Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

Abstract

Dopamine signaling encodes reward learning and motivated behavior through modulation of synaptic signaling in the nucleus accumbens, and aberrations in these processes are thought to underlie obsessive behaviors associated with alcohol abuse. The nucleus accumbens is divided into core and shell sub-regions with overlapping but also divergent contributions to behavior. Here we optogenetically targeted dopamine projections to the accumbens allowing us to isolate stimulation of dopamine terminals ex vivo. We applied 5 pulse (phasic) light stimulations to probe intrinsic differences in dopamine release parameters across regions. Also, we exposed animals to 4 weeks of chronic intermittent ethanol vapor and measured phasic release. We found that initial release probability, uptake rate and autoreceptor inhibition were greater in the accumbens core compared to the shell, yet the shell showed greater phasic release ratios. Following chronic ethanol, uptake rates were increased in the core but not the shell, suggesting region-specific neuronal adaptations. Conversely, kappa opioid receptor function was upregulated in both regions to a similar extent, suggesting a local mechanism of kappa opioid receptor regulation that is generalized across the nucleus accumbens. These data suggest that dopamine axons in the nucleus accumbens core and shell display differences in intrinsic release parameters, and that ethanol-induced adaptations to dopamine neuron terminal fields may not be homogeneous. Also, chronic ethanol exposure induces an upregulation in kappa opioid receptor function, providing a mechanism for potential over-inhibition of accumbens dopamine signaling which may negatively impact downstream synaptic function and ultimately bias choice towards previously reinforced alcohol use behaviors.

Dopamine Release Dynamics in the Tuberoinfundibular Dopamine System

“…One possible reason for this failure to detect dopamine may be that the axons connecting the TIDA cell somata in the dmArc and the terminals in the ME are largely severed in the coronal slice preparation, as indicated by cytoarchitectonic studies (van den Pol and Cassidy, 1982), interrupting impulse traffic. Similar observations have occurred in other dopamine systems, such as in the striatum (Threlfell et al, 2012;O'Neill et al, 2017) and nucleus accumbens (Melchior and Jones, 2017), where the absence of spontaneous dopamine release in slice preparations has motivated electrically or optically evoked investigations of dopamine release dynamics at different conditions. We therefore next sought to identify evoked dopamine release properties via optogenetic stimulation of the TIDA terminals.…”

Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors

“…To gain insight into whether guanfacine-induced cfos expression in the dBNST resulted from interactions with other brain regions in an experience-dependent manner, we combined the use of a cfos-eGFP transgenic mouse strain that expresses a GFP-labeled cfos fusion protein (Barth et al, 2004) with thick slice immunohistochemistry (Kupferschmidt et al, 2015) to determine whether guanfacine-induced cfos expression could be mimicked in an ex vivo brain slice. Coronal sections (300 m thick) containing the dBNST were exposed to ACSF, the ␣ 2A -AR agonist guanfacine (1 M) (pEC 50 ϭ 7.1-7.3) (MacLennan et al, 1997;Jasper et al, 1998), the ␣ 2 -AR antagonist atipamezole (1 M) (pK i ϭ 8.4 -9.5) (Blaxall et al, 1991;Vacher et al, 2010;Vucicevic et al, 2016), or a combination of guanfacine and atipamezole for 1 h at 28°C. Slices were fixed and stained for NeuN to identify neurons and GFP to quantify cfos-eGFP expression (Fig.…”

“…For example, the ␣ 2A -AR agonist guanfacine elicits antidepressant-like effects in the forced swim test (Mineur et al, 2015) and ␣ 2A -AR KO mice show elevated baseline anxiety-and depressive-like behaviors (Schramm et al, 2001;Lähdesmäki et al, 2002). Further, in rodent models of addiction, ␣ 2 -AR agonists block stress-induced reinstatement of drugseeking behaviors (Erb et al, 2000;Mantsch et al, 2010).…”

Dopaminergic Cellular and Circuit Contributions to Kappa Opioid Receptor Mediated Aversion

“…This KOR induced inhibition of dopamine release in the NAc is stronger in male than in female mice (Conway et al, 2018). Ex vivo voltammetric measurements show that the inhibitory effects of KOR activation on dopamine release are greater during single pulse compared to multiple pulse optogenetic stimulation in mice (Melchior and Jones, 2017). Moreover, KORs affect dopamine transmission in the NAc by interacting with the dopamine transporter (DAT).…”

“…KOR signaling clearly contributes to the aversiveness not only of acute and chronic external disruptive conditions (Donahue et al, 2015;Karkhanis et al, 2016b;Wells et al, 2017) but also interoceptive signals such as drug withdrawal (Walker et al, 2011;reviewed in Koob, 2013). KOR function, in particular in relation to control of dopamine, can also be upregulated during aversive conditions: acute withdrawal following cessation of ethanol vapor exposure and the ethanol vapor exposure itself augments KOR mediated inhibition of stimulated dopamine release in the NAc (Karkhanis et al, 2016a;Melchior and Jones, 2017;Rose et al, 2016). The KOR has also long been considered a target for alleviating ongoing pain, initially through activation (Gear et al, 1996;Pasternak, 1980) and more recently via blockade (Navratilova et al, 2019;Xie et al, 2017).…”