Abstract
A bidirectional relationship between stress and ethanol exists whereby stressful events are comorbid with problematic ethanol use and prolonged ethanol exposure results in adaptations of the physiological stress response. Endocrine response to stress is initiated in the hypothalamic paraventricular nucleus (PVN) with the synthesis and release of corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). Alterations in CRH and AVP following long-term ethanol exposure in rodents is well demonstrated, however little is known about the response to ethanol in primates or the mechanisms of adaptation. We hypothesized that long-term ethanol self-administration in nonhuman primates would lead to ultrastructural changes in the PVN underlying adaptation to chronic ethanol. Double-label immunogold electron microscopy (EM) was used to measure presynaptic gamma-aminobutyric acid (GABA) and glutamate density within synaptic terminals contacting CRH- and AVP-immunoreactive dendrites. Additionally, pituitary-adrenal hormones (ACTH, cortisol, DHEA-s and aldosterone) under two conditions (low and mild stress) were compared before and after self-administration. All hormones were elevated in response to the mild stressor independent of ethanol consumption. The presynaptic glutamate density in recurrent (i.e., intra-hypothalamic) CRH terminals was highly related to ethanol intake, and may be a permissive factor in increased drinking due to stress. Conversely, glutamate density within recurrent AVP terminals showed a trend-level increase following ethanol, but was not related to average daily consumption. Glutamate density in non-recurrent AVP terminals was related to aldosterone under the low stress condition while GABAergic density in this terminal population was related to water consumption. The results reveal distinct populations of presynaptic terminals whose glutamatergic or GABAergic density were uniquely related to water and ethanol consumption and circulating hormones.
Highlights
Alcohol use disorders are a major public health concern
A significant interaction between stress condition and experimental phase indicated that DHEA-s was lower after self-administration in the low stress condition, but increased following self-administration in response to the mild-stressor, there was no significant interaction with group (F1,6 = 3.84, p = 0.10)
Controls and drinkers did not differ significantly in cortisol, there was a trend towards an interaction of group and condition where monkeys in the ethanol group had lower concentration of cortisol during the low stress condition compared to controls and in response to the mild-stressor
Summary
Alcohol use disorders are a major public health concern. In 2014, 5.1% of the global burden of disease and injury was attributed to alcohol use [World Health Organization (WHO), 2014]. In response to real (i.e., external or physical) or perceived (i.e., sensory or psychological) stressors, these neurons synthesize and release corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). These neuropeptides induce HPA axis activation via CRH-R1 and AVP-1b receptors on corticotropes in the anterior pituitary, leading to synthesis and release of adrenocorticotropin hormone (ACTH). AVP produces a mild ACTH-stimulatory effect on its own, but when co-released with CRH, ACTH release is greater than after either neuropeptide alone (Rivier and Vale, 1983b; Antoni, 1993). Activation of parvocellular neurons, as measured by c-Fos, depends on the type and magnitude of the stressor (Pacák and Palkovits, 2001) suggesting varied sources of synaptic input that code for stress intensity. The majority of synaptic contacts onto the parvocellular neurons of the PVN contain glutamate and gamma-aminobutyric acid (GABA; Decavel and van den Pol, 1992); other neuropeptides and neurotransmitters are present such as norepinephrine (Liposits et al, 1986; Daftary et al, 2000) and serotonin (Qi et al, 2009)
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