A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses

Anantha Shekhar, Philip Johnson, Stephanie D. Fitz, Atsuro Nakazato, Shigeyuki Chaki, Thomas Steckler, Mark Schmidt

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Corticotropin releasing factor (CRF) is implicated in a variety of stress-related disorders such as depression and anxiety, and blocking CRF receptors is a putative strategy for treating such disorders. Using a well-studied animal model of panic, we tested the efficacy of JNJ19567470/CRA5626, a selective, non-peptidergic CRF type 1 receptor (CRF1) antagonist (3, 10 and 40 mg/kg intraperitoneal injection), in preventing the sodium lactate (NaLac)-induced panic-like behavioural and cardiovascular responses. Adult male rats with chronic reduction of GABA levels (by inhibition of GABA synthesis with l-allyglycine, a glutamic acid decarboxylase inhibitor) in the dorsomedial/perifornical hypothalamus are highly anxious and exhibit physiological and behavioural responses to intravenous NaLac infusions similar to patients with panic disorder. These 'panic-prone' rats pre-treated with vehicle injections displayed NaLac-induced increases in autonomic responses (i.e. tachycardia and hypertensive responses), anxiety-like behaviour in the social interaction test, and flight-like increases in locomotor activity. However, systemically injecting such panic-prone rats with the highest dose of CRF1 receptor antagonist prior to NaLac infusions blocked all NaLac-induced behaviour and cardiovascular responses. These data suggest that selective CRF1 receptor antagonists could be a novel target for developing anti-panic drugs that are as effective as benzodiazepines in acute treatment of a panic attack without the deleterious side-effects (e.g. sedation and cognitive impairment) associated with benzodiazepines.

Original languageEnglish
Pages (from-to)355-365
Number of pages11
JournalInternational Journal of Neuropsychopharmacology
Volume14
Issue number3
DOIs
StatePublished - Apr 2011

Fingerprint

Sodium Lactate
Panic
Panic Disorder
Benzodiazepines
gamma-Aminobutyric Acid
Anxiety
Corticotropin-Releasing Hormone Receptors
Glutamate Decarboxylase
Corticotropin-Releasing Hormone
Locomotion
Interpersonal Relations
Intraperitoneal Injections
Intravenous Infusions
Tachycardia
Hypothalamus
Animal Models
CRF receptor type 1
Depression
Injections
Pharmaceutical Preparations

Keywords

  • Anxiety
  • CRF
  • CRH
  • hypothalamus
  • lactate
  • panic

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health

Cite this

A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses. / Shekhar, Anantha; Johnson, Philip; Fitz, Stephanie D.; Nakazato, Atsuro; Chaki, Shigeyuki; Steckler, Thomas; Schmidt, Mark.

In: International Journal of Neuropsychopharmacology, Vol. 14, No. 3, 04.2011, p. 355-365.

Research output: Contribution to journalArticle

Shekhar, Anantha ; Johnson, Philip ; Fitz, Stephanie D. ; Nakazato, Atsuro ; Chaki, Shigeyuki ; Steckler, Thomas ; Schmidt, Mark. / A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses. In: International Journal of Neuropsychopharmacology. 2011 ; Vol. 14, No. 3. pp. 355-365.
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