A critical evaluation of cysteamine as a tool to deplete somatostatin in the rat central nervous system.
The wide central nervous system (CNS) distribution of somatostatin (SRIF) as well as the well documented reduction in SRIF concentration in the cerebral cortex in patients with Alzheimer's disease have served as an impetus for studies of this peptide's neurobiological role in the brain. These studies were designed to evaluate the efficacy of centrally administered cysteamine (CYS) as a tool to deplete SRIF in the hypothalamus (HYP) and extrahypothalamic brain areas. Somatostatin was measured by RIA in the frontal cortex (COR), hippocampus (HIP), and HYP in rats after seven daily infusions of CYS into unilateral cannulae stereotaxically positioned into either the lateral ventricle (LV; 300 micrograms/2 microliters) or the dorsal HIP (100 micrograms/2 microliters), and after single (300 mg/kg) or daily (100 mg/kg) sc injections; rats were killed 4 or 24 h after the last injection. After LV infusions, the SRIF concentration was significantly reduced only in the HYP (35% at 4 h and 27% at 24 h). After HIP infusions, the SRIF concentration was significantly reduced only in the HYP at 4 h (23%); no reductions were observed at 24 h. Both a single and repeated sc administrations of CYS reduced SRIF in the HYP only 24 h after treatment (54% and 50%, respectively). Acute sc CYS reduced SRIF in the COR (23%) and the HYP (29%) 4 h after treatment; repeated sc CYS reduced SRIF in the COR (25%) and the HYP (63%). Although the reduction of SRIF in the HYP was increased by repeated sc dosing, the reduction of extrahypothalamic SRIF by sc CYS was relatively small in magnitude and was not enhanced by repeated dosing. These results suggest that CYS is not an ideal tool for depletion of extrahypothalamic SRIF after sc or CNS administration and, moreover, raise serious questions about studies in which behavioral or endocrine alterations after CYS treatment were attributed to specific actions on SRIF-containing neurons.
Cook
L L
LL
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710.
Bissette
G
G
Dole
K
K
Nemeroff
C B
CB
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D003543:Cysteamine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013004:Somatostatin / Q000378:metabolism*
D013004:Somatostatin; D003543:Cysteamine