Homer2 regulates alcohol and stress cross-sensitization.
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 percent), 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 phospholipase Cβ 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 extracellular signal-regulated kinase 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 on neuroplasticity within NAC glutamate transmission.
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
Sema G
SG
Quadir
Department of Pharmacology, Institute of Biomedical Sciences, Universidade de São Paulo, São Paulo, Brazil.
Jaqueline Rocha Borges Dos
JR
Santos
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
Rianne R
RR
Campbell
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
Melissa G
MG
Wroten
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
Nimrita
N
Singh
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
John J
JJ
Holloway
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
Sukhmani K
SK
Bal
Department of Pharmacology, Institute of Biomedical Sciences, Universidade de São Paulo, São Paulo, Brazil.
Rosana
R
Camarini
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA.
Karen K
KK
Szumlinski
D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D000072233:Homer Scaffolding Proteins / Q000235:genetics* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D009714:Nucleus Accumbens / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
D002492:Central Nervous System Depressants; D000072233:Homer Scaffolding Proteins; C121001:NR2B NMDA receptor; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D000431:Ethanol; D054799:Phospholipase C beta
Homer proteins; alcoholism; glutamate; intoxication; nucleus accumbens; unpredictable chronic mild stress