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

Catecholamine neurotransmission plays a key role in regulating a variety of behavioral and physiologic processes, and its dysregulation is implicated in both neurodegenerative and neuropsychiatric disorders. Over the last four decades, in vivo electrochemistry has enabled the discovery of contrasting catecholamine regulation in the brain. These rapid and spatially resolved measurements have been conducted in brain slices, and in anesthetized and freely behaving animals. In this review, we describe the methods enabling in vivo measurements of dopamine and norepinephrine, and subsequent findings regarding their release and regulation in intact animals. We thereafter discuss key studies in awake animals, demonstrating that these catecholamines are not only differentially regulated, but are released in opposition of each other during appetitive and aversive stimuli

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

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 α2 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

Deforestation of watersheds of Panama : nutrient retention and export to streams

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biogeochemistry 115 (2013): 299-315, doi:10.1007/s10533-013-9836-2.A series of eight watersheds on the Pacific coast of Panama where conversion of mature lowland wet forest to pastures by artisanal burning provided watershed-scale experimental units with a wide range of forest cover (23, 29, 47, 56, 66, 73, 73, 91, and 92%). We used these watersheds as a landscape-scale experiment to assess effects of degree of deforestation on within-watershed retention and hydrological export of atmospheric inputs of nutrients. Retention was estimated by comparing rainfall nutrient concentrations (volume-weighted to allow for evapotranspiration) to concentrations in freshwater reaches of receiving streams. Retention of rain-derived nutrients in these Panama watersheds averaged 77, 85, 80, and 62% for nitrate, ammonium, dissolved organic N, and phosphate, respectively. Retention of rain-derived inorganic nitrogen, however, depended on watershed cover: retention of nitrate and ammonium in pasture-dominated watersheds was 95 and 98%, while fully forested watersheds retained 65 and 80% of atmospheric nitrate and ammonium inputs. Watershed forest cover did not affect retention of dissolved organic nitrogen and phosphate. Exports from more forested watersheds yielded DIN/P near 16, while pasture-dominated watersheds exported N/P near 2. The differences in magnitude of exports and ratios suggest that deforestation in these Panamanian forests results in exports that affect growth of plants and algae in the receiving stream and estuarine ecosystems. Watershed retention of dissolved inorganic nitrogen calculated from wet plus dry atmospheric deposition varied from 90% in pasture- to 65% in forest-dominated watersheds, respectively. Discharges of DIN to receiving waters from the watersheds therefore rose from 10% of atmospheric inputs for pasture-dominated watersheds, to about 35% of atmospheric inputs for fully forested watersheds. These results from watersheds with no agriculture or urbanization, but different conversion of forest to pasture by burning, show significant, deforestation-dependent retention within tropical watersheds, but also ecologically significant, and deforestation-dependent, exports that are biologically significant because of the paucity of nutrients in receiving tropical stream and coastal waters.This work was funded by NSF Grant BIO- 084241

Cross-hemispheric dopamine projections have functional significance

Decades of research have described dopamine’s importance in reward-seeking behavior and motor control. Although numerous investigations have focused on dopamine’s mechanisms in modulating behavior, the long-standing belief that dopamine neurons project solely unilaterally has limited the exploration of interhemispheric dopamine signaling. Here we resolve disparate descriptions of unilateral vs. bilateral projections by reporting that dopamine neurons can release dopamine in the contralateral hemisphere. Using voltammetry in awake and anesthetized rats, we reveal an unprecedented synchrony of dopamine fluctuations between hemispheres. Via stimulation with amphetamine, we demonstrate functional cross-hemispheric projections in a hemiparkinsonian model. This previously undescribed capacity for interhemispheric dopamine signaling can precipitate new areas of inquiry. Future work may exploit properties of bilateral dopamine release to improve treatments for Parkinson’s disease, including deep brain stimulation

Coral reef biofilm bacterial diversity and successional trajectories are structured by reef benthic organisms and shift under chronic nutrient enrichment

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Remple, K. L., Silbiger, N. J., Quinlan, Z. A., Fox, M. D., Kelly, L. W., Donahue, M. J., & Nelson, C. E. Coral reef biofilm bacterial diversity and successional trajectories are structured by reef benthic organisms and shift under chronic nutrient enrichment. Npj Biofilms and Microbiomes, 7(1), (2021): 84, https://doi.org/10.1038/s41522-021-00252-1.Work on marine biofilms has primarily focused on host-associated habitats for their roles in larval recruitment and disease dynamics; little is known about the factors regulating the composition of reef environmental biofilms. To contrast the roles of succession, benthic communities and nutrients in structuring marine biofilms, we surveyed bacteria communities in biofilms through a six-week succession in aquaria containing macroalgae, coral, or reef sand factorially crossed with three levels of continuous nutrient enrichment. Our findings demonstrate how biofilm successional trajectories diverge from temporal dynamics of the bacterioplankton and how biofilms are structured by the surrounding benthic organisms and nutrient enrichment. We identify a suite of biofilm-associated bacteria linked with the orthogonal influences of corals, algae and nutrients and distinct from the overlying water. Our results provide a comprehensive characterization of marine biofilm successional dynamics and contextualize the impact of widespread changes in reef community composition and nutrient pollution on biofilm community structure.This work was supported through grants from the National Science Foundation for Biological Oceanography (1923877 to C.E.N. and M.J.D., 1949033 to C.E.N. and 2118687 to L.W.K., and 1924281 to N.J.S.) and the National Fish and Wildlife Foundation (grant no. 44447 to C.E.N.). This paper is funded in part by the National Oceanic and Atmospheric Administration, Project A/AS-1, which is sponsored by the University of Hawaii Sea Grant College Program, SOEST, under Institutional Grant No. NA18OAR4170076 from NOAA Office of Sea Grant, Department of Commerce. This is CSUN marine biology contribution #365, UH Sea Grant contribution UNIHI-SEAGRANT-JC-21-06, and UH SOEST contribution 11435

Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

Previous work has demonstrated the importance of genetic factors and stress-sensitive circuits in the development of affective disorders. Anxiety and numerous psychological disorders are comorbid with substance abuse, and noradrenergic signaling in the bed nucleus of the stria terminalis (BNST) is thought to be a source of this convergence. Here, we examined the effects of different stressors on behavior and norepinephrine dynamics in the BNST of rat strains known to differ in their HPA-axis function. We compared the effects of acute morphine dependence and social isolation in non-anxious Sprague Dawley (SD) rats, and a depression model, Wistar-Kyoto (WKY) rats. We found a shared phenotype in drug-dependent and singly housed SD rats, characterized by slowed norepinephrine clearance, decreased autoreceptor function, and elevated anxiety. WKY rats exhibited changes in anxiety and autoreceptor function only following morphine dependence. To ascertain the influence of LC inhibition on this plasticity, we administered the LC-terminal-selective toxin DSP-4 to SD and WKY rats. DSP-4-treated SD rats demonstrated a dependence-like phenotype, whereas WKY rats were unchanged. Overall, our findings suggest that individuals with varying stress susceptibilities have different noradrenergic signaling changes in response to stress. These changes may establish conditions that favor stress-induced reinstatement and increase the risk for addiction

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

Central norepinephrine signaling influences a wide range of behavioral and physiological processes, and the ventral bed nucleus of the stria terminalis (vBNST) receives some of the densest norepinephrine innervation in the brain. Previous work describes norepinephrine neurons as projecting primarily unilaterally; however, recent evidence for cross-hemispheric catecholamine signaling challenges this idea. Here, we use fast-scan cyclic voltammetry and retrograde tracing to characterize cross-hemispheric norepinephrine signaling in the vBNST. We delivered stimulations to noradrenergic pathways originating in the A1/A2 and locus coeruleus and found hemispherically equivalent norepinephrine release in the vBNST regardless of stimulated hemisphere. Unilateral retrograde tracing revealed that medullary, but not locus coeruleus norepinephrine neurons send cross-hemispheric projections to the vBNST. Further characterization with pharmacological lesions revealed that stimulations of the locus coeruleus and its axon bundles likely elicit vBNST norepinephrine release through indirect activation. These experiments are the first to demonstrate contralateral norepinephrine release and establish that medullary, but not coerulean neurons are responsible for norepinephrine release in the vBNST

Facilitation of Serotonin Signaling by SSRIs is Attenuated by Social Isolation

Hypofunction of the serotonergic system is often associated with major depression and obsessive compulsive disorder (OCD). Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to treat these disorders, and require 3–6 weeks of chronic treatment before improvements in the symptoms are observed. SSRIs inhibit serotonin's transporter, and in doing so, increase extracellular serotonin concentrations. Thus, efficacy of SSRIs likely depends upon the brain's adaptive response to sustained increases in serotonin levels. Individual responsiveness to SSRI treatment may depend on a variety of factors that influence these changes, including ongoing stress. Social isolation is a passive, naturalistic form of chronic mild stress that can model depression in rodents. In this study, we examined how 20-day treatment with the SSRI citalopram (CIT) alters marble-burying (MB), open field behavior, and serotonin signaling in single- vs pair-housed animals. We used in vivo voltammetry to measure electrically evoked serotonin, comparing release rate, net overflow, and clearance. Pair-housed mice were significantly more responsive to CIT treatment, exhibiting reduced MB and facilitation of serotonin release that positively correlated with the frequency of electrical stimulation. These effects of CIT treatment were attenuated in single-housed mice. Notably, although CIT treatment enhanced serotonin release in pair-housed mice, it did not significantly alter uptake rate. In summary, we report that chronic SSRI treatment facilitates serotonin release in a frequency-dependent manner, and this effect is blocked by social isolation. These findings suggest that the efficacy of SSRIs in treating depression and OCD may depend on ongoing stressors during treatment

Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice

“Black” pigment gallstones form in sterile gallbladder bile in the presence of excess bilirubin conjugates (“hyperbilirubinbilia”) from ineffective erythropoiesis, hemolysis, or induced enterohepatic cycling (EHC) of unconjugated bilirubin. Impaired gallbladder motility is a less well-studied risk factor. We evaluated the spontaneous occurrence of gallstones in adult germfree (GF) and conventionally housed specific pathogen-free (SPF) Swiss Webster (SW) mice. GF SW mice were more likely to have gallstones than SPF SW mice, with 75% and 23% prevalence, respectively. In GF SW mice, gallstones were observed predominately in heavier, older females. Gallbladders of GF SW mice were markedly enlarged, contained sterile black gallstones composed of calcium bilirubinate and <1% cholesterol, and had low-grade inflammation, edema, and epithelial hyperplasia. Hemograms were normal, but serum cholesterol was elevated in GF compared with SPF SW mice, and serum glucose levels were positively related to increasing age. Aged GF and SPF SW mice had deficits in gallbladder smooth muscle activity. In response to cholecystokinin (CCK), gallbladders of fasted GF SW mice showed impaired emptying (females: 29%; males: 1% emptying), whereas SPF SW females and males emptied 89% and 53% of volume, respectively. Bilirubin secretion rates of GF SW mice were not greater than SPF SW mice, repudiating an induced EHC. Gallstones likely developed in GF SW mice because of gallbladder hypomotility, enabled by features of GF physiology, including decreased intestinal CCK concentration and delayed intestinal transit, as well as an apparent genetic predisposition of the SW stock. GF SW mice may provide a valuable model to study gallbladder stasis as a cause of black pigment gallstones.National Institutes of Health (U.S.) (Training Grant T32-OD10978-26)National Institutes of Health (U.S.) (Training Grant P30-ES002109)Kinship Foundation. Searle Scholars Progra

Medullary Norepinephrine Neurons Modulate Local Oxygen Concentrations in the Bed Nucleus of the Stria Terminalis

Neurovascular coupling is understood to be the underlying mechanism of functional hyperemia, but the actions of the neurotransmitters involved are not well characterized. Here we investigate the local role of the neurotransmitter norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat by measuring O2, which is delivered during functional hyperemia. Extracellular changes in norepinephrine and O2 were simultaneously monitored using fast-scan cyclic voltammetry. Introduction of norepinephrine by electrical stimulation of the ventral noradrenergic bundle or by iontophoretic ejection induced an initial increase in O2 levels followed by a brief dip below baseline. Supporting the role of a hyperemic response, the O2 increases were absent in a brain slice containing the vBNST. Administration of selective pharmacological agents demonstrated that both phases of this response involve β-adrenoceptor activation, where the delayed decrease in O2 is sensitive to both α- and β-receptor subtypes. Selective lesioning of the locus coeruleus with the neurotoxin DSP-4 confirmed that these responses are caused by the noradrenergic cells originating in the nucleus of the solitary tract and A1 cell groups. Overall, these results support that non-coerulean norepinephrine release can mediate activity-induced O2 influx in a deep brain region