Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

Abstract

Dysregulated catecholamine signaling has long been implicated in drug abuse. Although much is known about adaptations following chronic drug administration, little work has investigated how a single drug exposure paired with withdrawal influences catecholamine signaling in vivo. We used fast-scan cyclic voltammetry in freely moving rats to measure real-time catecholamine overflow during acute morphine exposure and naloxone-precipitated withdrawal in two regions associated with the addiction cycle: the dopamine-dense nucleus accumbens (NAc) and norepinephrine-rich ventral bed nucleus of the stria terminalis (vBNST). We compared dopamine transients in the NAc with norepinephrine concentration changes in the vBNST, and correlated release with specific withdrawal-related behaviors. Morphine increased dopamine transients in the NAc, but did not elicit norepinephrine responses in the vBNST. Conversely, dopamine output was decreased during withdrawal, while norepinephrine was released in the vBNST during specific withdrawal symptoms. Both norepinephrine and withdrawal symptoms could be elicited in the absence of morphine by administering naloxone with an α 2 antagonist. The data support reciprocal roles for dopamine and norepinephrine signaling during drug exposure and withdrawal. The data also support the allostasis model and show that negative-reinforcement may begin working after a single exposure/withdrawal episode.

Contrasting Regulation of Catecholamine Neurotransmission in the Behaving Brain: Pharmacological Insights from an Electrochemical Perspective

“…Importantly, FSCV measurements of dopamine transients provide a clearer picture of dopaminergic activity, as the time course of dopamine transients as measured by FSCV is more closely linked with uptake inhibition-induced stereotypy than microdialysis measurements (Budygin et al, 2000). In contrast to striatal dopamine, norepinephrine concentrations are not known to fluctuate spontaneously in the vBNST of animals at rest (Park et al, , 2013Fox et al, 2016b), further illustrating the differences in endogenous catecholamine signaling (Table 1).…”

“…Intracranial self-stimulation (ICSS) was first described by Olds and Milner (1954), and, through extensive mapping studies, it was determined that sites that supported the best self-stimulation were centered around the medial forebrain bundle, implicating Day et al, 2010;Brown et al, 2011;Cacciapaglia et al, 2012;McCutcheon et al, 2012;Saddoris et al, 2015b. i Budygin et al, 2001;Cheer et al, 2004;Heien et al, 2005;Aragona et al, 2008;Covey et al, 2014;Vander Weele et al, 2014;Fox et al, 2016b. Phillips et al, 2003;Stuber et al, 2005;Cameron et al, 2014.…”

Medullary Norepinephrine Projections Release Norepinephrine into the Contralateral Bed Nucleus of the Stria Terminalis

“…1,9−12 Norepinephrine is released in the vBNST during presentation of an aversive tastant, omission of an expected reward, and delivery of a noxious stimulus. 13−15 Furthermore, the vBNST is an important structure in mediating the aversive components of drug-withdrawal, 4,16,17 and norepinephrine signaling in the vBNST undergoes robust plasticity following stress or drug-withdrawal dependent on HPA axis function. 18,19 Norepinephrine signaling in the vBNST can integrate information about aversive and stressful stimuli to generate an appropriate physiological response, thus how it is regulated is an important topic of investigation.…”

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

“…Future studies of the VTA NAergic system will likely address both the distinct phenotypes of the DAergic neurons and their properties in relation to modulation by NA, as well as changes in NAergic signaling and its impact on DA release in the context of plasticity related to chronic stress or drugs of abuse (Anderson and Pierce ; Fox et al . ).…”

“…These findings suggest that NAergic signaling could be viewed in the context of phenotypic diversity in the VTA, with mesocortical and mesolimbic DAergic circuitry being markedly different in the degree of regulation by NAergic tone via a 1 -AR-as well as D 2 R-dependent mechanisms. Future studies of the VTA NAergic system will likely address both the distinct phenotypes of the DAergic neurons and their properties in relation to modulation by NA, as well as changes in NAergic signaling and its impact on DA release in the context of plasticity related to chronic stress or drugs of abuse (Anderson and Pierce 2005;Fox et al 2017).…”