Harris Andrew C, Muelken Peter, Liu Shirelle X, Smethells John R, LeSage Mark G, Gewirtz Jonathan C
Hennepin Healthcare Research Institute, Minneapolis, MN, United States.
Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
Front Behav Neurosci. 2024 Aug 29;18:1443364. doi: 10.3389/fnbeh.2024.1443364. eCollection 2024.
Sex differences in vulnerability to opioid use disorder (OUD) have been reported in some clinical and preclinical studies, but findings are mixed and further research is needed in this area. The goal of this study was to compare elasticity of demand (reinforcement efficacy) in an i.v. morphine self-administration (SA) model in male and female rats using a translationally relevant behavioral economics approach. Rate of acquisition and predictors of individual differences in demand (e.g., cumulative morphine infusions during acquisition) were also evaluated in both sexes.
Acquisition of morphine SA (0.4 mg/kg/infusion) under a fixed ratio (FR) 1 schedule of reinforcement was slower and infusions earned were lower in females than in males ( = 30-31/sex), but infusions earned did not differ between sexes during the FR 2 and FR 3 phases of acquisition. Increases in the FR response requirement across sessions during demand testing (FR 1-FR 96) resulted in a progressive reduction in morphine infusions in both sexes. Morphine consumption was well-described by an exponential demand function in both sexes and was associated with considerable individual vulnerability. There were no sex differences in elasticity of demand (rate of decline in morphine consumption with increasing price) or intensity of demand (consumption at zero price). A higher number of infusions earned during the FR 2 and FR 3 phases of acquisition and greater maximum response rates during demand testing were associated with lower demand elasticity (i.e., greater reinforcing efficacy) in both males and females, whereas other relationships were sex-specific (e.g., higher intensity of demand was associated with lower elasticity of demand in males but not in females).
Our findings indicate similar elasticity of demand and predictors of individual differences in demand for morphine in male and female rats, although sex differences were observed in initial rate of acquisition and in some correlations between morphine SA measures. These data are consistent with findings of similar OUD vulnerability in males and females in some human and animal studies.
一些临床和临床前研究报告了阿片类药物使用障碍(OUD)易感性方面的性别差异,但结果不一,该领域需要进一步研究。本研究的目的是使用具有转化相关性的行为经济学方法,比较雄性和雌性大鼠静脉注射吗啡自我给药(SA)模型中的需求弹性(强化效能)。还评估了两性的习得率和需求个体差异的预测因素(例如,习得期间累积的吗啡输注量)。
在固定比率(FR)1强化程序下,雌性大鼠吗啡SA(0.4mg/kg/输注)的习得速度比雄性大鼠慢,获得的输注量也低于雄性大鼠(每组n = 30 - 31),但在习得的FR 2和FR 3阶段,两性获得的输注量没有差异。在需求测试(FR 1 - FR 96)期间,各阶段FR反应要求的增加导致两性吗啡输注量逐渐减少。两性的吗啡消耗量均能很好地用指数需求函数描述,且与个体易感性相关。需求弹性(随着价格增加吗啡消耗量的下降率)或需求强度(零价格时的消耗量)没有性别差异。在习得的FR 2和FR 3阶段获得的输注量较多以及在需求测试期间最大反应率较高,与雄性和雌性较低的需求弹性(即更强的强化效能)相关,而其他关系具有性别特异性(例如,较高的需求强度与雄性较低的需求弹性相关,但与雌性无关)。
我们的研究结果表明,雄性和雌性大鼠对吗啡的需求弹性以及需求个体差异的预测因素相似,尽管在初始习得率以及吗啡SA测量之间的一些相关性方面观察到了性别差异。这些数据与一些人类和动物研究中关于雄性和雌性OUD易感性相似的结果一致。