Differential effects of two intraventricularly injected alpha 2 agonists, ST-91 and dexmedetomidine, on...

Central alpha 2 agonists induce feeding in animals, electroencephalographic (EEG) synchronization, and sedation. Recent observations suggest that the investigational compound ST-91 and dexmedetomidine (DMET) may interact with distinct alpha 2 subclasses at spinal sites. We examined these drugs in brain. To accomplish these aims, ST-91, DMET, or methoxamine (METH), an alpha 1 agonist, were administered into the cerebral ventricles of unanesthetized rats prepared with chronic intracerebroventricular (ICVT) cannulae and cortical EEG electrodes. Behavior, EEG, electromyography (EMG), and feeding were assessed. We found that DMET resulted in dose-dependent (1-32 nmol) sedation, EEG synchronization, and a reduced gastrocnemeus EMG, while ST-91 (up to 153 nmol) had no effect. In contrast, ST-91 (1-153 nmol) resulted in a dose-dependent evocation of feeding, while the effects of DMET on feeding, if any, were obscured by the sedation. All effects were antagonized in a dose-dependent fashion by ICVT yohimbine (an alpha 2 antagonist). ICVT atipamezole (an alpha 2 antagonist), but not prazosin (an alpha 1 antagonist), reversed the effects of DMET. With ST-91, both atipamezole and prazosin had modest, but significant, antagonistic effects. ICVT METH had no effect. The differential physiological actions of these two intracerebroventricularly injected drugs, in concert with previous pharmacological studies, suggest two distinct subclasses of yohimbine-sensitive alpha 2 adrenergic receptors in the brain.