D2/D3 Agonists(Wayne State University)

Dopamine D2/D3 receptor modulation with antipsychotics is thought to affect cognitive function, but causal evidence in humans is scant, and largely limited to single administrations. Clarifying this is of importance given the widespread use of antipsychotics, and to understand the role of D2/D3 signalling in human cognition. We therefore conducted a double-blind, placebo-controlled crossover study following sustained administration of either a dopamine D2/D3 receptor antagonist (amisulpride at 400 mg daily) or a D2/D3 partial agonist (aripiprazole at 10 mg daily) to two separate samples of healthy humans (total n = 50) for 7 days per condition. We assessed cognitive function using a computerised visuospatial working memory (VS-WM) task, and sustained attention and response inhibition using the Sustained Attention to Response Task (SART). We found that both amisulpride and aripiprazole caused impairments in VS-WM function compared to placebo on the Balanced Integration Score (amisulpride: p = 0.0079; aripiprazole: p = 0.015). Both antipsychotics impaired VS-WM performance in terms of response latency (amisulpride: p = 5.5 × 10−7; aripiprazole: p = 0.022), but did not affect response accuracy. Response latency deficits were not correlated with motor impairments induced by either drug, and we also found no effect of either drug on the SART measures, or on subjective alertness, suggesting that D2/D3 antagonism or partial agonism did not cause a generalised cognitive or motor deficit but specifically impaired cognition during VS-WM. This study provides the first causal evidence in healthy humans that working memory function is impaired following either sustained antagonism or partial agonism of D2/D3 receptors by antipsychotic drugs.

In humans, women are known to have a greater prevalence of eating-related disorders and stronger experience of food cravings than men. Similarly, in rodents, females display a greater preference and motivation for the highly palatable sweet food, sucrose, than do males. Pre-exposure to sucrose has been shown to enhance locomotor sensitization induced by dopaminergic agonists, however, evidence of sex differences in this effect is limited. Female (n = 16) and male (n = 16) Long-Evans rats received 30 min daily access to sucrose (0.3 M) or water for nine consecutive days followed by daily administration of the D2/D3 agonist, quinpirole (0.5 mg/kg), for nine consecutive days. Automated locomotor activity assessment occurred on the first, fifth, and ninth days of the sucrose and quinpirole phases. In the sucrose phase, sex × fluid interactions were broadly observed in activity measures across and within testing days with females but not males showing an effect of sucrose-induced locomotor sensitization. In the quinpirole phase, a sex × fluid interaction was only observed in a single activity measure across days, suggesting that sucrose pre-exposure does not robustly alter quinpirole sensitization by sex. A sex difference was identified in the effect of locomotor sensitization induced by sucrose, but not for sucrose pre-exposure on quinpirole sensitization. These results suggest that differences exist between sexes in sucrose-induced sensitization in rodents, perhaps underlying sex differences in food cravings and eating-related disorder prevalence in humans.