Adolescent alcohol exposure produces sex differences in negative affect-like behavior and group I mGluR BNST plasticity

Kasten, Chelsea R.; Carzoli, Kathryn L.; Sharfman, Nathan M.; Henderson, Theodore A.; Holmgren, Eleanor B.; Lerner, Mollie R.; Miller, M. Meghan; Wills, Tiffany A.

doi:10.1038/s41386-020-0670-7

Cited by 44 publications

(66 citation statements)

References 65 publications

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“…Interestingly, females were more resistant to adolescent alcohol exposure-induced alterations to the glutamate system, in that females required a full 10day exposure before exhibiting the changes described above, whereas males required only a 7day exposure to begin exhibiting alterations (Morales et al, 2018). In contrast to these findings in the BLA, including the current study, in the BNST of females sEPSC frequency was enhanced and NMDA receptor-mediated long term depression was attenuated during acute withdrawal, with this effect being absent 30 days later (Carzoli et al, 2019;Kasten et al, 2020).…”

Section: Discussioncontrasting

confidence: 72%

“…While our sEPSC findings in males do not reflect those of these studies, a major difference is the period of abstinence from ethanol, as our rats underwent prolonged (30+ days) abstinence following exposure. Two studies that exposed adolescent rats to eight cycles of 16 hours on and 8 hours off from vaporized ethanol found no apparent effects on NMDA receptor-mediated long term depression in the BNST 30 days after exposure (Carzoli et al, 2019;Kasten et al, 2020), despite observing alterations to this and increased sEPSC frequency 24 hours after exposure (Carzoli et al, 2019). Based on these studies in the BNST and our own findings, it seems likely that the disrupted mechanisms identified during acute withdrawal undergo additional compensatory adaptations during protracted abstinence.…”

Section: Discussionmentioning

confidence: 46%

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Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

Przybysz

Gamble

Diaz

2020

Preprint

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Adolescent alcohol exposure is associated with many negative outcomes that persist into adulthood, including altered affective and reward-related behaviors. However, the long-term neurological disruptions underlying these behavioral states are not fully understood. The basolateral amygdala (BLA) plays a critical role in many of these behaviors, and shifts in the excitatory/inhibitory balance in this area are capable of directly modulating their expression.While changes to BLA physiology have been demonstrated during the acute withdrawal phase following adolescent ethanol exposure, no studies to date have examined whether these persist long-term. The kappa opioid receptor (KOR) system is a neuromodulatory system that acts as a prominent mediator of negative affective behaviors, and alterations of this system have been implicated in the behavioral profile caused by chronic alcohol exposure in adulthood. Notably, in the BLA, the KOR system undergoes functional changes between adolescence and adulthood, but whether BLA KORs are functionally disrupted by adolescent ethanol exposure has not been examined. In this study, we exposed male and female Sprague-Dawley rats to a vapor inhalation model of moderate adolescent chronic intermittent ethanol (aCIE) and examined the long-term effects on GABAergic and glutamatergic neurotransmission within the adult BLA using whole-cell patch-clamp electrophysiology. We also assessed how KOR activation modulated these neurotransmitter systems in aCIE versus control rats using the selective KOR agonist, U69593. This investigation revealed that aCIE exposure disrupted basal glutamate transmission in females by increasing spontaneous excitatory postsynaptic current (sEPSC) frequency, while having no effects on glutamate transmission in males or GABA transmission in either sex.Interestingly, we also found that aCIE exposure unmasked a KOR-mediated suppression of spontaneous inhibitory postsynaptic current (sIPSC) frequency and sEPSC amplitude only in males, with no effects of aCIE exposure on KOR function in females. Together, these data suggest that moderate-level adolescent ethanol exposure produces long-term changes to BLA physiology and BLA KOR function, and that these changes are sex-dependent. This is the first study to examine persistent adaptations to both BLA physiology and KOR function following adolescent alcohol exposure, and opens a broad avenue for future investigation into other neurobiological and behavioral consequences of adolescent ethanol exposure-induced disruptions of these systems.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 46%

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

Przybysz

Gamble

Diaz

2020

Preprint

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“… 95 Likewise, acute stress elicited a negative affective state in the novelty-induced suppression of feeding task in adult female mice with a history of adolescent alcohol exposure. 76 A history of adolescent binge drinking and intermittent alcohol vapor exposure led to a negative affective-like state in the elevated plus maze task and fear conditioning response in male mice, but it did not emerge until later in abstinence. 96 …”

Section: Withdrawal/negative Affect Stagementioning

confidence: 99%

“… 71 – 75 Alterations in glutamate signaling from the stria terminalis projecting into the basolateral amygdala are thought to mediate these behavioral differences. 73 , 76 Shorter duration of exposure to chronic intermittent alcohol vapor intoxication and withdrawal cycles was sufficient to detect these synaptic alterations in male rats versus female rats. 73 Furthermore, a translational study using magnetic resonance spectroscopy showed that rats exposed to chronic intermittent alcohol vapors and people diagnosed with AUD have increased glutamatergic neurotransmission during acute alcohol withdrawal compared to their respective controls.…”

Section: Withdrawal/negative Affect Stagementioning

confidence: 99%

Sex Differences in the Neurobiology of Alcohol Use Disorder

Flores‐Bonilla

Richardson

2020

ARCR

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Sex differences may play a critical role in modulating how chronic or heavy alcohol use impacts the brain to cause the development of alcohol use disorder (AUD). AUD is a multifaceted and complex disorder driven by changes in key neurobiological structures that regulate executive function, memory, and stress. A three-stage framework of addiction (binge/intoxication; withdrawal/negative affect; preoccupation/anticipation) has been useful for conceptualizing the complexities of AUD and other addictions. Initially, alcohol drinking causes short-term effects that involve signaling mediated by several neurotransmitter systems such as dopamine, corticotropin releasing factor, and glutamate. With continued intoxication, alcohol leads to dysfunctional behaviors that are thought to be due in part to alterations of these and other neurotransmitter systems, along with alterations in neural pathways connecting prefrontal and limbic structures. Using the three-stage framework, this review highlights examples of research examining sex differences in drinking and differential modulation of neural systems contributing to the development of AUD. New insights addressing the role of sex differences in AUD are advancing the field forward by uncovering the complex interactions that mediate vulnerability.

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“…In addition to CRF, stress peptides like Pdyn and neurotensin modulate inhibition of BNST neurons during stress states (Normandeau et al 2018). In the current studies examining BNST Pdyn , it is likely that stress uncovers persistent alterations in BNST plasticity during withdrawal, as was recently shown in female mice after restraint stress during withdrawal from adolescent intermittent EtOH (Kasten et al 2020). Withdrawal-related disruptions in novelty-induced hypophagia were blocked by an mGluR5 antagonist, again revealed only after restraint stress (Kasten et al 2020).…”

Section: Glutamatergic Plasticity Of Bnst Pdyn Cellsmentioning

confidence: 51%

The Kappa Opioid Receptor is required for some intermittent alcohol drinking induced changes in stress and threat responding in male C57BL/6J mice

Hwa

Bowling

Calloway

et al. 2020

Preprint

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The dynorphin/kappa opioid receptor (KOR) system in the brain regulates both stressful experiences and negative, aversive states during withdrawal from drugs of abuse. We explored the role of this system during acute withdrawal from long-term alcohol drinking, focusing on the bed nucleus of the stria terminalis (BNST), a region strongly implicated in alcohol-withdrawal induced alterations of behavior. Male C57BL/6J mice were subjected to repeated forced swim tests, home cage exposure to a predator odor, and a visual threat after eight weeks intermittent access to alcohol or water. Systemic injection of KOR antagonist norBNI reversed alcohol-related differences in immobility time during the second swim test and reduced burying behavior in response to predator odor, but did not affect behavioral response to visual threat. In dynorphin-GFP reporter mice, c-Fos immunoreactivity was increased in dynorphin-containing neurons after repeated swim stress and alcohol drinking. Using dynorphin-GFP mice, there was enhanced spontaneous excitatory synaptic drive onto dynorphin neurons in the BNST after alcohol-drinking mice underwent forced swim stress. Finally, knockdown of dynorphin in the BNST using a viral shRNA affected swim stress behavior and responses to TMT in alcohol drinkers and controls, but did not affect alcohol drinking. These studies confirm BNST dynorphin recruitment during acute withdrawal as playing a key role in altered behavioral responses to stressful stimuli.HighlightsIntermittent alcohol drinking changed stress reactions in mice.KOR antagonist norBNI altered stress responses in alcohol drinkers.Alcohol and swim stress increased c-Fos immunoreactivity in BNST dynorphin neurons.Swim stress enhanced excitatory drive onto BNST dynorphin cells in alcohol mice.BNST dynorphin knockdown affected some stress behavior, but not alcohol drinking.

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Adolescent alcohol exposure produces sex differences in negative affect-like behavior and group I mGluR BNST plasticity

Cited by 44 publications

References 65 publications

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

Sex Differences in the Neurobiology of Alcohol Use Disorder

The Kappa Opioid Receptor is required for some intermittent alcohol drinking induced changes in stress and threat responding in male C57BL/6J mice

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