Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine.

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.

Intermittent dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to dopaminergic drugs.

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032-0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0-17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.

The Effects of Eating a High Fat Diet on Sensitivity of Male and Female Rats to Methamphetamine and Dopamine D1 Receptor Agonist SKF 82958.

Rats eating high fat chow are more sensitive to the behavioral effects of dopaminergic drugs, including methamphetamine and the dopamine D2/D3 receptor agonist quinpirole, than rats eating standard chow. However, limited work has explored possible sex differences regarding the impact of diet on drug sensitivity. It is also unknown whether eating high fat chow enhances sensitivity of rats to other dopamine (e.g., D1) receptor agonists. To explore these possibilities, male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) were tested once per week for 6 weeks with dopamine D1 receptor agonist SKF 82958 (0.01-3.2 mg/kg) or methamphetamine (0.1-3.2 mg/kg) using cumulative dosing procedures. Eating high fat chow increased sensitivity of male and female rats to methamphetamine-induced locomotion; however, only female rats eating high fat chow were more sensitive to SKF 82958-induced locomotion. SKF 82958-induced eye blinking was also marginally, although not significantly, enhanced among female rats eating high fat chow, but not males. Further, although dopamine D2 receptor expression was significantly increased for SKF 82958-treated rats eating high fat chow regardless of sex, no differences were observed in dopamine D1 receptor expression. Taken together, the present study suggests that although eating high fat chow enhances sensitivity of both sexes to dopaminergic drugs, the mechanism driving this effect might be different for males versus females. These data further demonstrate the importance of studying both sexes simultaneously when investigating factors that influence drug sensitivity. SIGNIFICANCE STATEMENT: Although it is known that diet can impact sensitivity to some dopaminergic drugs, sex differences regarding this effect are not well characterized. This report demonstrates that eating a high fat diet enhances sensitivity to methamphetamine, regardless of sex; however, sensitivity to dopamine D1 receptor agonist SKF 82958 is increased only among females eating high fat chow, but not males. This suggests that the mechanism(s) driving diet-induced changes in drug sensitivity might be different between sexes.