INDEXES OF BRAIN BETA-ADRENERGIC-RECEPTOR SIGNAL-TRANSDUCTION IN THE LEARNED HELPLESSNESS ANIMAL-MODEL OF DEPRESSION

Both stress response and antidepressant drug action may be mediated by beta-adrenergic receptors (beta AR). Since learned helplessness is a stress-induced animal model of depression, beta AR are relevant to inv estigate in this model. To date, studies have measured changes in tota l receptor density (R(T)), but have not examined more detailed aspects of signal transduction mechanisms such as coupling of the receptor to G(S) protein. We have investigated brain beta AR coupling in the fron tal cortex, hippocampus and hypothalamus of rats exposed to inescapabl e shock and then tested for learned helplessness, and in both tested a nd naive controls using [I-125]-iodocyanopindolol (ICYP) as the ligand . Both antagonist-saturation and agonist-displacement experiments were conducted, and the specificity for the beta AR was optimized by exclu ding ICYP binding to 5HT(1B) receptors. The percentage receptor densit y in the high-conformational state (%R(H)) and the ratio of agonist (i soproterenol) dissociation constant from the receptor in the low-/high -conformational states (K-L/K-H) were used as indices of coupling to G (S) protein. No significant differences were found between rats develo ping learned helplessness and non-helpless rats after inescapable stre ss in any parameter measured in any brain region. In the frontal corte x, exposure to inescapable shock induced beta AR uncoupling from G(S) protein as suggested by a low K-L/K-H ratio both in helpless and non-h elpless rats but not in either control group. In the hypothalamus, the re were trends for higher R(L), R(T) and K-L/K-H ratio in helpless rat s and stressed controls compared to naive controls. These findings sug gest that beta AR binding parameters in frontal cortex, hippocampus or hypothalamus did not differentiate between helpless and non-helpless rats. Changes in beta AR coupling observed in these brain regions may reflect effects of stress, which appeared to be region-specific, rathe r than stress-induced behavioral depression.