scholarly journals Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol

2021 ◽  
Vol 15 ◽  
Author(s):  
Hui Chen ◽  
Dan Xu ◽  
Yu Zhang ◽  
Yan Yan ◽  
JunXiao Liu ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Place Preference ◽  
Designer Drugs ◽  
Place Conditioning ◽  
General Anesthetic ◽  
Response Scale ◽  
Conditioning Paradigm

Propofol is a worldwide-used intravenous general anesthetic with ideal effects, but hedonic effects of propofol have been reported and cause addictive issue. There is little known about the neurobiological mechanism of hedonic effects of propofol. Increasing researches have shown that the dopaminergic nervous system of the ventral tegmental area (VTA) and the noradrenergic system of locus coeruleus (LC) play a crucial role in hedonic experiences, which are putative sites for mediating the hedonic effects of propofol. In the present study, rat hedonic response scale and place conditioning paradigm were employed to examine the euphoric effects of propofol. In vivo GCaMP-based (AVV-hSyn-GCaMP6s) fiber photometry calcium imaging was used to monitor the real-time neuronal activity in VTA and LC area in rats exhibiting propofol-induced euphoric behaviors. Then DREADDs (designer receptors exclusively activated by designer drugs) modulation using rAAV-hSyn-hM4D(Gi)-EGFP was performed to confirm the neuronal substrate that mediates the euphoric effects of propofol. The score of hedonic facial responses was significantly increased in the 4 mg/kg group compared with that of the 0 mg/kg group. The locomotor activity in the propofol-paired compartment was significantly increased at the 4 mg/kg dose compared with that of the saline-paired group. When compared with the 0 mg/kg group, the place preference increased in the 4 mg/kg group. Administration of 4 mg/kg of propofol triggers reliable increases in GcaMP fluorescence. However, in the VTA GcaMP-expressing rats, administration of 4 mg/kg of propofol did not induce any change of GcaMP signals. The facial score and the place preference, which increased by 4 mg/kg propofol were abolished by chemogenetic inhibition of the neuronal activity in the LC area. Our results suggest that LC noradrenergic neurons, not VTA dopaminergic neurons, are directly involved in the hedonic effects of sub-anesthetic dose of propofol.

In vivo comparison of two 5-HT1A receptors agonists alnespirone (S-20499) and buspirone on locus coeruleus neuronal activity

2003 ◽  
Vol 459 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Bernadette Astier ◽  
Laura Lambás Señas ◽  
Fabienne Soulière ◽  
Patricia Schmitt ◽  
Nadia Urbain ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Neuronal Activity

scholarly journals High-potency ligands for DREADD imaging and activation in rodents and monkeys

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jordi Bonaventura ◽  
Mark A. G. Eldridge ◽  
Feng Hu ◽  
Juan L. Gomez ◽  
Marta Sanchez-Soto ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Long Range ◽  
Neuronal Activity ◽  
Designer Drugs ◽  
Emission Tomography ◽  
High Potency ◽  
Projection Mapping ◽  
Positron Emission ◽  
Neuronal Projection

Abstract Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

Effect of Propofol on Affective State as Assessed by Place Conditioning Paradigm in Rats

1996 ◽  
Vol 85 (1) ◽  
pp. 121-128 ◽  
Author(s):  
L. Pain ◽  
P. Oberling ◽  
G. Sandner ◽  
G. Di Scala
Keyword(s):  
Free Choice ◽  
Recovery Period ◽  
Affective State ◽  
Conditioning Session ◽  
Place Preference ◽  
The Other ◽  
Choice Test ◽  
Place Conditioning ◽  
Short Term ◽  
Conditioning Paradigm

Background Whether propofol produces a pleasant affective state remains unclear from clinical studies. In the current study, the effect on affective state of subanesthetic and anesthetic doses of propofol was assessed at a preclinical level with rats in a place conditioning paradigm. Propofol was compared with methohexital. Methods In the place conditioning paradigm, propofol-induced effect was repeatedly paired with one of two distinguishable compartments of the apparatus, whereas the vehicle-induced effect was repeatedly paired with the other compartment. During a subsequent free-choice test, a preference for the drug-paired compartment over the vehicle-paired compartment would be indicative of pleasant state induced by the drug. For all experiments, the conditioning session lasted 8 days and consisted of four pairings of the drug with one compartment and four pairings of the equivalent volume of vehicle with the other compartment. In experiment 1A, four groups of rats were designated according to the dose of propofol that they received intraperitoneally: 0,30,60, or 90 mg/kg. In experiment 1B, the same procedure was used with subanesthetic doses of intraperitoneal methohexital: 0,10,20, or 30 mg/kg. In experiment 2, the rats were conditioned during the recovery period from short-term anesthesia. For one group, anesthesia was induced by propofol (100 mg/kg) whereas for the other group, anesthesia was induced by an equivalent anesthetic dose of methohexital (40 mg/kg). Results In experiment 1A, the 30-mg/kg, 60-mg/kg, and 90-mg/kg groups showed a place preference for the drug-paired compartment, but only the group conditioned with 60 mg/kg propofol significantly differed from the 0-mg/kg group. In experiment 1B, the groups conditioned with methohexital showed no place preference for the drug-paired compartment. In experiment 2, the rats showed a place preference for the compartment in which they recovered from propofol-induced anesthesia but no place preference for the compartment in which they recovered from methohexital-induced anesthesia. Conclusions Propofol, but not methohexital, induced a pleasant affective state in rats at subanesthetic doses as well as during recovery from an anesthetic dose.

scholarly journals Chemogenetic ligands for translational neurotheranostics

2018 ◽  
Author(s):  
Jordi Bonaventura ◽  
Mark A. Eldridge ◽  
Feng Hu ◽  
Juan L. Gomez ◽  
Marta Sanchez-Soto ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Neuronal Activity ◽  
Designer Drugs ◽  
Emission Tomography ◽  
Projection Mapping ◽  
Positron Emission ◽  
Neuronal Projection ◽  
Compound 21 ◽  
First Time

AbstractDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

In vivo catechol activity in the rat locus coeruleus following different nociceptive stimuli and naloxone

1992 ◽  
Vol 70 (8) ◽  
pp. 1082-1089 ◽  
Author(s):  
M. Hong ◽  
B. Milne ◽  
C. W. Loomis ◽  
K. Jhamandas
Keyword(s):  
Locus Coeruleus ◽  
Neuronal Activity ◽  
Neuronal Firing ◽  
Spinal Reflexes ◽  
Opioid Antagonist ◽  
Thermal Stimulus ◽  
Anaesthetized Rats ◽  
Noxious Stimuli ◽  
Neurochemical Changes

The nucleus locus coeruleus (LC) has been implicated in the processing of spinal reflexes following noxious stimuli. It has been demonstrated that noxious stimuli activate LC neuronal firing, but little is known about the neurochemical changes that might occur following such activation. To determine the effects of different noxious stimuli on LC neuronal activity, anaesthetized rats were exposed to mechanical (tail pinch), thermal (55 °C water), and chemical (5% Formalin injected in the hind paw) stimuli; the catechol oxidation current (CA∙OC), an index of noradrenergic neuronal activity, in the locus coeruleus was monitored using differential normal pulse voltammetry. In addition, the effect of the opioid antagonist naloxone on the CA∙OC in the LC was examined. Exposure to both mechanical and chemical stimuli significantly increased CA∙OC indicating an increase in LC noradrenergic neuronal activity, while the thermal stimulus had no effect. Treatment with naloxone (1 mg/kg i.v.) had no effect on CA∙OC in the LC. The results show a differential responsiveness of LC noradrenergic neurons to different modes of noxious stimuli and fail to demonstrate a tonic opioid regulation of these neurons in the anaesthetized rat.Key words: nociception, in vivo voltammetry, locus coeruleus, opioid, noradrenergic activity, naloxone.

scholarly journals In vivo electrophysiological validation of DREADD-based inhibition of pallidal neurons in the non-human primate

2020 ◽  
Author(s):  
Marc Deffains ◽  
Tho Haï Nguyen ◽  
Hugues Orignac ◽  
Nathalie Biendon ◽  
Sandra Dovero ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Structure And Function ◽  
Designer Drugs ◽  
Post Mortem ◽  
Histochemical Analysis ◽  
High Level ◽  
And Function ◽  
Human Primate ◽  
Do So

AbstractDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) are widely used in rodents to manipulate neuronal activity and establish causal links between structure and function. Their utilization in non-human primates (NHPs) is however limited and their efficacy still debated. Here, we tested DREADD expression in the NHP external globus pallidus (GPe) and electrophysiologically validated DREADD-based inhibition of GPe neurons in the anesthetized monkey.To do so, we performed intracerebral injections of viral construct expressing hM4Di receptor under a neuron-specific promoter into the GPe. Then, we recorded the neuronal activity in the DREADD-transduced (test condition) and DREADD-free (control condition) GPe of two anesthetized animals following local intra-GPe microinjection of clozapine-N-oxide (CNO). In total, 19 and 8 well-isolated and stable units were recorded in the DREADD-transduced and DREADD-free GPe, respectively. Overall, we found that almost half (9/19) of the units modulated their activity following CNO injection in DREADD-transduced GPe. Surprisingly, neuronal activity of the GPe units exhibited diverse patterns in timing and polarity (increase/decrease) of firing rate modulations during and after CNO injection. Nevertheless, decreases were exclusive and stronger after CNO injection. In contrast, only one unit modulated its activity after CNO injection in DREADD-free GPe. Moreover, post-mortem histochemical analysis revealed that hM4Di DREADDs were expressed at high level in the GPe neurons located in the vicinity of the viral construct injection sites. Our results therefore show in vivo DREADD-based inhibition of pallidal neurons in the NHP model and reinforce the view that DREADD technology can be effective in NHPs.

scholarly journals α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abeer Dagra ◽  
Douglas R. Miller ◽  
Min Lin ◽  
Adithya Gopinath ◽  
Fatemeh Shaerzadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Prolonged Exposure ◽  
D2 Receptor ◽  
Neuronal Firing ◽  
Dopamine Neurons ◽  
Loss Of Function ◽  
Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

scholarly journals Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Maria Mensch ◽  
Jade Dunot ◽  
Sandy M. Yishan ◽  
Samuel S. Harris ◽  
Aline Blistein ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Ex Vivo ◽  
Long Term Potentiation ◽  
Network Activity ◽  
Strongly Correlated ◽  
App Processing ◽  
Term Potentiation ◽  
Hippocampal Network

Abstract Background Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Methods With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. Results We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo. Conclusions These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

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