Abstract
Major depression and alcohol‐related disorders frequently co‐occur. Depression severity weighs on the magnitude and persistence of comorbid alcohol use disorder (AUD), with severe implications for disease prognosis. Here, we investigated whether depression vulnerability drives propensity to AUD at the preclinical level. We used the social defeat–induced persistent stress (SDPS) model of chronic depression in combination with operant alcohol self‐administration (SA). Male Wistar rats were subjected to social defeat (five episodes) and prolonged social isolation (~12 weeks) and subsequently classified as SDPS‐prone or SDPS‐resilient based on their affective and cognitive performance. Using an operant alcohol SA paradigm, acquisition, motivation, extinction, and cue‐induced reinstatement of alcohol seeking were examined in the two subpopulations. SDPS‐prone animals showed increased alcohol SA, heightened motivation to acquire alcohol, persistent alcohol seeking despite alcohol unavailability, signs of extinction resistance, and increased cue‐induced relapse; the latter could be blocked by the α2 adrenoreceptor agonist guanfacine. In SDPS‐resilient rats, prior exposure to social defeat increased alcohol SA without affecting any other measures of alcohol seeking and alcohol taking. Our data revealed that depression proneness confers vulnerability to alcohol, emulating patterns of alcohol dependence seen in human addicts, and that depression resilience to a large extent protects from the development of AUD‐like phenotypes. Furthermore, our data suggest that stress exposure alone, independently of depressive symptoms, alters alcohol intake in the long‐term.
Highlights
Major Depressive Disorder (MDD) is characterized by (a) persistent negative mood, (b) loss of interest or inability to experience pleasure, and (c) mild cognitive impairment.[1]
In the present preclinical study, we examined the effects of depression vulnerability on alcohol seeking and alcohol‐taking behaviors
This was to establish whether social defeat–induced persistent stress (SDPS)‐proneness, which is associated with primary depressive‐like symptoms, promotes secondary alcohol use disorder, two phenotypes that are often comorbid in humans.[3]
Summary
Major Depressive Disorder (MDD) is characterized by (a) persistent negative mood, (b) loss of interest or inability to experience pleasure (anhedonia), and (c) mild cognitive impairment.[1]. Response to stress determines the extent of depressive symptoms, and this is substantiated by an accumulating body of preclinical data examining individual variability to the effects of stress.[9,10,11] Notably, susceptibility to stress is characterized by dysregulation of the brain reward pathways[12,13,14] and is accompanied by severe reward‐associated behavioral deficits.[15,16] For example, stress‐ susceptible animals display facilitation of drug‐seeking behaviors, as observed in increased alcohol, amphetamine, and cocaine intake[17,18] and sensitization to the effects of cocaine and amphetamine.[15,19]. Clinical and preclinical data support the interplay between the individual response to stress, depression severity, and subsequent vulnerability to substance use disorder. We measured (a) alcohol preference and consumption, (b) motivation for alcohol taking, (c) persistence of alcohol seeking during periods of unavailability, (d) extinction resistance, and (e) reinstatement of alcohol‐seeking behaviors in animals prone to the effects of SPDS and their resilient counterparts
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