PMID- 16997409
OWN - NLM
STAT- MEDLINE
DCOM- 20070112
LR  - 20151119
IS  - 0168-0102 (Print)
IS  - 0168-0102 (Linking)
VI  - 56
IP  - 3
DP  - 2006 Nov
TI  - Type II glucocorticoid receptor involvement in habituated activation of lateral 
      hypothalamic area orexin-A-immunopositive neurons during recurring 
      insulin-induced hypoglycemia.
PG  - 309-13
AB  - Neurons that synthesize the potent orexigenic neuropeptide, orexin-A (ORX-A) are 
      confined to the lateral hypothalamic area (LHA) and adjacent structures, and 
      project throughout the central neuroaxis to structures that govern central 
      nervous system responses to energy imbalance. Insulin-induced hypoglycemia (IIH) 
      upregulates prepro-orexin mRNA and Fos immunostaining of LHA ORX-A neurons. These 
      neurons apparently become desensitized to this metabolic challenge, since both 
      responses are diminished by recurrent insulin-induced hypoglycemia (RIIH). Recent 
      studies implicate central type II glucocorticoid receptors (GR) in 
      RIIH-associated glucose counterregulatory collapse and decline in Fos labeling of 
      central metabolic loci, including the LHA. The present studies evaluated the role 
      of GR in patterns of LHA ORX-A neuronal transcriptional activation during RIIH. 
      Groups of adult male rats were injected subcutaneously with one or four doses of 
      the intermediate-acting insulin, Humulin NPH, on as many days, or with diluent 
      alone. Rats injected with four doses of insulin were pretreated by 
      intracerebroventricular (icv) administration of the selective GR antagonist, 
      CP-472555, or the vehicle, propylene glycol, prior to insulin administration on 
      days 1-3. All animals were sacrificed by transcardial perfusion 2h after 
      injections on day 4. Processing of LHA tissue sections for dual-immunoperoxidase 
      staining of ORX-A- and Fos-immunoreactivity (-ir) showed that colabeling of ORX-A 
      neurons for Fos was increased by a single injection of NPH, whereas this genomic 
      response was diminished by RIIH. Icv administration of CP-472555 during 
      antecedent hypoglycemia prevented RIIH-associated reductions in Fos expression by 
      these neurons. Antagonist treatment of diluent-injected controls did not alter 
      mean numbers of ORX-A- plus Fos-ir neurons. Total numbers of ORX-A-immunopositive 
      neurons were not different among treatment groups. These data demonstrate that 
      precedent central GR blockade prevents adaptation of LHA ORX-A neuronal 
      reactivity to RIIH. These results provide unique pharmacological evidence that 
      hypoglycemic hypercorticosteronemia diminishes activation of this 
      neurotransmitter phenotype in this critical metabolic structure to subsequent 
      hypoglycemia via central GR-dependent mechanisms.
FAU - Kale, Ajay Y
AU  - Kale AY
AD  - Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University 
      of Louisiana at Monroe, Monroe, LA 71209, United States.
FAU - Paranjape, Sachin A
AU  - Paranjape SA
FAU - Briski, Karen P
AU  - Briski KP
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060925
PL  - Ireland
TA  - Neurosci Res
JT  - Neuroscience research
JID - 8500749
RN  - 0 (CP 472555)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Neuropeptides)
RN  - 0 (Oncogene Proteins v-fos)
RN  - 0 (Orexins)
RN  - 0 (Phenanthrenes)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 53027-39-7 (Insulin, Isophane)
SB  - IM
MH  - Animals
MH  - Behavior, Animal
MH  - Drug Interactions
MH  - Hypoglycemia/chemically induced/*pathology
MH  - Hypoglycemic Agents/pharmacology
MH  - Hypothalamic Area, Lateral/*pathology
MH  - Immunohistochemistry/methods
MH  - Insulin/*pharmacology
MH  - Insulin, Isophane/pharmacology
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Male
MH  - Neurons/*metabolism
MH  - Neuropeptides/*metabolism
MH  - Oncogene Proteins v-fos/metabolism
MH  - Orexins
MH  - Phenanthrenes/pharmacology
MH  - Pyridines/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Glucocorticoid/antagonists & inhibitors/*physiology
MH  - Time Factors
EDAT- 2006/09/26 09:00
MHDA- 2007/01/16 09:00
CRDT- 2006/09/26 09:00
PHST- 2006/02/18 00:00 [received]
PHST- 2006/07/25 00:00 [revised]
PHST- 2006/07/27 00:00 [accepted]
PHST- 2006/09/26 09:00 [pubmed]
PHST- 2007/01/16 09:00 [medline]
PHST- 2006/09/26 09:00 [entrez]
AID - S0168-0102(06)00186-6 [pii]
AID - 10.1016/j.neures.2006.07.013 [doi]
PST - ppublish
SO  - Neurosci Res. 2006 Nov;56(3):309-13. doi: 10.1016/j.neures.2006.07.013. Epub 2006 
      Sep 25.