Amphetamine-induced activation of forebrain EEG is prevented by noradrenergic β-receptor blockade in the halothane-anesthetized rat

Abstract 

Rationale: Amphetamine (AMPH)-like stimulants represent an intensively studied class of psychoactive drugs. Despite the well-known and potent arousal-enhancing effects of these drugs, the neurobiological substrates of AMPH-induced arousal have rarely been examined explicitly. Activity of the locus coeruleus-noradrenergic system is causally and positively related to behavioral and electroencephalographic (EEG) indices of arousal. For example, activation of locus coeruleus neurons or stimulation of medial basal forebrain noradrenergic β-receptors elicits activation of forebrain EEG in the anesthetized rat. Further, stimulation of noradrenergic β-receptors within the medial basal forebrain elicits a substantial increase in alert, active waking. These and other observations suggest that at least some of the arousal-enhancing actions of AMPH-like stimulants derive from AMPH-induced increases in noradrenergic neurotransmission at β-receptors. The current study examines the extent to which AMPH-induced activation of cortical EEG is dependent on actions of central β-receptors. Methods: The effects of intracerebroventricular (ICV; 2 µl) pretreatment with either vehicle (artificial extracellular fluid) or the β-antagonist, timolol (25, 50 or 100 µg), on the cortical EEG activating effects of intravenous AMPH (0.15 mg/kg) were examined in the halothane-anesthetized rat. EEG was recorded on polygraph and video recording tape and later analyzed using power spectral analyses (PSA). AMPH-induced alteration in cortical EEG activity was measured using PSA in vehicle- and timolol-pretreated animals. Results: Neither vehicle nor timolol ICV infusions altered cortical EEG activity patterns. In vehicle-pretreated animals, AMPH elicited a robust activation of cortical EEG, characterized by the substantial decrease in large-amplitude, slow-wave activity. Timolol pretreatment dose-dependently prevented AMPH-induced cortical EEG activation. This effect of timolol was statistically significant at the 50 µg and 100 µg dose. Conclusions: These observations indicate that, under these experimental conditions, AMPH-induced activation of the forebrain is dependent on actions of noradrenergic β-receptors. Combined with previous observations, these observations support the hypothesis that AMPH-induced increases in arousal involve noradrenergic neurotransmission at β-receptors.