Ethanol vapor self-administration in adult C57BL/6J male mice

2007 ◽  
Vol 86 (2-3) ◽  
pp. 123-131 ◽  
Author(s):  
Kathleen M. Kantak ◽  
Christopher Luzzo
2019 ◽  
Author(s):  
Alysabeth G. Phillips ◽  
Dillon J. McGovern ◽  
Soo Lee ◽  
Kyu Ro ◽  
David T. Huynh ◽  
...  

AbstractA significant portion of prescription opioid users self-administer orally rather than intravenously. Animal models of opioid addiction have demonstrated that intravenous cues are sufficient to cause drug-seeking. However, intravenous models may not model oral users, and the preference to self-administer orally appears to be partially influenced by the user’s sex. Our objectives were to determine whether oral opioid-associated cues are sufficient for relapse and whether sex differences exist in relapse susceptibility. Mice orally self-administered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated robust cue-induced reinstatement. In separate mice we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior in the absence of postprandial or prior water self-administration training. During self-administration, we found that female mice earned significantly more mg/kg oxycodone than male mice. Follow-up studies indicated sex differences in psychomotor stimulation and plasma oxycodone/oxymorphone following oral oxycodone administration. In addition, gonadal steroid studies were performed in which we found divergent responses where ovariectomy enhanced and orchiectomy suppressed oral self-administration. While the suppressive effects of orchiectomy were identified across doses and postprandial conditions, the enhancing effects of ovariectomy were selective to non-postprandial conditions. These studies establish that 1) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, 2) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and 3) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.


2019 ◽  
Vol 9 (12) ◽  
pp. 367 ◽  
Author(s):  
Sucharita S. Somkuwar ◽  
Chitra D. Mandyam

Chronic intermittent ethanol vapor exposure (CIE) in rodents produces reliable and high blood ethanol concentration and behavioral symptoms associated with moderate to severe alcohol use disorder (AUD)—for example, escalation of operant ethanol self-administration, a feature suggestive of transition from recreational to addictive use, is a widely replicated behavior in rats that experience CIE. Herein, we present evidence from a subset of rats that do not demonstrate escalation of ethanol self-administration following seven weeks of CIE. These low responders (LR) maintain low ethanol self-administration during CIE, demonstrate lower relapse to drinking during abstinence and reduced reinstatement of ethanol seeking triggered by ethanol cues when compared with high responders (HR). We examined the blood ethanol levels in LR and HR rats during CIE and show higher levels in LR compared with HR. We also examined peak corticosterone levels during CIE and show that LR rats have higher levels compared with HR rats. Lastly, we evaluated the levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in HR rats compared with LR rats. These findings demonstrate that dysregulation of the hypothalamic–pituitary–adrenal axis activity and plasticity-related proteins regulating molecular memory in the nucleus accumbens shell are associated with higher ethanol-drinking and -seeking in HR rats. Future mechanistic studies should evaluate CaMKII autophosphorylation-dependent remodeling of glutamatergic synapses in the ventral striatum as a plausible mechanism for the CIE-induced enhanced ethanol drinking and seeking behaviors.


2017 ◽  
Author(s):  
Giordano de Guglielmo ◽  
Marsida Kallupi ◽  
Matthew B. Pomrenze ◽  
Elena Crawford ◽  
Sierra Simpson ◽  
...  

AbstractAlcohol withdrawal activates a neuronal ensemble in the central nucleus of the amygdala (CeA) that is responsible for high levels of uncontrolled alcohol drinking. However, the neuronal phenotypes and circuits controlled by these neurons are unknown. We investigated the cellular identity of this CeA neuronal ensemble and found that most neurons expressed corticotropin-releasing factor (CRF). Using Crh-Cre transgenic rats combined with in vivo optogenetics, we tested the role of CeA CRF neurons and their projections in excessive alcohol self-administration during withdrawal. Rats were injected with AAV-DIO-NpHR-eYFP or AAV-DIO-eYFP and implanted with optical fibers over the CeA. Animals were then exposed to chronic intermittent ethanol vapor to induce alcohol dependence. Inactivation of CeA CRF neurons decreased alcohol drinking in dependent rats to non-dependent levels and completely suppressed activation of the CeA neuronal ensemble (Fos+ neurons) during withdrawal. No effects were observed on water or saccharin self-administration. In a second experiment, CeA CRF neurons were infected with AAV-DIO-NpHR-eYFP and optical fibers were implanted into downstream projection regions, including the bed nucleus of the stria terminalis (BNST), lateral hypothalamus (LH), parasubthalamic nucleus (pSTN), substantia innominata (SI), and parabrachial nuclei (PBN). Optogenetic inactivation of CRF terminals in the BNST reduced alcohol drinking and withdrawal signs, whereas inactivation of all other projections had no effect. These results demonstrate that CeA CRF neurons and their projections to the BNST drive excessive alcohol drinking and withdrawal in dependent rats.


2019 ◽  
Vol 236 (7) ◽  
pp. 2027-2037 ◽  
Author(s):  
Danielle T. Arena ◽  
Herbert E. Covington ◽  
Joseph F. DeBold ◽  
Klaus A. Miczek

2020 ◽  
Author(s):  
Christopher D. Walker ◽  
Hannah G. Sexton ◽  
Mary-Louise Risher

ABSTRACTIntroductionPeer interactions are a crucial part of social and personal development, particularly during adolescence. Adolescence is characterized as a transitional developmental period between childhood and adulthood that is often associated with increased freedom, self-exploration, and novel experiences that are frequently peer-influenced. Due to newfound independence, there is a higher prevalence of alcohol consumption, which is in part due to the heightened social facilitating and rewarding effects of alcohol. Previous work shows that males and females who consume excessive alcohol during adolescence are at an increased risk of developing an alcohol use disorder (AUD) later in life. However, the contributions of social interaction and sexual dimorphism in alcohol consumption, two driving factors that influence AUD risk, are not fully understood. Many current rat models used to study the characteristics of alcohol use and the emergence of AUD coerce the animals into consuming liquid ethanol by the addition of a sweetener, which has been proven to confound results in adolescent rats. Here we use a novel self-administration ethanol vapor system to investigate the sexual dimorphic nature of socially facilitated ethanol consumption without the addition of sweeteners.MethodsAdolescent and adult male and female Sprague-Dawley rats underwent a novel voluntary chronic intermittent self-administration ethanol vapor paradigm. Nose poke-initiated self-administration vapor chambers (La Jolla Alcohol Research, Inc.) administered 20mg/L of vaporized ethanol or air (control) into the chamber in response to each individual nose poke. Beginning on postnatal day (PND) 30 or PND70, animals were placed in vapor chambers for 4 hours every other day for a total of 40 sessions. All animals underwent 10 sessions with their cagemate (social access) followed by 10 sessions in isolation (isolated access), a 10 day forced abstinence period, 10 sessions in isolation (isolated access), and 10 sessions with their cagemate (social access).ResultsFemale rats consumed more alcohol per body weight than age-matched males, while male rats increased ethanol preference over sessions regardless of age. In addition, all rats regardless of sex or age consumed more ethanol per body weight during the first social access session than during the subsequent isolated access sessions. Interestingly, there was an increase in ethanol consumption in adult male and females during the second social access session compared to the previous isolated access session that was not observed in either adolescent groups.ConclusionThese data demonstrate that female and male rats, regardless of age, are vulnerable to socially facilitated ethanol consumption. This is consistent with human data showing that increased levels of alcohol consumption among adolescents and young adults is associated with high levels of alcohol use within their social group (Sudhinaraset, Wigglesworth, & Takeuchi, 2016). However, only male rats demonstrate escalation across sessions. This may indicate that male rats are more vulnerable to escalated drinking and the emergence of ethanol dependence compared to females regardless of peer interaction. These data demonstrate that the self-administration ethanol vapor system is an effective alternative to other methods of voluntary ethanol administration for investigating factors that contribute to alcohol use and escalation.


F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 298 ◽  
Author(s):  
Lara Hwa ◽  
Joyce Besheer ◽  
Thomas Kash

Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.


2008 ◽  
Vol 103 (4) ◽  
pp. 297-304 ◽  
Author(s):  
Anne Tammimäki ◽  
Markus M. Forsberg ◽  
Maria Karayiorgou ◽  
Joseph A. Gogos ◽  
Pekka T. Männistö

Author(s):  
Skylar Y Cooper ◽  
Austin T Akers ◽  
Brandon J Henderson

Abstract Introduction Although the use of combustible cigarettes has decreased in many urban regions of America, the use of electronic nicotine delivery systems (ENDS) has dramatically increased. ENDS, or electronic cigarettes (e-cigarettes), differ from combustible cigarettes given that there are no restrictions on flavorant additives in e-liquids. With 95% of ENDS users vaping flavored e-liquids, it is critical to understand how flavors alter vaping-related behaviors. We have previously shown that menthol and green apple flavors enhance nicotine reward-related behavior in a mouse model and in the present study have investigated how menthol and green apple flavors alter e-Vape self-administration behavior in male mice. Methods Adult C57/BL6J male mice were used in vapor-inhalation self-administration assays. Mice were assigned vaping e-liquids (6 mg/mL nicotine with or without menthol or green apple flavor) to escalate on a fixed-ratio 1 (FR1) schedule in daily 3-hour sessions to examine initiation-related behaviors. Following escalation, mice were transitioned to a FR3 and progressive ratio schedules in 3-hour sessions to examine reinforcement-related behaviors. Results Here we observed that male mice exhibited increased rates of self-administration escalation on a FR1 schedule when assigned to flavored e-liquids. Upon transition to FR3, mice continued to exhibit enhanced levels of reinforcement with flavored e-liquids. We also observed that mice self-administer zero-nicotine green apple flavored e-liquids. Conclusions These data provide additional evidence that ENDS flavors enhance vaping-related initiation and reinforcement-related behavior and promote the need to continue investigating the role ENDS flavors play in vaping-related behaviors. Implications There has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our study here shows that flavors significantly enhance the acquisition and reinforcement of vaping-related behavior. This suggests that flavors in electronic nicotine delivery systems significantly increase the risk of addiction-related behaviors among users of vaping products.


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