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John D Salamone - One of the best experts on this subject based on the ideXlab platform.
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dopamine antagonists alter response allocation but do not suppress appetite for food in rats contrast between the effects of skf 83566 raclopride and fenfluramine on a concurrent choice task
Psychopharmacology, 2002Co-Authors: John D Salamone, M N Arizzi, M D Sandoval, K M Cervone, J AbermanAbstract:Rationale: Dopamine is important for enabling organisms to overcome work-related response costs. One way of investigating this function has been with concurrent choice procedures using food reinforcement. In the present study, rats were given a choice between pressing a Lever for preferred Bioserve pellets, or approaching and consuming a less-preferred laboratory chow that was concurrently available. In previous work with this task, dopamine antagonists and accumbens dopamine depletions decreased Lever pressing but increased chow consumption. Objective: The present study assessed three drugs (two dopamine antagonists and one appetite suppressant) using the Lever pressing/chow feeding task. Results: Under baseline conditions, rats pressed the Lever at high rates (1,300–1,500 responses) to obtain the preferred food, and little of the laboratory chow was eaten (1–2 g). Selective D1 and D2 antagonists (SKF 83566 and raclopride) reduced fixed ratio 5 Lever pressing, but substantially increased chow consumption. In contrast, the serotonergic appetite suppressant fenfluramine reduced both Lever pressing and chow consumption. With the dopamine antagonists, Lever pressing and chow consumption were inversely correlated across treatments, while these two measures were unrelated in the fenfluramine experiment. Conclusions: Dopamine antagonists and accumbens dopamine depletions do not simply reduce appetite. Rats with accumbens dopamine depletions, or rats treated with low doses of selective or non-selective dopamine antagonists, remain directed toward the acquisition and consumption of food. These results demonstrate that fundamental aspects of food reinforcement are left intact after treatment with low doses of dopamine antagonists.
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pharmacological characterization of performance on a concurrent Lever pressing feeding choice procedure effects of dopamine antagonist cholinomimetic sedative and stimulant drugs
Psychopharmacology, 1994Co-Authors: Michael S Cousins, Wei Wei, John D SalamoneAbstract:This experiment was undertaken to provide a pharmacological characterization of performance on a task involving food-related instrumental and consummatory behavior. Rats were tested in an operant chamber in which there was a choice between pressing a Lever to receive a preferred food (Bioserve pellets) or approaching and consuming a less-preferred food (Lab Chow). The Lever pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the Lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the Lever pressing schedule. Previous work has shown that injection of dopamine (DA) antagonists, or depletion of DA in the nucleus accumbens, caused a substantial shift in behavior such that Lever pressing was reduced but chow consumption increased. In the present study it was shown that the DA antagonist haloperidol decreased Lever pressing and increased chow consumption at doses of 0.1 and 0.15 mg/kg. The D1 antagonist SCH 23390 (0.05, 0.1 and 0.15 mg/kg) and the non-selective DA antagonistcis-flupenthixol (0.3 and 0.45 mg/kg) decreased Lever pressing and produced substantial increases in chow consumption. The D2 antagonist sulpiride decreased Lever pressing, but produced only slight increases in chow intake at the highest dose. Pentobarbital reduced Lever pressing and increased chow consumption at 10.0 mg/kg. The muscarinic agonist pilocarpine produced dose-related decreases in Lever pressing, but failed to increase chow consumption. Amphetamine produced dose-related decreases in both Lever pressing and chow consumption. These results indicate that low/moderate doses of the DA antagonists haloperidol,cis-flupenthixol and SCH 23390 can suppress Lever pressing in doses that leave the animal directed towards food acquisition and consumption.
Dave Thirumalai - One of the best experts on this subject based on the ideXlab platform.
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Kinematics of the Lever arm swing in myosin VI.
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Mauro L. Mugnai, Dave ThirumalaiAbstract:Myosin VI (MVI) is the only known member of the myosin superfamily that, upon dimerization, walks processively toward the pointed end of the actin filament. The leading head of the dimer directs the trailing head forward with a power stroke, a conformational change of the motor domain exaggerated by the Lever arm. Using a unique coarse-grained model for the power stroke of a single MVI, we provide the molecular basis for its motility. We show that the power stroke occurs in two major steps. First, the motor domain attains the poststroke conformation without directing the Lever arm forward; and second, the Lever arm reaches the poststroke orientation by undergoing a rotational diffusion. From the analysis of the trajectories, we discover that the potential that directs the rotating Lever arm toward the poststroke conformation is almost flat, implying that the Lever arm rotation is mostly uncoupled from the motor domain. Because a backward load comparable to the largest interhead tension in a MVI dimer prevents the rotation of the Lever arm, our model suggests that the leading-head Lever arm of a MVI dimer is uncoupled, in accord with the inference drawn from polarized total internal reflection fluorescence (polTIRF) experiments. Without any adjustable parameter, our simulations lead to quantitative agreement with polTIRF experiments, which validates the structural insights. Finally, in addition to making testable predictions, we also discuss the implications of our model in explaining the broad step-size distribution of the MVI stepping pattern.
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Kinematics of the Lever Arm Swing in Myosin VI
2016Co-Authors: Mauro L. Mugnai, Dave ThirumalaiAbstract:Myosin VI (MVI) is the only known member of the myosin superfamily that, upon dimerization, walks processively towards the pointed end of the actin filament. The leading head of the dimer directs the trailing head forward with a power stroke, a conformational change of the motor domain exaggerated by the Lever arm. Using a new coarse-grained model for the power stroke of a single MVI, we provide the molecular basis for its motility. We show that the power stroke occurs in two major steps: first, the motor domain attains the post-stroke conformation without directing the Lever arm forward; second, the Lever arm reaches the post-stroke orientation by undergoing a rotational diffusion. From the analysis of the trajectories, we discover that the potential that directs the rotating Lever arm towards the post-stroke conformation is almost flat, implying that the Lever arm rotation is mostly uncoupled from the motor domain. Because a backward load comparable with the largest inter-head tension in a MVI dimer prevents the rotation of the Lever arm, our model suggests that the leading-head Lever arm of a MVI dimer is uncoupled, in accord with the inference drawn from polarized Total Internal Reflection Fluorescence (polTIRF) experiments. Our simulations are in quantitative agreement with polTIRF experiments, which validates our structural insights. Finally, we discuss the implications of our model in explaining the broad step-size distribution of MVI stepping pattern, and we make testable predictions.
Christopher M. Yengo - One of the best experts on this subject based on the ideXlab platform.
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direct measurements of the coordination of Lever arm swing and the catalytic cycle in myosin v
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Darshan V. Trivedi, Jonathan P. Davis, Anja M. Swenson, Joseph M Muretta, David D Thomas, Christopher M. YengoAbstract:Myosins use a conserved structural mechanism to convert the energy from ATP hydrolysis into a large swing of the force-generating Lever arm. The precise timing of the Lever arm movement with respect to the steps in the actomyosin ATPase cycle has not been determined. We have developed a FRET system in myosin V that uses three donor–acceptor pairs to examine the kinetics of Lever arm swing during the recovery and power stroke phases of the ATPase cycle. During the recovery stroke the Lever arm swing is tightly coupled to priming the active site for ATP hydrolysis. The Lever arm swing during the power stroke occurs in two steps, a fast step that occurs before phosphate release and a slow step that occurs before ADP release. Time-resolved FRET demonstrates a 20-A change in distance between the pre- and postpower stroke states and shows that the Lever arm is more dynamic in the postpower stroke state. Our results suggest myosin binding to actin in the ADP.Pi complex triggers a rapid power stroke that gates the release of phosphate, whereas a second slower power stroke may be important for mediating strain sensitivity.
Barry J Everitt - One of the best experts on this subject based on the ideXlab platform.
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bilateral intra accumbens self administration of d amphetamine antagonism with intra accumbens sch 23390 and sulpiride
Psychopharmacology, 1994Co-Authors: G D Phillips, Trevor W Robbins, Barry J EverittAbstract:The efficacy ofd-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions ofd-amphetamine were made contingent upon the acquisition of a Lever-pressing response. Two identical Levers were available within the operant chamber. Depression of the drug Lever resulted in the intra-accumbens delivery of 1 µgd-amphetamine; responses upon the second, control Lever were recorded but had no programmed consequences. Animals were not ‘primed’ with non-contingent infusions ofd-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug Lever. Removal of thed-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug Lever. Adulteration of the infusate with either the D1 dopamine receptor antagonist SCH-23390 or the D2 dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug Lever. Reductions in the dose ofd-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D1 and D2 dopamine receptors within the nucleus accumbens are discussed.
J Aberman - One of the best experts on this subject based on the ideXlab platform.
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dopamine antagonists alter response allocation but do not suppress appetite for food in rats contrast between the effects of skf 83566 raclopride and fenfluramine on a concurrent choice task
Psychopharmacology, 2002Co-Authors: John D Salamone, M N Arizzi, M D Sandoval, K M Cervone, J AbermanAbstract:Rationale: Dopamine is important for enabling organisms to overcome work-related response costs. One way of investigating this function has been with concurrent choice procedures using food reinforcement. In the present study, rats were given a choice between pressing a Lever for preferred Bioserve pellets, or approaching and consuming a less-preferred laboratory chow that was concurrently available. In previous work with this task, dopamine antagonists and accumbens dopamine depletions decreased Lever pressing but increased chow consumption. Objective: The present study assessed three drugs (two dopamine antagonists and one appetite suppressant) using the Lever pressing/chow feeding task. Results: Under baseline conditions, rats pressed the Lever at high rates (1,300–1,500 responses) to obtain the preferred food, and little of the laboratory chow was eaten (1–2 g). Selective D1 and D2 antagonists (SKF 83566 and raclopride) reduced fixed ratio 5 Lever pressing, but substantially increased chow consumption. In contrast, the serotonergic appetite suppressant fenfluramine reduced both Lever pressing and chow consumption. With the dopamine antagonists, Lever pressing and chow consumption were inversely correlated across treatments, while these two measures were unrelated in the fenfluramine experiment. Conclusions: Dopamine antagonists and accumbens dopamine depletions do not simply reduce appetite. Rats with accumbens dopamine depletions, or rats treated with low doses of selective or non-selective dopamine antagonists, remain directed toward the acquisition and consumption of food. These results demonstrate that fundamental aspects of food reinforcement are left intact after treatment with low doses of dopamine antagonists.
