Synergistic sedative effects of noradrenergic alpha(1)- and beta-receptor blockade on forebrain...

The locus coeruleus-noradrenergic system exerts an activating influence on forebrain neuronal and behavioral activity states. For example, in the anesthetized rat, unilateral locus coeruleus stimulation elicits bilateral activation of forebrain electroencephalographic activity. Pretreatment with a noradrenergic beta-antagonist blocks this effect, suggesting that beta-receptors play a critical role in locus coeruleus-dependent activation of the forebrain. Consistent with this, stimulation of beta-receptors located in certain basal forebrain structures evokes sustained periods of alert waking in the unanesthetized rat. Similar forebrain and behavioral activating effects are observed with alpha(1)-receptor stimulation within these basal forebrain regions. To assess the extent to which alpha(1)- and beta-receptors contribute to the maintenance of behavioral and forebrain activation, we examined the electroencephalographic and behavioral effects of alpha(1)-, beta- and combined alpha(1)/beta-receptor blockade in the unanesthetized rat. Rats were treated individually or in combination with either varying doses of the alpha(1)-antagonist, prazosin (intraperitoneally), and/or the beta-antagonist, timolol (intracerebroventricularly). Thirty minutes following treatment, animals were placed in a mildly-arousing novel environment, which has been demonstrated previously to elicit activation of central noradrenergic systems and sustained waking in vehicle-treated controls. Behavior and electroencephalographic activity were recorded and later scored. Electroencephalographic activity was analysed using power spectrum analysis. The following were observed: (i) beta-receptor blockade alone does not alter behavioral or electroencephalographic indices of alert waking; (ii) alpha(1)-receptor blockade alone increases high-voltage spindle activity in cortical electroencephalographic activity that was associated with decreased behavioral activity; (iii) combined alpha(1)- and beta-receptor blockade elicits a substantial increase in slow-wave activity (0.33-2.0Hz), also in association with decreased behavioral activity. All of these effects were dependent on the dose administered and time following initiation of testing. These results indicate that the combined actions of alpha(1)- and beta-receptors exert distinct and synergistic actions on cortical neuronal activity patterns that are essential elements of alert waking.