Indices 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 (βAR). Since learned helplessness is a stress-induced animal model of depression, βAR are relevant to investigate in this model. To date, studies have measured changes in total 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 βAR coupling in the frontal cortex, hippocampus and hypothalamus of rats exposed to inescapable shock and then tested for learned helplessness, and in both tested and naive controls using [¹²⁵I]-iodocyanopindolol (ICYP) as the ligand. Both antagonist-saturation and agonist-displacement experiments were conducted, and the specificity for the βAR was optimized by excluding ICYP binding to 5HT(1B) receptors. The percentage receptor density in the high-conformational state (%R(H)) and the ratio of agonist (isoproterenol) 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 developing learned helplessness and non-helpless rats after inescapable stress in any parameter measured in any brain region. In the frontal cortex, exposure to inescapable shock induced βAR uncoupling from G(S) protein as suggested by a low K(L)/K(H) ratio both in helpless and non-helpless rats but not in either control group. In the hypothalamus, there were trends for higher R(L), R(T) and K(L)/K(H) ratio in helpless rats and stressed controls compared to naive controls. These findings suggest that βAR binding parameters in frontal cortex, hippocampus or hypothalamus did not differentiate between helpless and non-helpless rats. Changes in βAR coupling observed in these brain regions may reflect effects of stress, which appeared to be region-specific, rather than stress-induced behavioral depression.