Short communicationThe neurochemical consequences of methamphetamine self-administration in male and female rats
Introduction
The use of the highly addictive psychostimulant, methamphetamine (METH), occurs in both genders. Within the United States, females make up approximately 40% of lifetime METH users and approximately 50% of adolescent METH users (Chen et al., 2014). Recent studies suggest that gender differences exist in the use of METH, and its behavioral and psychological effects. Reports suggest that females start using METH at a younger age, transition from recreational use to addiction more quickly, and initiate the injection METH earlier than their male counterparts (Dluzen and Liu, 2008, Hadland et al., 2010, Liu et al., 2013, Rawson et al., 2005). Drug craving was also significantly correlated with depression and anxiety measures in male METH users but not females (Hartwell et al., 2016). Increased rates of depression, psychosis, and suicide have also been reported in females compared to males (Glasner-Edwards et al., 2008a, Glasner-Edwards et al., 2008b, Mahoney et al., 2010). Female METH users also reported a greater severity of drug use and psychological burden than their male counterpart (Simpson et al., 2016), further demonstrating the importance of investigating gender differences in METH users.
Recent clinical findings suggest that female METH/stimulant users show greater changes in the brain compared to their male counterparts. Female METH users currently in abstinence had reductions in hippocampal volumes compared to control females, whereas no difference was observed between METH-abusing and control male subjects (Du et al., 2015). Furthermore, female METH users had significantly lower phosphocreatine levels in the frontal lobe compared to male METH users (Sung et al., 2013). Researchers have also found that female METH/stimulant users displayed wide-spread reductions in grey matter volumes following prolonged abstinence (Regner et al., 2015). These changes in the female brain may in turn contribute to addictive behaviors and an increased risk of neurodegenerative diseases later in life.
Similar to findings in humans, preclinical studies utilizing METH self-administration have found sex-differences in drug use parameters. Female rats acquired METH self-administration more quickly than males (Kucerova et al., 2009, Reichel et al., 2012, Roth and Carroll, 2004). Further, female rats with a history of METH self-administration more vigorously reinstated drug-seeking compared to males (Cox et al., 2013, Holtz et al., 2012, Reichel et al., 2012). However, few studies have investigated the neurochemical consequences of METH self-administration in male and female rats. Previous research in male rats suggests METH self-administration increases brain-derived neurotrophic factor (BDNF) in various areas of the brain which may reduce the toxic effects of METH including attenuating the reduction of dopamine transporter (DAT) in the striatum (Krasnova et al., 2013, McFadden et al., 2014). This increase in BDNF declines during abstinences from METH (Krasnova et al., 2013). Therefore, the current study investigated the acute neurochemical consequences of METH self-administration in male and female rats.
Section snippets
Animals
Male and female Sprague-Dawley rats (postnatal day 59–62; Charles River Laboratories) were housed two rats/cage. After surgery, rats were individually housed in transparent plastic cages. Water was available ad libitum. During food training, rats were food restricted such that no rat dropped below 90% of their starting body weight. Rats were maintained in a 14:10 h light/dark cycle. Animals were euthanized by rapid decapitation. All experiments were approved by the University of Utah’s
Results
Saline self-administering rats decreased active lever pressing over the course of the 7 d, whereas METH rats increased lever pressing (Group x Day: F(6,228) = 26.44, p < 0.05; Fig. 1A). No sex differences were found (Sex: F(1,28) = 1.74, ns; Sex x Day: F(6,228) = 0.49, ns; Sex x Group x Day: F(6,228) = 0.46, ns). Due to sex-differences in body weight, daily METH intake was normalized to body weight. Male and female rats increased daily METH intake over the course of the 7 days (F(6,108) = 6.35, p < 0.05; Fig.
Discussion
The current study investigated the potential sex-differences in the neurochemical effects of METH self-administration. Results revealed similar METH intake between male and female rats, but females and METH rats had higher body temperatures. In both sexes, METH self-administration reduced striatal DAT immunoreactivity. However, only male rats that self-administered METH had elevated hippocampal BDNF levels.
In previous self-administration studies, female rats acquired METH self-administration
Contributors
Participated in research design: McFadden and Johansen; Performed data analysis: McFadden and Johansen; Wrote or contributed to the writing of the manuscript: McFadden and Johansen; Conducted experiments: McFadden and Johansen; All authors contributed to and have approved the final manuscript.
Role of funding source
Funding for this study was provided by National Institute of Health, National Institute on Drug Abuse grant, DA036012. The National Institute of Health had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Conflict of interest
No conflict declared.
Acknowledgements
METH was generously supplied by the NIDA Drug Supply Program.
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2020, Drug and Alcohol DependenceCitation Excerpt :Rats were food trained and underwent surgery as previously described (McFadden et al., 2012). Briefly, animals underwent 4–5 overnight sessions of food training (14 h each), where active lever presses resulted in the delivery of a 45 mg food pellet as previously described (Johansen and McFadden, 2017). Animals then underwent surgery to implant a jugular catheter under ketamine (100 mg/kg i.p.) and xylazine (7 mg/kg i.p.) anesthesia.
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2019, Behavioural Brain ResearchCitation Excerpt :Interestingly, comparison of the present results to those of a past study show that male rats self-administered more saline than female rats (average infusions/session male: 7.2; female: 4.5) [32]. A few prior studies found no sex differences in saline self-administration; however, these studies used sessions that were 6 h in length or longer [56,57], or used a social context during self-administration [58], which complicates comparison to the present study. Synthetic cathinone administration, and duration of exposure to experimental conditions produced several effects on neurotransmitters in the present study.
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2019, Behavioural Brain ResearchCitation Excerpt :Rather, a shift from involvement of the ventral striatum to the dorsal striatum likely contributes to the addiction-like phenotype [21,51,52]. The dorsal striatum is thought to play an important role in goal directed behaviors and habit formation [21–51]. Thus, applied to the current experiment, control and stress exposed females may experience similar rewarding properties of MA, but the greater increase in dopamine in the dorsal striatum may increase the probability of further engaging in drug-seeking and drug-related habitual behaviors that are associated with addiction.