Sex differences in learning and inhibition in spontaneously hypertensive rats

Abstract

Few studies have addressed potential differences in the nature of cognitive impairment observed in males and females with ADHD. In Experiment 1, we examined sex differences in conditioned inhibitory behaviour in Spontaneously-Hypertensive rats (SHR strain), a purported animal model of ADHD. Rats were presented with two types of trials during each of fifteen conditioning sessions. On some trials an auditory stimulus (a tone) was presented and followed immediately by delivery of food reward. On the remaining trials the tone was preceded by presentation of a visual stimulus and on those trials food was not delivered after the tone was presented. As training progressed, conditioned responding during presentation of the tone increased on reinforced trials and decreased during the non-reinforced trials, indicative of successful discrimination and inhibition. Female SHR rats exhibited less conditioned food cup behaviour overall compared to male rats. In addition, female SHR rats required more training sessions until they responded significantly more during presentation of the tone on reinforced trials versus non-reinforced trials. In contrast, no sex differences were observed in WKY rats (commonly-used control strain) in Experiment 2. Importantly, there were no significant sex differences in baseline activity or motivation during either experiment, indicating that performance differences could not account for the observed results. These results suggest that male and female SHR rats differ in their ability to form conditioned associations and inhibit behavioural responses and may provide a useful model for sex differences in cognitive dysfunction specific to ADHD.

Re-evaluation of an animal model for ADHD using a free-operant choice task

“…These symptoms have also been shown to be ameliorated by administration of low doses of psychostimulants such as methylphenidate and d-amphetamine, common pharmacotherapies for ADHD (Sagvolden et al, 1992Boix et al, 1998;Sagvolden, 2000). While the characteristic higher prevalence of ADHD in boys over girls is not shared by the SHR, there is a difference in the types of ADHD behavioural traits displayed by male and female animals Bucci et al, 2008). Altered dopamine function in the SHR conforms to the theoretical rationale for ADHD, providing construct validity for this animal model (Sagvolden, 2000;Sagvolden et al, 2005).…”

Sex, ADHD symptoms, and smoking outcomes: An integrative model

“…Specific to ADHD, during prenatal development testosterone may interact with dopaminergic circuitry to delay maturation in brain areas related to cognitive control and reward processing, which, in turn, may contribute to the 3:1 ratio of males to females in childhood ADHD [34]. Upon sexual maturity, however, these sex differences in rates of ADHD equalize [35] and animal research suggests that in adulthood estrogen interacts with dopaminergic systems to more specifically impair conditioned learning in females with ADHD [36, 37]. …”

“…Most research examining mechanisms in sex differences in adults with ADHD has been undertaken using the spontaneously hypertensive rat (SHR), an established animal model of ADHD [36, 37, 74, 75, 134, 135]. Findings have provided some provocative evidence of neurobiological mechanisms of sex-differences in the disorder.…”

“…Specifically, sexually mature females SHR rats appear to demonstrate greater behavioral problems and more impulsivity than do male SHR rats [136]. Also, mature female SHR rats have greater difficulty with extinction learning [135]; have more difficulty learning conditioned associations; and require more trials to learn to respond to a discriminative stimulus [37] than mature male SHR rats. Interestingly, one study found that estrogen impairs conditioned associations in male and female adult SHR rats but not in the actively normal control strain of Wistar rats [36, 37].…”

“…Second, Hypothesis 2 is represented by the overlapping ovals of female sex and nicotine, reflecting that nicotine may have unique affects in adult females by interacting with estrogen and the dopamine reward system in ways that increase both the positive and the negative reinforcement afforded by smoking [21, 31, 104, 106, 114, 117, 119, 121, 129–132, 143]. Third, the overlapping ovals of female sex and ADHD represent Hypothesis 3, indicating that ovarian hormones may act within the dopamine reward system to exacerbate deficits in the capacity to form conditioned associations, thereby worsening attentional and response inhibition deficits of ADHD [36, 37, 135, 136]. Finally, all three ovals overlap to represent Hypothesis 4, reflecting the two hypothesized mechanisms by which sex, ADHD, and nicotine may interact over the course of the menstrual cycle: 1) during the follicular phase, estrogen may interact with nicotine within the dopamine reward system to ameliorate ADHD-related conditioned learning deficits that are particularly pronounced with females with the disorder; and 2) during the luteal phase, nicotine may diminish the compounded discomfort of premenstrual symptoms, nicotine withdrawal, and ADHD symptoms.…”