Effects of adolescent methylphenidate administration on methamphetamine conditioned place preference in an animal model of attention-deficit/hyperactivity disorder: Examination of potential sex differences

Abstract

Background: Individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with a substance use disorder; however, the effects of long-term psychostimulant treatment on addiction are mixed. Preclinical studies are useful for further elucidating the relationship between ADHD and addiction-like behaviors, but these studies have focused on male subjects only. The goal of the current study was to determine if early-life administration of methylphenidate (MPH) augments methamphetamine (METH) conditioned place preference (CPP) and/or potentiates reinstatement of CPP in both male and female rats.

Methods: Male and female spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) received either MPH (1.5mg/kg; p.o.) or vehicle (1.0ml/kg) during adolescence (postnatal day [PND] ~29-57). Two weeks after cessation of MPH treatment, rats were tested for METH CPP (1.0mg/kg or 2.0mg/kg; s.c.). Rats were then given extinction sessions. Once rats met extinction criteria, they were tested for reinstatement of CPP following a priming injection of METH (0.25mg/kg; s.c.).

Results: All groups developed METH CPP, except vehicle-treated SHR males and vehicle-treated WKY females conditioned with the higher dose of METH (2.0mg/kg). Female SHRs treated with MPH showed greater reinstatement of METH CPP compared to female SHRs treated with vehicle. Adolescent MPH treatment did not augment the locomotor-stimulant effects of METH in adulthood.

Conclusions: These results demonstrate the importance of considering biological sex when prescribing psychostimulant medications for ADHD as long-term MPH administration may increase the risk of continued drug use in females with ADHD following a period of abstinence.

Keywords: Attention-deficit/hyperactivity disorder; Conditioned place preference; Reinstatement; Sex differences; Spontaneously hypertensive rat; Wistar Kyoto rat.

Figure 1.

Mean (± SEM) time spent (in s) in the METH-paired compartment during the pretest and the posttest. Data for SHRs are presented in panels a, b, e, and f; data for WKYs are presented in panels c, d, g, and h. The top row shows data for rats conditioned with the lower dose of METH (1.0 mg/kg). The bottom row shows data for rats conditioned with the higher dose of METH (2.0 mg/kg). Note, one vehicle-treated SHR male in the 1.0 mg/kg METH experiment is not depicted as the time spent in the METH-paired compartment during the pretest was 0 s. *p < .05, relative to the pretest. #p < .05, relative to SHR females and WKY males tested for METH (2.0 mg/kg) CPP.

Figure 2.

Mean (± SEM) time spent (in s) in the METH-paired compartment during the posttest, at the end of extinction, and during the reinstatement test. Data for SHRs are presented in panels a and b. Data for WKYs are presented in panels c and d. Note, only rats that met extinction criteria are presented in this figure. Because extinction and reinstatement of METH CPP were not influenced by the dose of METH used during conditioning, data are collapsed across METH dose. #p < .05, relative to the posttest. *p < .05, relative to extinction.

Figure 3.

Mean (± SEM) non-repeating photobeam breaks (measure of horizontal activity) during each conditioning session of CPP. Data for SHRs are presented in panels a, b, e, and f; data for WKYs are presented in panels c, d, g, and h. The top row shows data for rats conditioned with the lower dose of METH (1.0 mg/kg). The bottom row shows data for rats conditioned with the higher dose of METH (2.0 mg/kg). *p < .05, relative to WKYs. $p < .05, compared to male SHRs. #p < .05, compared to male WKYs. @p < .05, compared to rats conditioned with the higher dose of METH. Note, although not denoted by a symbol on the figure, METH increased non-repeating photobeam breaks in each group of animals.

Figure 4.

Mean (± SEM) repeating photobeam breaks (measure of stereotypy-like behavior) during each conditioning session of CPP. Data for SHRs are presented in panels a, b, e, and f; data for WKYs are presented in panels c, d, g, and h. The top row shows data for rats conditioned with the lower dose of METH (1.0 mg/kg). The bottom row shows data for rats conditioned with the higher dose of METH (2.0 mg/kg). *p < .05, relative to WKYs. #p < .05, relative to saline.