Cocaine Augments Dopamine-Mediated Inhibition of Neuronal Activity in the Dorsal Bed Nucleus of the Stria Terminalis

Abstract

The dorsal region of the bed nucleus of the stria terminalis (dBNST) receives substantial dopaminergic input which overlaps with norepinephrine input implicated in stress responses. Using ex vivo fast scan cyclic voltammetry in male C57BL6 mouse brain slices, we demonstrate that electrically stimulated dBNST catecholamine signals are of substantially lower magnitude and have slower uptake rates compared with caudate signals. Dopamine terminal autoreceptor activation inhibited roughly half of the catecholamine transient, and noradrenergic autoreceptor activation produced an ;30% inhibition. Dopamine transporter blockade with either cocaine or GBR12909 significantly augmented catecholamine signal duration. We optogenetically targeted dopamine terminals in the dBNST of transgenic (TH:Cre) mice of either sex and, using ex vivo whole-cell electrophysiology, we demonstrate that optically stimulated dopamine release induces slow outward membrane currents and an associated hyperpolarization response in a subset of dBNST neurons. These cellular responses had a similar temporal profile to dopamine release, were significantly reduced by the D2/D3 receptor antagonist raclopride, and were potentiated by cocaine. Using in vivo fiber photometry in male C57BL/6 mice during training sessions for cocaine conditioned place preference, we show that acute cocaine administration results in a significant inhibition of calcium transient activity in dBNST neurons compared with saline administration. These data provide evidence for a mechanism of dopamine-mediated cellular inhibition in the dBNST and demonstrate that cocaine augments this inhibition while also decreasing net activity in the dBNST in a drug reinforcement paradigm.

Partial connectomes of labeled dopaminergic circuits reveal non-synaptic communication and axonal remodeling after exposure to cocaine

“…A second problem is that, unlike ionotropic excitatory or inhibitory connections, there is much less known about the ultrastructural characteristics of potential DA synapses, where they occur on neurons, or how frequently ( Liu et al, 2018 ; Rice and Cragg, 2008 ). Thus, analyzing DA circuits has required specific labeling, either with immunohistochemistry ( Bérubé-Carrière et al, 2012 ; Moss and Bolam, 2008 ; Omelchenko and Sesack, 2009 ; Liu et al, 2018 ) or with genetic targeting ( Dos Santos et al, 2018 ; Melchior et al, 2021 ; Mingote et al, 2019 ; Nasirova et al, 2021 ; Poulin et al, 2018 ). However, fundamental questions remain unanswered: (1) how often do DA axons make synapses that appear like classic chemical synapses (i.e., with synaptic vesicles and post-synaptic densities [PSDs]), (2) where do DA synapses occur on target neurons, (3) what do DA axonal varicosities contain, and (4) are there signs of other physical interactions between DA axons and their targets?…”

Distinct Effects of Methamphetamine Isomers on Limbic Norepinephrine and Dopamine Transmission in the Rat Brain

“…Indistinguishable catecholamine redox potentials present a major limitation of in vivo electroanalytical methods, including FSCV, to selectively measure NE or DA in target brain areas/tissues with substantial innervation of both catecholamines. Importantly, our and other prior pharmacological, neurochemical, and histological evidence established that NE is the predominant catecholamine in the v BNST for the past decade as described in the Introduction ,− (for review, see ref ).…”

“…Although FSCV has widely been applied to DA rich brain regions for the study of their roles in drug use disorders and mental disorders, fewer studies have incorporated FSCV to investigate NE in vivo . Our and other labs have shown that the major catecholamine in the ventral ( v ) BNST is NE (>92%), while other subregions of the BNST (e.g., dorsal and lateral) receive both NE and DA innervation, as demonstrated through neurochemical, pharmacological, and anatomical evidence ,− (for review, see ref ). Herein, we determined in anesthetized male rats how d- and l-METH modulate both NE and DA regulation.…”

The role of the bed nucleus of the stria terminalis in the motivational control of instrumental action

“…Our result positions BNST in the encoding of CS’s motivational properties, and such a role is likely to be amplified by BNST’s descending connections with VTA. BNST both sends and receives robust projections to and from VTA GABA and DA neurons, which enable BNST to exert a direct influence over DA release (Melchior et al, 2021 ; Yu et al, 2021 ). VTA-projecting BNST neurons are overwhelmingly GABAergic and these neurons preferentially synapse onto VTA GABA neurons.…”