RESUMO
Introduction: Alcohol use disorder (AUD) is commonly associated with anxiety disorders and enhanced stress-sensitivity; symptoms that can worsen during withdrawal to perpetuate continued alcohol use. Alcohol increases neuroimmune activity in the brain. Our recent evidence indicates that alcohol directly modulates neuroimmune function in the central amygdala (CeA), a key brain region regulating anxiety and alcohol intake, to alter neurotransmitter signaling. We hypothesized that cannabinoids, such as cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), which are thought to reduce neuroinflammation and anxiety, may have potential utility to alleviate alcohol withdrawal-induced stress-sensitivity and anxiety-like behaviors via modulation of CeA neuroimmune function. Methods: We tested the effects of CBD and CBD:THC (3:1 ratio) on anxiety-like behaviors and neuroimmune function in the CeA of mice undergoing acute (4-h) and short-term (24-h) withdrawal from chronic intermittent alcohol vapor exposure (CIE). We further examined the impact of CBD and CBD:THC on alcohol withdrawal behaviors in the presence of an additional stressor. Results: We found that CBD and 3:1 CBD:THC increased anxiety-like behaviors at 4-h withdrawal. At 24-h withdrawal, CBD alone reduced anxiety-like behaviors while CBD:THC had mixed effects, showing increased center time indicating reduced anxiety-like behaviors, but increased immobility time that may indicate increased anxiety-like behaviors. These mixed effects may be due to altered metabolism of CBD and THC during alcohol withdrawal. Immunohistochemical analysis showed decreased S100ß and Iba1 cell counts in the CeA at 4-h withdrawal, but not at 24-h withdrawal, with CBD and CBD:THC reversing alcohol withdrawal effects.. Discussion: These results suggest that the use of cannabinoids during alcohol withdrawal may lead to exacerbated anxiety depending on timing of use, which may be related to neuroimmune cell function in the CeA.
RESUMO
Alcohol use disorders (AUDs) are common mental health issues worldwide and can lead to other chronic diseases. Stress is a major factor in the development and continuation of AUDs, and adolescent alcohol exposure can lead to enhanced stress-responsivity and increased risk for AUD development in adulthood. The exact mechanisms behind the interaction between adolescence, stress, and alcohol are not fully understood and require further research. In this regard, the nucleus of the tractus solitarius (NTS) provides dense norepinephrine projections to the extended amygdala, providing a key pathway for stress-related alcohol behaviors. While NTS norepinephrine neurons are known to be alcohol sensitive, whether adolescent alcohol disrupts NTS-norepinephrine neuron development and if this is related to altered stress-sensitivity and alcohol preference in adulthood has not previously been examined. Here, we exposed male and female C57Bl/6J mice to the commonly used adolescent intermittent ethanol (AIE) vapor model during postnatal day 28-42 and examined AIE effects on: 1) tyrosine hydroxylase (TH) mRNA expression in the NTS across various ages (postnatal day 21-90), 2) behavioral responses to acute stress in the light/dark box test in adulthood, 3) NTS TH neuron responses to acute stress and ethanol challenges in adulthood, and 4) ethanol conditioned place preference behavior in adulthood. Overall the findings indicate that AIE alters NTS TH mRNA expression and increases anxiety-like behaviors following acute stress exposure in a sex-dependent manner. These mRNA expression and behavioral changes occur in the absence of AIE-induced changes in NTS TH neuron sensitivity to either acute stress or acute alcohol exposure or changes to ethanol conditioned place preference.