Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake

Abstract

Background: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. Methods: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. Results: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. Conclusions: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.

Elevated serum levels of TNF‐α, IL‐6, and IL‐18 in chronic methamphetamine users

“…Chronic methamphetamine use in animals and humans causes neuropsychiatric symptoms including psychosis, depression, anxiety, and cognitive impairments (Beirami et al, 2017;Glasner-Edwards et al, 2010;Huckans et al, 2015Huckans et al, , 2017McKetin et al, 2016;Nookala et al, 2018;Scott et al, 2007). A large number of studies suggest that upregulation of pro-inflammatory cytokines is involved in methamphetamine-mediated neuropsychiatric symptoms (Krasnova & Cadet, 2009;Loftis & Janowsky, 2014).…”

Aerobic exercise as a promising nonpharmacological therapy for the treatment of substance use disorders

“…Methamphetamine abuse disorder has been characterized as a debilitating neuropsychiatric disorder, and its manifested behavioral phenomena are led by brain dysfunction (Dluzen & Liu, 2008; Huckans et al., 2017; Lyketsos et al., 2007; Radfar & Rawson, 2014). It is known that methamphetamine also causes deficits in cognitive functions, such as verbal learning and memory, and that these impairments can worsen with higher doses of METH ((Salo et al., 2009; Zhan et al., 2018); for reviews, see Dean et al, 2013; Huang et al., 2020).…”

Prolonged Peripheral Immunosuppressive Responses as Consequences of Random Amphetamine Treatment, Amphetamine Withdrawal and Subsequent Amphetamine Challenges in Rats

“…The psychostimulants amphetamine (AMPH) and methamphetamine (METH) are potent and addictive illicit drugs that are frequently abused worldwide. Chronic AMPH/METH use can result in serious and pronounced cognitive (Sahaklan et al 2000 ), neurological (Volkow et al 2001 ) and psychiatric dysfunctions (Dyer and Cruickshank 2007 ; Huckans et al 2017 ) in addition to physical health problems (Turnipseed et al 2003 ). The reinforcing properties of AMPH/METH are associated with prolonged and enhanced functionality monoamine neurotransmitter dopamine and noradrenaline within the mesocorticolimbic circuit (Goodman et al 1990 ; Meredith et al 2005 ; Barr et al 2010 ).…”