Homer2 regulates alcohol and stress cross-sensitization

Abstract

An interaction exists between stress and alcohol in the etiology and chronicity of alcohol use disorders; yet a knowledge gap exists regarding the neurobiological underpinnings of this interaction. In this regard, we employed an 11-day unpredictable, chronic, mild stress (UCMS) procedure to examine for stress-alcohol cross-sensitization of motor activity, as well as alcohol consumption/preference and intoxication. We also employed immunoblotting to relate the expression of glutamate receptor-related proteins within subregions of the nucleus accumbens (NAC) to the manifestation of behavioral cross-sensitization. UCMS mice exhibited a greater locomotor response to an acute injection of 2 g/kg alcohol than unstressed controls and this cross-sensitization extended to alcohol intake (0–20%), as well as to the intoxicating and sedative properties of 3 and 5 g/kg alcohol, respectively. Regardless of prior alcohol injection (2 g/kg), UCMS mice exhibited elevated NAC shell levels of mGlu1α, GluN2b and Homer2, as well as lower PLCβ within this subregion. GluN2b levels were also lower within the NAC core of UCMS mice. The expression of stress-alcohol locomotor cross-sensitization was associated with lower mGlu1α within the NAC core and lower ERK activity within both NAC subregions. As Homer2 regulates alcohol sensitization, we assayed also for locomotor cross-sensitization in Homer2 wild-type (WT) and knock-out (KO) mice. WT mice exhibited a very robust cross-sensitization, that was absent in KO animals. These results indicate that a history of mild stress renders an animal more sensitive to the psychomotor and rewarding properties of alcohol, which may depend upon neuroplasticity within NAC glutamate transmission.

Involvement of neuronal nitric oxide synthase in cross-sensitization between chronic unpredictable stress and ethanol in adolescent and adult mice

“…The results obtained from this study confirm cross-sensitization between CUS and ethanol in adult mice (Quadir et al, 2016; *corticosterone serum levels are higher than their respective basal level after challenge injections (p < 0.01); þ corticosterone levels are higher than SAL or ETOH groups at 15 min, regardless of the challenge injection, within adolescent mice; & corticosterone levels are higher at 15 min compared to other groups, except CUS-ETOH in adults; # different from the respective ETOH/ETOH adolescent group (p < 0.01). n ¼ 10 mice/group.…”

“…To better understand the effects of chronic stress on behavioral sensitization and nNOS activity, animals from the CUS group underwent a chronic unpredictable stress paradigm, as previously described (Araújo, DeLucia, Scavone, & Planeta, 2003;Fitzgerald, Ortiz, Hamedani, & Nestler, 1996;Ortiz, Fitzgerald, Lane, Terwilliger, & Nestler, 1996;Quadir et al, 2016), with minor modifications.…”

“…Indeed, behavioral crosssensitization is observed between stress and ethanol in both adolescent and adult rodents (for review, see Burke & Miczek, 2014). Stress exposure can raise ethanol intake and preference in both animals (Morais-Silva, Fernandes-Santos, Moreira-Silva, & Marin, 2016;Norman et al, 2015;Quadir et al, 2016) and humans (Sinha, 2001), although some studies have shown no impact of stress or a reduction in ethanol intake when rodents have access to alcohol during or immediately after stress (van Erp & Miczek, 2001;Marianno, Abrahao, & Camarini, 2017). Stress exposure also increases behavioral sensitivity to ethanol (Quadir et al, 2016).…”

“…Stress exposure can raise ethanol intake and preference in both animals (Morais-Silva, Fernandes-Santos, Moreira-Silva, & Marin, 2016;Norman et al, 2015;Quadir et al, 2016) and humans (Sinha, 2001), although some studies have shown no impact of stress or a reduction in ethanol intake when rodents have access to alcohol during or immediately after stress (van Erp & Miczek, 2001;Marianno, Abrahao, & Camarini, 2017). Stress exposure also increases behavioral sensitivity to ethanol (Quadir et al, 2016). As such, cross-sensitization may help explain why stress exposure is so closely involved in alcohol relapse (Becker, 2012), and in the high rate of comorbidity between alcoholism and affective disorders (Fuehrlein et al, 2014).…”

Homer2 within the nucleus accumbens core bidirectionally regulates alcohol intake by both P and Wistar rats

“…This neuroadaptation is proposed to contribute to the hyper-glutamatergic state that promotes addiction/alcoholism-related behaviors (e.g., Cui et al, 2013; Gass & Olive, 2008) and genetic predisposition to alcoholism-related behaviors is associated with elevated indices of Homer2/glutamate signaling within the NAc, as well as other mesolimbic structures (Cozzoli et al, 2009, 2012, 2014; Goulding et al, 2011; Szumlinski et al, 2005; Szumlinski, Ary, Lominac, et al, 2008). Nearly a decade of transgenic research supports an active role for Homer2b, particularly within the NAc, in bidirectionally regulating behavior in various animal models of alcoholism/alcohol-induced neuroplasticity, including behavioral sensitization (Szumlinski et al, 2005; Szumlinski, Ary, Lominac, et al, 2008), stress-alcohol cross-sensitization (Quadir et al, 2015), place-preference (Szumlinski et al, 2005; Szumlinski, Ary, Lominac, et al, 2008), and alcohol intake under both operant (Szumlinski et al, 2005) and non-operant procedures (Cozzoli et al, 2009, 2012; Goulding et al, 2011; Szumlinski et al, 2005; Szumlinski, Ary, Lominac, et al, 2008). However, in our view, one major shortcoming of this collection of prior behavioral work relates to the exclusive use of mice as the experimental subjects.…”