CRF1 but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine

Q4 · PSYCHOLOGY

Article

Author: Millan, Mark J ; van Esterik, Joantine C J ; Verdouw, P Monika ; Peeters, Bernard W M M ; Groenink, Lucianne

RATIONALEGiven the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment.OBJECTIVESWe evaluated the anxiolytic effects of corticotropin releasing factor (CRF)₁ receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI).METHODSIn guinea pig pups, the CRF₁ receptor antagonists CP-154,526 and DMP695, and the GR antagonists mifepristone and Org34517 (all at 2.5, 10 and 40mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63mg/kg paroxetine IP. In CRF overexpressing mouse pups and wild type littermates, effects of CP-154,526 (10, 20 and 40mg/kg subcutaneously (SC)) and mifepristone (5, 15, 45mg/kg SC) were studied alone or in combination with 0.03mg/kg paroxetine SC.RESULTSCRF₁ but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF₁ receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice.CONCLUSIONSCurrent results indicate robust anxiolytic properties of CRF₁ receptor antagonists in guinea pigs and mice overexpressing CRF, and lack thereof of GR antagonists. Although no combined treatment effects were observed, it would be interesting to study combined treatment of CRF₁ receptor antagonists with SSRIs following chronic drug administration.

01 Apr 2014·PsychopharmacologyQ3 · MEDICINE

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents

Q3 · MEDICINE

Article

Author: G. Griebel ; K. G. Westphal ; P. M. Verdouw ; B. Olivier ; D. Boulay ; L. Groenink ; T. N. Douma ; M. J. Millan

RATIONALEAs enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF₁ receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating.OBJECTIVESTo determine the effects of CRF₁ receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs.METHODSCP154,526 (10-40 mg/kg), SSR125543 (3-30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by D-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of D-amphetamine (2.5-5 mg/kg) and MK801 (0.3-1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on D-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis.RESULTSNo CRF₁-antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not D-amphetamine. Further, D-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526.CONCLUSIONThe inability of CRF₁ receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF₁ receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.

01 Feb 2012·PsychopharmacologyQ3 · MEDICINE

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

Q3 · MEDICINE

Article

Author: Huang, Shengming ; van Oorschot, Ruud ; Groenink, Lucianne ; Vinkers, Christiaan H. ; Hendriksen, Hendrikus ; Cook, James M. ; Rallipalli, Sundari ; Millan, Mark J. ; Olivier, Berend

RATIONALERepeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission.OBJECTIVEThe present study investigated molecular and functional alterations in GABA(A) receptor (GABA(A)R) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF.METHODSCRF(1) receptor, GABA(A)R, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABA(A)R α subunits and mGluRs in the amygdala and hypothalamus.RESULTSCRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF(1) receptor antagonists CP154,526 and DMP695, the GABA(A)R α(3)-selective agonist TP003 (0-3 mg/kg) and the mGluR(2/3) agonist LY379268 (0-10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABA(A)R agonist diazepam (0-4 mg/kg) and the α(1)-subunit-selective GABA(A)R agonist zolpidem (0-10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA(A)R α(5)-subunit preferential compound SH-053-2'F-R-CH(3) and mGluR(5) antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABA(A)R α(2) subunit and mGluR(3) mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α(1) and α(5) GABA(A)R subunits.CONCLUSIONSWe found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABA(A) and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission.

100 Deals associated with DMP-695

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Preclinical	US	Bristol Myers Squibb Co.	-
Depressive Disorder, Major	Preclinical	US	Bristol Myers Squibb Co.	-

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