Browsing by Author "Zorrilla, Eric P."

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    Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats
    Bertotto, Luísa B.; Lampson-Stixrud, Dolly; Sinha, Anushka; Rohani, Nicki K.; Myer, Isabella; Zorrilla, Eric P. (MDPI, 2024-02-09)
    Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5–6/grp) and post-CIE (n = 6–8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking.
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    Linking drug and food addiction via compulsive appetite
    Laque, Amanda; Wagner, Grant E.; Matzeu, Alessandra; De Ness, Genna L.; Kerr, Tony M.; Carroll, Ayla M.; de Guglielmo, Giordano; Nedelescu, Hermina; Buczynski, Matthew W.; Gregus, Ann M.; Jhou, Thomas C.; Zorrilla, Eric P.; Martin-Fardon, Remi; Koya, Eisuke; Ritter, Robert C.; Weiss, Friedbert; Suto, Nobuyoshi (Wiley, 2022-06)
    Background and Purpose: ‘Food addiction’ is the subject of intense public and research interest. However, this nosology based on neurobehavioural similarities among obese individuals, patients with eating disorders and those with substance use disorders (drug addiction) remains controversial. We thus sought to determine which aspects of disordered eating are causally linked to preclinical models of drug addiction. We hypothesized that extensive drug histories, known to cause addiction-like brain changes and drug motivation in rats, would also cause addiction-like food motivation. Experimental Approach: Rats underwent extensive cocaine, alcohol, caffeine or obesogenic diet histories and were subsequently tested for punishment-resistant food self-administration or ‘compulsive appetite’, as a measure of addiction-like food motivation. Key Results: Extensive cocaine and alcohol (but not caffeine) histories caused compulsive appetite that persisted long after the last drug exposure. Extensive obesogenic diet histories also caused compulsive appetite, although neither cocaine nor alcohol histories caused excess calorie intake and bodyweight during abstinence. Hence, compulsive appetite and obesity appear to be dissociable, with the former sharing common mechanisms with preclinical drug addiction models. Conclusion and Implications: Compulsive appetite, as seen in subsets of obese individuals and patients with binge-eating disorder and bulimia nervosa (eating disorders that do not necessarily result in obesity), appears to epitomize ‘food addiction’. Because different drug and obesogenic diet histories caused compulsive appetite, overlapping dysregulations in the reward circuits, which control drug and food motivation independently of energy homeostasis, may offer common therapeutic targets for treating addictive behaviours across drug addiction, eating disorders and obesity.