Amphetamine-induced activation of forebrain EEG is prevented by noradrenergic beta-receptor blockade in the halothane-anesthetized rat.
BACKGROUND
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 beta-receptors elicits activation of forebrain EEG in the anesthetized rat. Further, stimulation of noradrenergic beta-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 beta-receptors. The current study examines the extent to which AMPH-induced activation of cortical EEG is dependent on actions of central beta-receptors.


METHODS
The effects of intracerebroventricular (ICV; 2 microl) pretreatment with either vehicle (artificial extracellular fluid) or the beta-antagonist, timolol (25, 50 or 100 microg), 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 microg and 100 microg dose.


CONCLUSIONS
These observations indicate that, under these experimental conditions, AMPH-induced activation of the forebrain is dependent on actions of noradrenergic beta-receptors. Combined with previous observations, these observations support the hypothesis that AMPH-induced increases in arousal involve noradrenergic neurotransmission at beta-receptors.
Berridge
C W
CW
Department of Psychology, University of Wisconsin, Madison 53706, USA. berridge@facstaff.wisc.edu
Morris
M F
MF
D000661:Amphetamine / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D004569:Electroencephalography / Q000187:drug effects*; D006221:Halothane / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000502:physiology*; D016548:Prosencephalon / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013999:Timolol / Q000494:pharmacology
D011943:Receptors, Adrenergic, beta; D013999:Timolol; D000661:Amphetamine; D006221:Halothane; D009638:Norepinephrine