Highlights • D2-autoreceptors provide feedback inhibition that regulates the activity of the dopamine system. • Axonal autoreceptors control the synthesis, release, and uptake of dopamine. • Midbrain ...autoreceptors mediate transmission controlling dopamine neuron firing. • This review summarizes the actions of D2-autoreceptors in regulating dopamine signaling.
The balance of dopamine and acetylcholine in the dorsal striatum is critical for motor and learning functions. Midbrain dopamine cells and local cholinergic interneurons (ChIs) densely innervate the ...striatum and have strong reciprocal actions on each other. Although dopamine inputs regulate ChIs, the functional consequences of dopamine neuron activity across dorsal striatal regions is poorly understood. Here, we find that midbrain dopamine neurons drive pauses in the firing of dorsomedial ChIs but robust bursts in dorsolateral ChIs. Pauses are mediated by dopamine D2 receptors, while bursts are driven by glutamate corelease and activation of a mGluR-mediated excitatory conductance. We find the frequency of muscarinic cholinergic transmission to medium spiny neurons is greater in the dorsomedial striatum. This regional variation in transmission is moderated by the different actions of dopamine and glutamate corelease. These results delineate a mechanism by which dopamine inputs maintain consistent levels of cholinergic activity across the dorsal striatum.
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•The frequency of cholinergic transmission onto dMSNs is higher in the DMS than the DLS•SNc inputs drive pauses in DMS cholinergic interneurons via D2 receptors•SNc inputs drive bursts in DLS cholinergic interneurons via mGluR receptors•DA cells differentially modulate ChIs to maintain constant ACh release across areas
Cai and Ford identify regional differences in the extent of ACh transmission onto direct pathway medium spiny neurons between the dorsomedial and the dorsolateral striatum. These differences were normalized by SNc inputs, which had opposing actions on the firing of cholinergic interneurons in each region.
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many ...different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone+ (CRH+) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders.
•Inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior•Increased tonic LC-NE neuronal activity promotes anxiety-like and aversive behavior•CRH+ CeA-LC projections increase LC-NE activity and promote anxiogenic responses•CRH+ CeA-LC-induced anxiety-like behavior is mediated by CRHR1 receptors
McCall et al. identify locus coeruleus (LC) neuronal activity as a critical mediator of stress-induced anxiety. Selective modulation of LC activity bidirectionally controls anxiety-like and aversive behaviors. Anatomical studies identify amygdalar CRH+ inputs that modulate LC activity and drive anxiety-like behavior.
Summary Background Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could ...mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. Methods We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov , number NCT01432730. Findings Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. Interpretation P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. Funding Afferent Pharmaceuticals
Background and Purpose
The P2X3 receptor is an ATP‐gated ion channel expressed by sensory afferent neurons and is used as a target to treat chronic sensitisation conditions. The first‐in‐class, ...selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK‐7264 (gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We used patch clamp to elucidate the pharmacology and kinetics of MK‐7264 and rat models of hypersensitivity and hyperalgesia to test its efficacy on these conditions.
Experimental Approach
Whole‐cell patch clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK‐7264 action, potency, and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic, and neuropathic sensitisation.
Key Results
MK‐7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration‐ and state‐dependency to wash‐on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. The wash‐on rate (τ value) for MK‐7264 at maximal concentrations was much lower when applied before compared to during agonist application. In vivo, MK‐7264 displayed efficacy comparable to naproxen in inflammatory and osteoarthritic sensitisation models and gabapentin in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight‐bearing discomfort.
Conclusions and Implications
MK‐7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Its efficacy in rat models supports its clinical investigation for chronic sensitisation conditions.
Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a ...synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum, and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory postsynaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals.
The replacement of native C₄‐dominated grassland by C₃‐dominated shrubland is considered an ecological state transition where different ecological communities can exist under similar environmental ...conditions. These state transitions are occurring globally, and may be exacerbated by climate change. One consequence of the global increase in woody vegetation may be enhanced ecosystem carbon sequestration, although the responses of arid and semiarid ecosystems may be highly variable. During a drier than average period from 2007 to 2011 in the northern Chihuahuan Desert, we found established shrubland to sequester 49 g C m⁻² yr⁻¹on average, while nearby native C₄grassland was a net source of 31 g C m⁻² yr⁻¹over this same period. Differences in C exchange between these ecosystems were pronounced – grassland had similar productivity compared to shrubland but experienced higher C efflux via ecosystem respiration, while shrubland was a consistent C sink because of a longer growing season and lower ecosystem respiration. At daily timescales, rates of carbon exchange were more sensitive to soil moisture variation in grassland than shrubland, such that grassland had a net uptake of C when wet but lost C when dry. Thus, even under unfavorable, drier than average climate conditions, the state transition from grassland to shrubland resulted in a substantial increase in terrestrial C sequestration. These results illustrate the inherent tradeoffs in quantifying ecosystem services that result from ecological state transitions, such as shrub encroachment. In this case, the deleterious changes to ecosystem services often linked to grassland to shrubland state transitions may at least be partially offset by increased ecosystem carbon sequestration.
In recent years, the population of neurons in the ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that the projections, ...neurochemistry, and receptor and ion channel expression in this cell population vary widely. This review centers on the intrinsic properties and synaptic regulation that control the activity of dopamine neurons. Although all dopamine neurons fire action potentials in a pacemaker pattern in the absence of synaptic input, the intrinsic properties that underlie this activity differ considerably. Likewise, the transition into a burst pause pattern results from combinations of intrinsic ion conductances, inhibitory and excitatory synaptic inputs that differ among this cell population. Finally, synaptic plasticity is a key regulator of the rate and pattern of activity in different groups of dopamine neurons. Through these fundamental properties, the activity of dopamine neurons is regulated and underlies the wide-ranging functions that have been attributed to dopamine.
In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently ...needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.
The mesolimbic dopamine system, which mediates the rewarding properties of nearly all drugs of abuse, originates in the ventral tegmental area (VTA) and sends major projections to both the nucleus ...accumbens (NAc) and the basolateral amygdala (BLA). To address whether differences occur between neurons that project to these separate areas, retrograde microspheres were injected to either the BLA or the NAc of DBA/2J mice. Whole-cell recordings were made from labeled VTA dopamine neurons. We found that identified neurons that projected to the BLA and NAc originated within different quadrants of the VTA with neither group exhibiting large-amplitude h-currents. Neurons that projected to the NAc exhibited a greater outward current in response to the kappa-opioid agonist (5alpha,7alpha,8alpha)-(+)-N-methyl-N-7-(pyrrolidinyl)-1-oxaspiro 4,5dec-8-yl-benzeneacetamide (U69593; 200 nM), whereas neurons that projected to the BLA exhibited greater inhibition to the mu/delta opioid agonist Met5 enkephalin (ME; 3 microM). In addition, we found that the presynaptic inhibition of GABAergic transmission at both GABAA and GABAB receptors was differentially regulated by U69593 between the two groups. When dopamine IPSCs were examined, U69593 caused a greater inhibition in NAc- than BLA-projecting neurons. ME had no effect on either. Finally, the regulation of extracellular dopamine by dopamine uptake transporters was equal across the VTA. These results suggest that opioids differentially inhibit mesolimbic neurons depending on their target projections. Identifying the properties of projecting mesolimbic VTA dopamine neurons is crucial to understanding the action of drugs of abuse.
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