Sex Differences in Animal Models: Focus on Addiction

Abstract

The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self-administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences.

Fig. 1.

Illustration of the four types of sex differences that can be observed in animal models: qualitative, quantitative, population, and mechanistic. Some sex differences are so dramatic that the traits that are exhibited by males and females do not look the same. These “qualitative differences” are exemplified by sexual behavior in the rat. Many sex differences are also “quantitative differences,” in which males and females differ in the magnitude of their response. Sex differences in the incidence or distribution of individual traits are called “population differences.” Finally, for some behaviors or processes, the expression of a trait may look the same for males and females, but there are sex differences in the neural “mechanisms” that mediate the behaviors.

Fig. 2.

Sagittal section of a rodent brain showing the major neurotransmitter systems implicated in sex differences associated with drug addiction. The basal ganglia (blue) are implicated in the rewarding and incentive salience effects of the binge/intoxication stage, with inputs from the mesocorticolimbic dopamine system and opioid peptides. The extended amygdala (red) is implicated in the stress surfeit effects of the withdrawal/negative affect stage and contains the stress neurotransmitters corticotropin-releasing factor and dynorphin. The frontal cortex (green) is implicated in executive function deficits that are associated with the preoccupation/anticipation stage, with glutamatergic projections to the basal ganglia and extended amygdala. Fcx, frontal cortex; DS, dorsal striatum; NAc, nucleus accumbens; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; LC, locus coeruleus; VTA, ventral tegmental area; SN, substantia nigra; NST, nucleus tractus solitarius.