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John D. Salamone - One of the best experts on this subject based on the ideXlab platform.
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Selection of sucrose concentration depends on the effort required to obtain it: studies using tetrabenazine, D_1, D_2, and D_3 receptor antagonists
Psychopharmacology, 2015Co-Authors: Marta Pardo, John D. Salamone, Laura López-cruz, Noemí San Miguel, Mercè CorreaAbstract:Rationale Low doses of dopamine (DA) antagonists and accumbens DA depletions reduce food-reinforced instrumental behavior but do not impair primary food motivation, causing animals to reallocate behavior away from food-reinforced tasks with high response requirements and select less effortful alternatives. However, it is uncertain if this same pattern of effects would occur if sucrose was used as the reinforcer . Objectives These experiments studied the impact of DA depletion and antagonism on performance of an effort-related choice task using sucrose as the reinforcer, as well as sucrose consumption, preference, and taste reactivity tests. Methods The effects of DA manipulations were assessed using a task in which rats chose between lever pressing on a fixed ratio 7 schedule for 5.0 % sucrose versus freely consuming a less concentrated solution (0.3 %). Results The DA depleting agent tetrabenazine shifted effort-related choice, decreasing lever pressing for 5.0 % sucrose but increasing intake of the concurrently available 0.3 % sucrose. Tetrabenazine did not affect sucrose appetitive taste reactivity, or sucrose consumption or preference, in free consumption tests. The D_1 antagonist Ecopipam and the D_2 antagonist haloperidol also shifted choice behavior at doses that did not alter sucrose consumption or preference. In contrast, sucrose pre-exposure reduced consumption across all conditions. D_3 antagonism had no effects. Conclusions D_1 and D_2 receptor blockade and DA depletion reduce the tendency to work for sucrose under conditions that leave fundamental aspects of sucrose motivation (intake, preference, hedonic reactivity) intact. These findings have implications for studies employing sucrose intake or preference in animal models of depression.
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The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.
Pharmacology biochemistry and behavior, 2015Co-Authors: Samantha E. Yohn, Eric J. Nunes, Jessica L. Santerre, Mercè Correa, Rouba Kozak, Samantha J. Podurgiel, John D. SalamoneAbstract:Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist Ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, Ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, Ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of Ecopipam, and in each case the D1 agonist significantly attenuated the effects of Ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.
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Deep brain stimulation of the subthalamic nucleus reverses oral tremor in pharmacological models of parkinsonism: interaction with the effects of adenosine A2A antagonism
The European journal of neuroscience, 2013Co-Authors: Lyndsey E. Collins-praino, Christa E. Müller, Nicholas E. Paul, Samantha J. Podurgiel, Felicia Ledgard, Rotem Kovner, Younis Baqi, Patrick B. Senatus, John D. SalamoneAbstract:Deep brain stimulation (DBS) of the subthalamic nucleus is increasingly being employed as a treatment for parkinsonian symptoms, including tremor. The present studies used tremulous jaw movements, a pharmacological model of tremor in rodents, to investigate the tremorolytic effects of subthalamic DBS in rats. Subthalamic DBS reduced the tremulous jaw movements induced by the dopamine D2 family antagonist pimozide and the D1 family antagonist Ecopipam, as well as the cholinomimetics pilocarpine and galantamine. The ability of DBS to suppress tremulous jaw movements was dependent on the neuroanatomical locus being stimulated (subthalamic nucleus vs. a striatal control site), as well as the frequency and intensity of stimulation used. Importantly, administration of the adenosine A2A receptor antagonist MSX-3 reduced the frequency and intensity parameters needed to attenuate tremulous jaw movements. These results have implications for the clinical use of DBS, and future studies should determine whether adenosine A2A antagonism could be used to enhance the tremorolytic efficacy of subthalamic DBS at low frequencies and intensities in human patients.
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Interactions between adenosine and dopamine receptor antagonists with different selectivity profiles: Effects on locomotor activity.
Behavioural Brain Research, 2010Co-Authors: Lyndsey E. Collins, Jörg Hockemeyer, Christa E. Müller, Daniel J. Galtieri, Patricia A. Collins, Shawnet K. Jones, Russell G. Port, Nicholas E. Paul, John D. SalamoneAbstract:Forebrain dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation. Adenosine A(2A) antagonists reverse many of the behavioral effects of DA antagonists, and A(2A) receptors are co-localized with D(2) receptors on striatal medium spiny neurons. The present work was undertaken to determine if the ability of an A(2A) antagonist, a non-selective adenosine antagonist, or an A(1) antagonist to reverse the locomotor effects of DA blockade in rats differed depending upon whether D(1) or D(2) family receptors were being antagonized. The adenosine antagonists MSX-3, caffeine, DPCPX and CPT were studied for their ability to reverse the locomotor suppression induced by the D(1) antagonist SCH 39166 (Ecopipam) and the D(2) antagonist eticlopride. The D(1) and D(2) antagonists suppressed locomotion in all experiments. The adenosine A(2A) receptor antagonist MSX-3 (0.5-2.0 mg/kg IP) significantly reversed the suppression of locomotion induced by eticlopride. The non-selective adenosine antagonist caffeine (5.0-20.0 mg/kg IP) also reversed the effect of eticlopride, though the effect was not as robust as that seen with MSX-3. The adenosine A(1) antagonists DPCPX (0.375-1.5 mg/kg) and CPT (3.0-12.0 mg/kg IP) were unable to reverse the locomotor impairment elicited by eticlopride. Furthermore, the attenuation of locomotion induced by the D(1) antagonist could only be reversed by the highest dose of MSX-3, but not by caffeine, DPCPX or CPT. DA and adenosine receptor antagonists interact in the regulation of locomotor activation, but the nature of this interaction appears to depend upon the receptor selectivity profiles of the specific drugs being tested.
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Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism.
Neuroscience, 2010Co-Authors: Eric J. Nunes, Patrick A. Randall, Jessica L. Santerre, Ashby B. Given, Thomas N. Sager, Mercè Correa, John D. SalamoneAbstract:Abstract Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice. However, less is known about the effects of adenosine A1 antagonists. Despite anatomical data showing that A1 and D1 receptors are co-localized on the same striatal neurons, it is uncertain if A1 antagonists can reverse the effects DA D1 antagonists. The present work systematically compared the ability of adenosine A1 and A2A receptor antagonists to reverse the effects of DA D1 and D2 antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D1 antagonist Ecopipam (0.2 mg/kg i.p.) and the D2 antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D1 or D2 antagonist. In contrast, the adenosine A2A antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of Ecopipam. Adenosine A2A and DA D2 receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.
Eric J. Nunes - One of the best experts on this subject based on the ideXlab platform.
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The VMAT-2 Inhibitor Tetrabenazine Affects Effort- Related Decision Making in a Progressive Ratio/Chow Feeding Choice Task: Reversal with Antidepressant Drugs
2016Co-Authors: Patrick A. R, Eric J. Nunes, Samantha E. Yohn, Christie A. Lee, Victoria Nowak, Bilal Khan, Priya Shah, Kiran V. Vemuri, Saagar P, Alex MakriyannisAbstract:Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists Ecopipam (D1) an
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The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.
Pharmacology biochemistry and behavior, 2015Co-Authors: Samantha E. Yohn, Eric J. Nunes, Jessica L. Santerre, Mercè Correa, Rouba Kozak, Samantha J. Podurgiel, John D. SalamoneAbstract:Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist Ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, Ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, Ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of Ecopipam, and in each case the D1 agonist significantly attenuated the effects of Ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.
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The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.
PloS one, 2014Co-Authors: Patrick A. Randall, Eric J. Nunes, Samantha E. Yohn, Christie A. Lee, Victoria Nowak, Bilal Khan, Priya Shah, Saagar Pandit, V. Kiran Vemuri, Alexandros MakriyannisAbstract:Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists Ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.
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Effects of the DA D1 antagonist Ecopipam on PROG/chow performance.
2014Co-Authors: Patrick A. Randall, Eric J. Nunes, Samantha E. Yohn, Christie A. Lee, Victoria Nowak, Bilal Khan, Priya Shah, Saagar Pandit, Kiran V. Vemuri, Alex MakriyannisAbstract:On measures of lever pressing, mean (+SEM) total lever presses (A), highest ratio achieved (B), and active lever time (measured in seconds, C), Ecopipam produced significant decreases at 0.1 and 0.2 mg/kg. Chow consumption (mean +SEM, in grams) during test sessions was unaffected by any dose tested (D). (* p
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Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism.
Neuroscience, 2010Co-Authors: Eric J. Nunes, Patrick A. Randall, Jessica L. Santerre, Ashby B. Given, Thomas N. Sager, Mercè Correa, John D. SalamoneAbstract:Abstract Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice. However, less is known about the effects of adenosine A1 antagonists. Despite anatomical data showing that A1 and D1 receptors are co-localized on the same striatal neurons, it is uncertain if A1 antagonists can reverse the effects DA D1 antagonists. The present work systematically compared the ability of adenosine A1 and A2A receptor antagonists to reverse the effects of DA D1 and D2 antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D1 antagonist Ecopipam (0.2 mg/kg i.p.) and the D2 antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D1 or D2 antagonist. In contrast, the adenosine A2A antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of Ecopipam. Adenosine A2A and DA D2 receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.
Samantha E. Yohn - One of the best experts on this subject based on the ideXlab platform.
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The VMAT-2 Inhibitor Tetrabenazine Affects Effort- Related Decision Making in a Progressive Ratio/Chow Feeding Choice Task: Reversal with Antidepressant Drugs
2016Co-Authors: Patrick A. R, Eric J. Nunes, Samantha E. Yohn, Christie A. Lee, Victoria Nowak, Bilal Khan, Priya Shah, Kiran V. Vemuri, Saagar P, Alex MakriyannisAbstract:Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists Ecopipam (D1) an
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The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.
Pharmacology biochemistry and behavior, 2015Co-Authors: Samantha E. Yohn, Eric J. Nunes, Jessica L. Santerre, Mercè Correa, Rouba Kozak, Samantha J. Podurgiel, John D. SalamoneAbstract:Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist Ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, Ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, Ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of Ecopipam, and in each case the D1 agonist significantly attenuated the effects of Ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.
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The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.
PloS one, 2014Co-Authors: Patrick A. Randall, Eric J. Nunes, Samantha E. Yohn, Christie A. Lee, Victoria Nowak, Bilal Khan, Priya Shah, Saagar Pandit, V. Kiran Vemuri, Alexandros MakriyannisAbstract:Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists Ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.
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Effects of the DA D1 antagonist Ecopipam on PROG/chow performance.
2014Co-Authors: Patrick A. Randall, Eric J. Nunes, Samantha E. Yohn, Christie A. Lee, Victoria Nowak, Bilal Khan, Priya Shah, Saagar Pandit, Kiran V. Vemuri, Alex MakriyannisAbstract:On measures of lever pressing, mean (+SEM) total lever presses (A), highest ratio achieved (B), and active lever time (measured in seconds, C), Ecopipam produced significant decreases at 0.1 and 0.2 mg/kg. Chow consumption (mean +SEM, in grams) during test sessions was unaffected by any dose tested (D). (* p
Mercè Correa - One of the best experts on this subject based on the ideXlab platform.
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Selection of sucrose concentration depends on the effort required to obtain it: studies using tetrabenazine, D_1, D_2, and D_3 receptor antagonists
Psychopharmacology, 2015Co-Authors: Marta Pardo, John D. Salamone, Laura López-cruz, Noemí San Miguel, Mercè CorreaAbstract:Rationale Low doses of dopamine (DA) antagonists and accumbens DA depletions reduce food-reinforced instrumental behavior but do not impair primary food motivation, causing animals to reallocate behavior away from food-reinforced tasks with high response requirements and select less effortful alternatives. However, it is uncertain if this same pattern of effects would occur if sucrose was used as the reinforcer . Objectives These experiments studied the impact of DA depletion and antagonism on performance of an effort-related choice task using sucrose as the reinforcer, as well as sucrose consumption, preference, and taste reactivity tests. Methods The effects of DA manipulations were assessed using a task in which rats chose between lever pressing on a fixed ratio 7 schedule for 5.0 % sucrose versus freely consuming a less concentrated solution (0.3 %). Results The DA depleting agent tetrabenazine shifted effort-related choice, decreasing lever pressing for 5.0 % sucrose but increasing intake of the concurrently available 0.3 % sucrose. Tetrabenazine did not affect sucrose appetitive taste reactivity, or sucrose consumption or preference, in free consumption tests. The D_1 antagonist Ecopipam and the D_2 antagonist haloperidol also shifted choice behavior at doses that did not alter sucrose consumption or preference. In contrast, sucrose pre-exposure reduced consumption across all conditions. D_3 antagonism had no effects. Conclusions D_1 and D_2 receptor blockade and DA depletion reduce the tendency to work for sucrose under conditions that leave fundamental aspects of sucrose motivation (intake, preference, hedonic reactivity) intact. These findings have implications for studies employing sucrose intake or preference in animal models of depression.
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The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.
Pharmacology biochemistry and behavior, 2015Co-Authors: Samantha E. Yohn, Eric J. Nunes, Jessica L. Santerre, Mercè Correa, Rouba Kozak, Samantha J. Podurgiel, John D. SalamoneAbstract:Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist Ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, Ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, Ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of Ecopipam, and in each case the D1 agonist significantly attenuated the effects of Ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.
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Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism.
Neuroscience, 2010Co-Authors: Eric J. Nunes, Patrick A. Randall, Jessica L. Santerre, Ashby B. Given, Thomas N. Sager, Mercè Correa, John D. SalamoneAbstract:Abstract Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice. However, less is known about the effects of adenosine A1 antagonists. Despite anatomical data showing that A1 and D1 receptors are co-localized on the same striatal neurons, it is uncertain if A1 antagonists can reverse the effects DA D1 antagonists. The present work systematically compared the ability of adenosine A1 and A2A receptor antagonists to reverse the effects of DA D1 and D2 antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D1 antagonist Ecopipam (0.2 mg/kg i.p.) and the D2 antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D1 or D2 antagonist. In contrast, the adenosine A2A antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of Ecopipam. Adenosine A2A and DA D2 receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.
Sharon L. Walsh - One of the best experts on this subject based on the ideXlab platform.
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Repeated administration of the D_1/5 antagonist Ecopipam fails to attenuate the subjective effects of cocaine
Psychopharmacology, 2001Co-Authors: Ellen Nann-vernotica, Eric C. Donny, George E. Bigelow, Sharon L. WalshAbstract:Rationale: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D_1/5 antagonist, SCH 39166 (Ecopipam), as a potential therapeutic agent. Objectives: The objective of the present study was to determine whether treatment with chronic Ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. Methods: Four doses of Ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient cocaine-dependent volunteers ( n =10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. Results: Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, Ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. Conclusions: Although the performance effects verify that these doses of Ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects or craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.
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Repeated administration of the D1/5 antagonist Ecopipam fails to attenuate the subjective effects of cocaine.
Psychopharmacology, 2001Co-Authors: Ellen Nann-vernotica, Eric C. Donny, George E. Bigelow, Sharon L. WalshAbstract:Rationale: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D1/5 antagonist, SCH 39166 (Ecopipam), as a potential therapeutic agent. Objectives: The objective of the present study was to determine whether treatment with chronic Ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. Methods: Four doses of Ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient cocaine-dependent volunteers (n=10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. Results: Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, Ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. Conclusions: Although the performance effects verify that these doses of Ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects or craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.
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repeated administration of the d1 5 antagonist Ecopipam fails to attenuate the subjective effects of cocaine
Psychopharmacology, 2001Co-Authors: Ellen Nannvernotica, Eric C. Donny, George E. Bigelow, Sharon L. WalshAbstract:Rationale: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D1/5 antagonist, SCH 39166 (Ecopipam), as a potential therapeutic agent. Objectives: The objective of the present study was to determine whether treatment with chronic Ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. Methods: Four doses of Ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient cocaine-dependent volunteers (n=10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. Results: Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, Ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. Conclusions: Although the performance effects verify that these doses of Ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects or craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.
