, Motevalian M, Gholami M.

Duloxetine by modulating the Akt/GSK3 signaling pathways

has neuroprotective effects against methamphetamine‑induced

neurodegeneration and cognition impairment in rats. Iran J Med

Sci 2019;44:146‑54.

Harro J. Neuropsychiatric adverse effects of amphetamine and

methamphetamine. Int Rev Neurobiol 2015;120:179‑204.

Alam‑mehrjerdi Z, Mokri A, Dolan K. Methamphetamine use and

treatment in Iran: A systematic review from the most populated

Persian Gulf country. Asian J Psychiatry 2015;16:17‑25.

Majdi F, Taheri F, Salehi P, Motaghinejad M, Safari S.

Cannabinoids ∆9‑tetrahydrocannabinol and cannabidiol may

be effective against methamphetamine induced mitochondrial

dysfunction and inflammation by modulation of Toll‑like

type‑4 (Toll‑like 4) receptors and NF‑κB signaling. Med

Hypotheses 2019;133:109371.

Tábi T, Vécsei L, Youdim MB, Riederer P, Szökő É. Selegiline:

A molecule with innovative potential. J Neural Trans


Amini‑Khoei H, Saghaei E, Mobini G‑R,

Sabzevary‑Ghahfarokhi M, Ahmadi R, Bagheri N, et al.

Possible involvement of PI3K/AKT/mTOR signaling pathway

in the protective effect of selegiline (deprenyl) against memory

impairment following ischemia reperfusion in rat. Neuropeptides


Martinez D, Narendran R. Imaging neurotransmitter release by

drugs of abuse. Curr Top Behav Neurosci 2010;3:219‑45.

Chiu VM, Schenk JO, Mechanism of action of methamphetamine

within the catecholamine and serotonin areas of the central

nervous system. Curr Drug Abuse Rev 2012;5:227‑42.

Büttner A. The neuropathology of drug abuse. Neuropathol Appl

Neurobiol 2011;37:118‑34.

Granado N, Ares‑Santos S, Oliva I, O’Shea E, Martin ED,

Colado MI, et al. Dopamine D2‑receptor knockout mice are

protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA. Neurobiol Dis 2011;42:391‑403.

Hadlock GC, Chu PW, Walters ET, Hanson GR, Fleckenstein AE.

Methamphetamine‑induced dopamine transporter complex

formation and dopaminergic deficits: The role of D2 receptor

activation. J Pharmacol Exp Ther 2010;335:207‑12.

Doyle JR, Yamamoto BK. Serotonin 2 receptor modulation

of hyperthermia, corticosterone, and hippocampal serotonin

depletions following serial exposure to chronic stress and

methamphetamine. Psychoneuroendocrinology 2010;35:629‑33.

van Wel JH, Kuypers KPC, Theunissen EL, Bosker WM,

Bakker K, Ramaekers JG. Effects of acute MDMA intoxication

on mood and impulsivity: Role of the 5‑HT2 and 5‑HT1

receptors. PLoS One 2012;7:e40187.

Wahdan SA, Tadros MG, Khalifa AE. Antioxidant and

antiapoptotic actions of selegiline protect against 3‑NP‑induced

neurotoxicity in rats. Naunyn Schmiedeberg’s Arch Pharmacol


Onur MA, SEKKİN S. The neuroprotective effect of selegiline in

streptozotocin induced diabetic rats. J Cell Neurosci Oxid Stress


Gould TD, Dao DT, Kovacsics CE. The Open Field test, in

Mood and Anxiety Related Phenotypes in Mice. Springer; 2009.

p. 1‑20.

File SE, Lippa AS, Beer B, Lippa MT. Animal tests of

anxiety. Curr Protoc Neurosci 2004; Chapter 8: Unit 8.3. doi:


Ghafarimoghadam M, Mashayekh R, Gholami M, Fereydani P,

Shelley‑Tremblay J, Kandezi N, et al. A review of behavioral

methods for the evaluation of cognitive performance in animal

models: Current techniques and links to human cognition.

Physiol Behav 2022;244:113652.

Castagné V, et al. Rodent models of depression: Forced

swim and tail suspension behavioral despair tests in rats and

mice. Curr Protoc Pharmacol 2010; Chapter 5: Unit 5.8. doi:

1002/ 0508s49.

Walf AA, Frye CA. The use of the elevated plus maze as

an assay of anxiety‑related behavior in rodents. Nat Protoc


Xie Z, Miller GM. A receptor mechanism for methamphetamine

action in dopamine transporter regulation in brain. J Pharmacol

Exp Ther 2009;330:316‑25.

NOVÁKOVÁ, Jana. Pharmacological manipulation with 5-HT2

receptor subtype affects methamphetamine i.v. self-administration

in rats. In Abstract Book of Sixth IBRO World Congress of

Neuroscience. Prague (Czech Republic): Neuveden, 2003. s.

-205. ISBN 80-239-0887-1.

Fonseca R, Carvalho RA, Lemos C, Sequeira AC, Pita IR,

Carvalho F, et al. Methamphetamine induces anhedonic-like

behavior and impairs frontal cortical energetics in mice. CNS

Neurosci Ther 2017;23:119‑26.

Moore JJ, Saadabadi A. Selegiline. Stat Pearls; 2020.

Amiri S, Amini‑Khoei H, Mohammadi‑Asl A, Alijanpour S,

Haj‑Mirzaian A, Rahimi‑Balaei M, et al. Involvement of D1

and D2 dopamine receptors in the antidepressant‑like effects of

selegiline in maternal separation model of mouse. Physiol Behav


Ishikawa T, Okano M, Minami A, Tsunekawa H, Satoyoshi H,

Tsukamoto Y, et al. Selegiline ameliorates depression‑like

behaviors in rodents and modulates hippocampal dopaminergic

transmission and synaptic plasticity. Behav Brain Res


Ayano G. Dopamine: Receptors, functions, synthesis, pathways,

locations and mental disorders: Review of literatures. J Ment

Disord Treat 2016;2:2.

Zarrindast M‑R, Khakpai F. The modulatory role of dopamine in

anxiety‑like behavior. Arch Iran Med 2015;18:591‑603.

Healy D. Serotonin and depression. BMJ 2015;350:h1771.

Paulus MP, Stewart JL. Neurobiology, clinical presentation, and

treatment of methamphetamine use disorder: A review. JAMA

Psychiatry 2020;77:959‑66.

Magyar K. The pharmacology of selegiline. Int Rev Neurobiol