Concurrent exposure to methamphetamine and sexual behavior enhances subsequent drug reward and causes compulsive sexual behavior in male rats

Abstract

Methamphetamine (Meth) users report having heightened sexual pleasure, numerous sexual partners, and engaging in unprotected sex due to loss of inhibitory control. This compulsive sexual behavior contributes to increased prevalence of sexually transmitted infections, but the neural basis for this is unknown. We previously established a paradigm for compulsive sexual behavior in male rats in which visceral illness induced by lithium chloride was paired with sexual behavior (Davis et al., 2010; Frohmader et al., 2010a). The current study examined the effects of repeated Meth administration on sexual performance, compulsive sexual behavior, and sex or Meth reward. First, results demonstrated that seven daily administrations of 2 mg/kg, but not 1 mg/kg, Meth increased latencies to initiate mating. This impairment was evident 30 min after last Meth administration, but dissipated after 1 or 7 d of subsequent drug abstinence. Repeated 1 mg/kg Meth exposure resulted in compulsive sex-seeking behavior 2 weeks following last Meth administration. This effect was dependent on Meth administration being concurrent with sexual experience and was not observed in sexually experienced animals that received Meth alone. Moreover, concurrent Meth and sexual experience enhanced conditioned place preference (CPP) for Meth, and for concurrent Meth and mating compared with Meth or mating alone. In contrast, CPP for mating alone was decreased. Together, these data indicate that the association between drug use and mating may be required for expression of compulsive sexual behavior and is correlated with increased reward seeking for concurrent Meth exposure and mating.

Figure 1.

Effects of repeated Meth on sexual performance. A–C, Latencies to mount (ML), intromission (IL), and ejaculation (EL) following administration of 0, 1, or 2 mg/kg Meth 30 min after the seventh and last drug injection (A) and drug abstinence days 1 (B) and 7 (C). Data are presented as mean ± SEM. *Significant differences from saline-injected males (p < 0.05).

Figure 2.

Effects of repeated Meth on locomotor activity. A, B, Distance traveled by males administered 0, 1, or 2 mg/kg Meth following the first (A) and last (B) Meth injection. Data are presented as mean ± SEM. *Significant differences from control for all treatment groups (p < 0.05); ^#significant differences between 1 mg/kg Meth and control only (p < 0.05). C, Meth-induced sensitized locomotor response. Distance traveled by males administered 0, 1, or 2 mg/kg Meth following the first and last Meth injection during the last 10 min of locomotor activity recordings. Data are presented as mean ± SEM. *Significant difference from sexually naive males of the same treatment group (p < 0.05).

Figure 3.

Effects of concurrent mating (sex) and Meth pretreatment on conditioned sex aversion (Experiment 1). A, Experimental groups included saline- (Sal) or Meth-pretreated males that received LiCl following mating (Paired males) and saline- or Meth-pretreated males that received saline following mating (Unpaired males). During the second day of each conditioning trial, paired males received saline and unpaired males received LiCl. B, C, Percentage of males mounting (B) and ejaculating (C) during conditioned sex aversion following Meth pretreatment administered simultaneously with sexual experience. *Significant difference from saline-pretreated unpaired males (p < 0.05); ^#significant difference from Meth-pretreated unpaired males (p < 0.05).

Figure 4.

Effects of nonconcurrent mating (sex) and Meth pretreatment on conditioned sex aversion (Experiment 2). Percentage of males mounting (A) and ejaculating (B) during LiCl conditioned sex aversion following Meth pretreatment not associated with sexual experience. Two groups were included: LiCl-paired pretreated with saline and LiCl-paired pretreated with Meth.

Figure 5.

Effects of concurrent mating (sex) and Meth pretreatment on LiCl-induced CPA. A, B, Preference score (time spent on paired chamber divided by time in paired + unpaired chamber × 100; A) and CPA score (difference in time spent in the paired chamber during the posttest minus pretest; B) in mated males pretreated with saline (Sal; sex + saline) or Meth (sex + Meth). Data are presented as mean ± SEM. *Significant differences from pretest within the same experimental group (p < 0.05).

Figure 6.

Effects of concurrent mating (sex) and Meth pretreatment on mating- and Meth-induced CPP (Experiment 1). Four groups were included. A, Two groups received sex + saline (Sal) pretreatment and the following treatment in the paired/unpaired chamber: sex + saline/sex, sex + saline/saline. The first group served as a negative control, as saline was not expected to alter CPP for sex. The second group served as a positive control, as sex was expected to cause CPP. B, The other two groups received sex + Meth pretreatment and the following in the paired/unpaired chambers: sex + Meth/sex or sex + Meth/Meth. The order in which the animals were exposed to the paired and unpaired chambers was counterbalanced within each experimental group. C, Preference score (time spent on paired chamber divided by time in paired + unpaired chamber × 100). Data are presented as mean ± SEM. *Significant differences from pretest within the same experimental group (p < 0.05). D, CPP score (difference in time spent in the paired chamber during the posttest minus the pretest). Data are presented as mean ± SEM. *Significant differences from the sex + saline/sex group (p < 0.05).

Figure 7.

Effects of concurrent mating (sex) and Meth pretreatment on Meth-induced CPP (Experiment 2). Preference score (time spent on paired chamber divided by time in paired + unpaired chamber × 100) in males pretreated with saline (Sal), Meth, or sex + Meth. Data are presented as mean ± SEM. *Significant difference from pretest within the same experimental group (p < 0.05).

Figure 8.

Effects of concurrent mating (sex) and Meth pretreatment on mating-induced CPP (Experiment 3). Preference score (time spent on paired chamber divided by time in paired + unpaired chamber × 100) in males pretreated with sex + saline (Sal) or sex + Meth. Data are presented as mean ± SEM.