Browsing by Subject "Reinstatement"

Now showing 1 - 3 of 3
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    Alcohol reinstatement after prolonged abstinence from alcohol drinking by female adolescent rats: Roles of cyclooxygenase-2 and the prostaglandin E2 receptor 1
    (Elsevier, 2022) Kline, Hannah L.; Yamamoto, Bryan K.; Pharmacology and Toxicology, School of Medicine
    Background: Adolescent alcohol misuse is a global problem that can significantly increase the reinstatement of alcohol drinking during re-exposure after abstinence, but the mechanism that causes this increase is unknown. Female adolescents are an understudied population but they are particularly vulnerable to adolescent-onset alcohol abuse. We aimed to determine how adolescent-onset alcohol drinking affects pro-inflammatory mediators endothelin-1 (ET-1), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) in the brain and the role of COX-2 and PGE2 in EtOH reinstatement in adolescent females. Methods: Adolescent female rats were exposed to a 2-bottle choice paradigm of water vs 5% ethanol (EtOH) every other day over a 21 day period. ET-1 and COX-2 proteins were measured in the dorsal striatum (DS) after a 4 week abstinence from EtOH drinking. The COX-2 inhibitor nimesulide was then administered during abstinence prior to an EtOH reinstatement or sucrose preference or to measure PGE2 content. The PGE2 receptor 1 (EP1) antagonist SC-51089 was then administered prior to EtOH reinstatement during which EtOH intake was measured. Results: EtOH drinking significantly increased ET-1 by 33.8 ± 8.9% and COX-2 by 71.4 ± 24.3% in the DS. Treatment with nimesulide during abstinence attenuated EtOH intake during reinstatement after prolonged abstinence by 40.3 ± 12.4% compared to saline controls. Adolescent EtOH drinking and abstinence increased PGE2 150.5 ± 30.9% in the DS and nimesulide attenuated this increase. SC-51089 treatment during abstinence attenuated EtOH reinstatement by 48.1 ± 8.4% compared to DMSO controls. Conclusions: These experiments identified a prostaglandin-mediated mechanism that offers a putative pharmacological target to attenuate EtOH reinstatement after adolescent-onset EtOH drinking.
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    Prostaglandin-Mediated Reinstatement of Drug Taking After Alcohol Drinking by Female Adolescent Rats
    (2022-04) Kline, Hannah L.; Engleman, Eric A.; Atwood, Brady K.; McKinzie, David L.; Truitt, William A.; Yamamoto, Bryan K.
    Adolescent alcohol abuse is a global problem that initiates lifelong addiction. Alcohol use during adolescence is associated with subsequent Meth dependence in humans. Specifically, female adolescents are particularly vulnerable to serial alcohol and Meth use. However, it is unknown if prior voluntary alcohol drinking impacts subsequent Meth-taking in female adolescent rats. Both alcohol and Meth increase the prostaglandin synthesis enzyme cyclooxygenase-2 (COX-2) in the brain but the effect of serial exposure to alcohol and Meth on COX-2 has not been determined. The first study uses a novel method of serial voluntary alcohol drinking and Meth self-administration in female adolescent rats to model human patterns of co-abuse. Prior alcohol drinking did not affect subsequent Meth self-administration, but it reduced the cue-primed reinstatement of Methseeking after abstinence from Meth. Rats with a history of adolescent alcohol drinking also had increased COX-2 in the dorsal striatum, regardless of subsequent Meth selfadministration. These findings demonstrate that a history of adolescent alcohol drinking does not alter Meth self-administration but persistently reduces cue-primed Meth seeking and increases COX-2 after prolonged abstinence from alcohol. To further examine the role of COX-2 in alcohol drinking, the second study found that adolescent alcohol drinking not only increased COX-2 after four weeks of alcohol abstinence, but also increased endothelin-1 (ET-1) and prostaglandin E2 (PGE2) in the dorsal striatum. Furthermore, adolescent alcohol drinking increased alcohol drinking after abstinence, and this increase was attenuated by treatment with the COX-2 inhibitor nimesulide during abstinence. Antagonism of the interaction between PGE2 and its receptor 1 (EP1) also attenuated the increase in relapse drinking and restored alcohol drinking to the rate of alcohol naïve rats. Overall, these experiments identified a prostaglandin-mediated mechanism that is a putative target for the treatment of alcohol relapse following abstinence in individuals with a history of adolescent alcohol abuse.
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    Roflumilast Treatment During Forced Abstinence Reduces Relapse to Methamphetamine Seeking and Taking
    (Wiley, 2022) Baek, James J.; Kline, Hannah; Deveau, Carmen M.; Yamamoto, Bryan K.; Pharmacology and Toxicology, School of Medicine
    Methamphetamine (METH) is a psychostimulant with high abuse potential. Currently there are no pharmacological treatments specific for METH abuse or stimulant use disorder generally. Although phosphodiesterase inhibitors have shown some promise, current animal models have not examined their use in abstinence from stimulant abuse. We employed a METH self-administration model in the rat followed by a forced abstinence period during which roflumilast, a phosphodiesterase 4 inhibitor, was administered. A detailed behavioral analysis of chronic treatment with roflumilast during 7 days of forced abstinence showed that roflumilast reduced METH seeking and METH taking upon subsequent relapse test. Roflumilast treatment during 7 days of forced abstinence did not affect sucrose seeking and sucrose taking behaviors. These data suggest that roflumilast may be a treatment for METH use disorder that is effective when administered only during abstinence.