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[Preprint]. 2024 Mar 8:2024.03.04.583431.
doi: 10.1101/2024.03.04.583431.

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

Affiliations

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

Michelle R Doyle et al. bioRxiv. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Timeline and Initial Phenotype Score Endpoints Experimental timeline showing the total study duration in days as well as each aspect of the experiment. Violin plots representing the mean number of infusions (A), pre-session responses (B), intercomponent interval responses (C), punishment score (D) and SUD-like phenotype score (E) in female (shaded) and male (white) rats self-administering cocaine (red) or MPDV (blue) during the first phenotyping period. Solid lines indicate median and dashed lines indicate quartiles. * =P<0.05, **=P<0.01, ***=P<0.001, ****P=<0.0001 for post-hoc analyses.
Figure 2.
Figure 2.
Access Condition Manipulations Violin plots representing the number of infusions (top) and rate of responding (bottom) averaged across the 21-session access condition manipulation. Female (shaded) and male (white) rats self-administering cocaine (red) or MPDV (blue) under short- (left), long- (middle), or intermittent-access (right). Solid lines indicate median and dashed lines indicate quartiles. Main effect of access condition where ****=P<0.0001 compared to short-access; ####=P<0.0001 compared to long-access for post-hoc analyses.
Figure 3.
Figure 3.
Final Phenotype Score Endpoints Violin plots representing the mean number of infusions (A), pre-session responses (B), intercomponent interval responses (C), punishment score (D), SUD-like phenotype score (E), and change in phenotype score in female (shaded) and male (white) rats self-administering cocaine (red) or MPDV (blue) during the second phenotyping period. Data are split by access condition. Solid lines indicate median and dashed lines indicate quartiles. *=significant change in phenotype score, where confidence intervals did not overlap with 0. Main effects of drug and sex are not indicated on figures.
Figure 4.
Figure 4.
Responses During Cue Reactivity Test Violin plots representing the mean number of responses during the cue reactivity test, split by access condition (top) or phenotype score (bottom) in female (shaded) and male (white) rats self-administering cocaine (red) or MPDV (blue). Solid lines indicate median and dashed lines indicate quartiles. Top: main effect of access condition where *=P<0.05 compared to short-access; #=P<0.05 compared to long-access. Bottom: main effect of phenotype where **=P<0.01 compared to low score; #=P<0.05 compared to mid score.

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