The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions

Jessica L. Santerre, Eric J. Nunes, Rotem Kovner, Chelsea E. Leser, Patrick A. Randall, Lyndsey E. Collins-Praino, Laura Lopez Cruz, Merce Correa, Younis Baqi, Christa E. Müller, John D. Salamone

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Adenosine A2A and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A2A receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.

Original languageEnglish
Pages (from-to)477-487
Number of pages11
JournalPharmacology Biochemistry and Behavior
Volume102
Issue number4
DOIs
Publication statusPublished - Oct 2012

Fingerprint

eticlopride
Prodrugs
Adenosine
Animals
Animal Models
Parkinsonian Disorders
Adenosine A2 Receptor Antagonists
Galantamine
Choice Behavior
Depression
Antiparkinson Agents
Corpus Striatum
Aptitude
Dopamine D2 Receptors
Cholinesterase Inhibitors
Nucleus Accumbens
Tremor
Esters
Amino Acids
Injections

Keywords

  • C-Fos
  • DARPP-32
  • Depression
  • Drug-induced parkinsonism
  • Effort-related choice behavior
  • Locomotion
  • Parkinson's disease
  • Tremulous jaw movements

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Pharmacology
  • Toxicology
  • Behavioral Neuroscience
  • Biological Psychiatry

Cite this

Santerre, J. L., Nunes, E. J., Kovner, R., Leser, C. E., Randall, P. A., Collins-Praino, L. E., ... Salamone, J. D. (2012). The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. Pharmacology Biochemistry and Behavior, 102(4), 477-487. https://doi.org/10.1016/j.pbb.2012.06.009

The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. / Santerre, Jessica L.; Nunes, Eric J.; Kovner, Rotem; Leser, Chelsea E.; Randall, Patrick A.; Collins-Praino, Lyndsey E.; Lopez Cruz, Laura; Correa, Merce; Baqi, Younis; Müller, Christa E.; Salamone, John D.

In: Pharmacology Biochemistry and Behavior, Vol. 102, No. 4, 10.2012, p. 477-487.

Research output: Contribution to journalArticle

Santerre, JL, Nunes, EJ, Kovner, R, Leser, CE, Randall, PA, Collins-Praino, LE, Lopez Cruz, L, Correa, M, Baqi, Y, Müller, CE & Salamone, JD 2012, 'The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions', Pharmacology Biochemistry and Behavior, vol. 102, no. 4, pp. 477-487. https://doi.org/10.1016/j.pbb.2012.06.009
Santerre, Jessica L. ; Nunes, Eric J. ; Kovner, Rotem ; Leser, Chelsea E. ; Randall, Patrick A. ; Collins-Praino, Lyndsey E. ; Lopez Cruz, Laura ; Correa, Merce ; Baqi, Younis ; Müller, Christa E. ; Salamone, John D. / The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. In: Pharmacology Biochemistry and Behavior. 2012 ; Vol. 102, No. 4. pp. 477-487.
@article{de7a5703290749ecb9a2e02b041e2653,
title = "The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions",
abstract = "Adenosine A2A and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A2A receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.",
keywords = "C-Fos, DARPP-32, Depression, Drug-induced parkinsonism, Effort-related choice behavior, Locomotion, Parkinson's disease, Tremulous jaw movements",
author = "Santerre, {Jessica L.} and Nunes, {Eric J.} and Rotem Kovner and Leser, {Chelsea E.} and Randall, {Patrick A.} and Collins-Praino, {Lyndsey E.} and {Lopez Cruz}, Laura and Merce Correa and Younis Baqi and M{\"u}ller, {Christa E.} and Salamone, {John D.}",
year = "2012",
month = "10",
doi = "10.1016/j.pbb.2012.06.009",
language = "English",
volume = "102",
pages = "477--487",
journal = "Pharmacology, Biochemistry and Behavior",
issn = "0091-3057",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions

AU - Santerre, Jessica L.

AU - Nunes, Eric J.

AU - Kovner, Rotem

AU - Leser, Chelsea E.

AU - Randall, Patrick A.

AU - Collins-Praino, Lyndsey E.

AU - Lopez Cruz, Laura

AU - Correa, Merce

AU - Baqi, Younis

AU - Müller, Christa E.

AU - Salamone, John D.

PY - 2012/10

Y1 - 2012/10

N2 - Adenosine A2A and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A2A receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.

AB - Adenosine A2A and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A2A receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.

KW - C-Fos

KW - DARPP-32

KW - Depression

KW - Drug-induced parkinsonism

KW - Effort-related choice behavior

KW - Locomotion

KW - Parkinson's disease

KW - Tremulous jaw movements

UR - http://www.scopus.com/inward/record.url?scp=84864153282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864153282&partnerID=8YFLogxK

U2 - 10.1016/j.pbb.2012.06.009

DO - 10.1016/j.pbb.2012.06.009

M3 - Article

VL - 102

SP - 477

EP - 487

JO - Pharmacology, Biochemistry and Behavior

JF - Pharmacology, Biochemistry and Behavior

SN - 0091-3057

IS - 4

ER -