Methamphetamine acts on subpopulations of neurons regulating sexual behavior in male rats

Abstract

Methamphetamine (Meth) is a highly addictive stimulant. Meth abuse is commonly associated with the practice of sexual risk behavior and increased prevalence of Human Immunodeficiency Virus and Meth users report heightened sexual desire, arousal, and sexual pleasure. The biological basis for this drug-sex nexus is unknown. The current study demonstrates that Meth administration in male rats activates neurons in brain regions of the mesolimbic system that are involved in the regulation of sexual behavior. Specifically, Meth and mating co-activate cells in the nucleus accumbens core and shell, basolateral amygdala, and anterior cingulate cortex. These findings illustrate that in contrast to current belief drugs of abuse can activate the same cells as a natural reinforcer, that is sexual behavior, and in turn may influence compulsive seeking of this natural reward.

Keywords: addiction; basolateral amygdala; nucleus accumbens; prefrontal cortex; reproduction; substance abuse.

Figure 1

Schematic drawings and images illustrating brain areas of analysis. Areas of analysis indicated were based on landmarks unique for each brain region, did not differ between experimental groups, and were 1.25 mm² in mPFC subregions (a), 1.3 mm² in the NAc core and shell (b), 1.0 mm² in the MPN (c), 1.25 mm² in the BNST subregions (d), 1.6, 2.25, and 2.5 mm² in the BLA, CeA, and MEApd respectively (e), and 3.15 mm² in the VTA (f). Abbreviations: aco, anterior commisure; AQ, cerebral aqueduct; cc, corpus callosum; CP, caudate putamen; fr, fasciculus retroflexus; fx, fornix; ml, medial lemniscus; MM, medial mammillary nucleus; opt, optic tract; V3, third ventricle; sm, stria medullaris; st, stria terminalis VL, lateral ventricle. Brain drawings were modified from Swanson (1998).

Figure 2

Sex-induced Fos and Meth-induced pERK expression in NAc, BLA, and ACA neurons 10 min following administration of 4 mg/kg Meth. Mean numbers ± s.e.m. of Fos (a, d, g, j), pERK (b, e, h, k), and dual (c, f, i, l) labeled cells in the NAc core (a, b, c) and shell (d, e, f), the BLA (g, h, i), and ACA (j, k, l). * indicate significant differences from unmated males of the same saline or Meth injected groups (p < 0.05); # indicates significant differences from saline injected groups of the same sex or no sex treatment (p < 0.05).

Figure 3

Representative images of NAc sections immunostained for Fos (red; a, d, g, j) and pERK (green; b, e, h, k) of animals of each experimental group: No Sex+Sal (a, b, c), Sex+Sal (d, e, f), No Sex+Meth (g, h, i), and Sex+Meth (j, k, l). Right panels are merged images illustrating co-localization of Fos and pERK. Arrows indicate dual labeled cells. Scale bar indicates 50 μm.

Figure 4

Sex-induced Fos and Meth-induced pERK expression in NAc, BLA, and ACA neurons 15 min following administration of 4 mg/kg Meth. Mean numbers ± s.e.m. of Fos (a, d, g, j), pERK (b, e, h, k), and dual (c, f, i, l) labeled cells in the NAc core (a, b, c) and shell (d, e, f), the BLA (g, h, i), and ACA (j, k, l). * indicate significant differences from unmated males of the same saline or Meth injected groups (p < 0.05); # indicates significant differences from saline injected groups of the same sex or no sex treatment (p < 0.05).

Figure 5

Sex-induced Fos and Meth-induced pERK expression in NAc, BLA, and ACA neurons 15 min following administration of 1 mg/kg Meth. Mean numbers ± s.e.m. of Fos (a, d, g, j), pERK (b, e, h, k), and dual (c, f, i, l) labeled cells in the NAc core (a, b, c) and shell (d, e, f), the BLA (g, h, i), and ACA (j, k, l). * indicate significant differences from unmated males of the same Meth injected groups (p < 0.05).

Figure 6

Sex-induced Fos and Amph-induced pERK expression in NAc, BLA, and ACA neurons 15 min following administration of 5 mg/kg Amph. Mean numbers ± s.e.m. of Fos (a, d, g, j), pERK (b, e, h, k), and dual (c, f, i, l) labeled cells in the NAc core (a, b, c) and shell (d, e, f), the BLA (g, h, i), and ACA (j, k, l). * indicate significant differences from unmated males of the same saline or Meth injected groups (p < 0.05); # indicates significant differences from saline injected groups of the same sex or no sex treatment (p < 0.05)