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The locus coeruleus (LC)-noradrenergic system modulates forebrain electroencephalographic (EEG) activity in halothane-anesthetized rat. For example, unilateral enhancement of LC neuronal activity increases cortical EEG (ECoG) and hippocampal EEG (HEEG) indices of arousal bilaterally (Berridge and Foote, 1991). Conversely, bilateral suppression of LC discharge activity increases EEG measures of sedation (Berridge, et al., 1993b). The EEG-activating effects of LC stimulation appear to involve noradrenergic beta-receptors (Berridge and Foote, 1991). Two candidate sites at which LC efferents could influence ECoG and HEEG are the medial septum/vertical limb of the diagonal band of Broca (MS) and the substantia innominata/nucleus basalis of Meynert (SI). To determine whether norepinephrine mediates such actions within either of these regions, the EEG effects of small infusions of a beta-agonist or antagonist into MS or SI were examined in halothane-anesthetized rat. Unilateral infusions (150 nl) of the beta-agonist isoproterenol (ISO) (3.75 microg, 17 nmol) into MS, but not SI (150-450 nl), elicited robust bilateral activation of ECoG and HEEG. Infusions of glutamate (0.5 microg, 3.0 nmol) into either MS or SI elicited bilateral ECoG and HEEG activation. Neither vehicle infusions into MS nor infusions of ISO into regions adjacent to MS altered forebrain EEG activity. Bilateral, but not unilateral, MS infusions of the beta-antagonist timolol (3.75 microg, 8.7 nmol) decreased EEG indices of arousal in the lightly anesthetized preparation. Power spectral analyses provided quantitative confirmation of these qualitative observations. These results indicate that under these experimental conditions, noradrenergic efferents, presumably arising from LC, modulate forebrain EEG state via actions at beta-receptors located within MS. The results presented in the accompanying report extend these observations to the unanesthetized preparation and incorporate additional measures of behavioral state.

Persistent tardive dyskinesia is a serious side effect of long-term treatment with neuroleptics. Although striatal pathologic changes are believed to underlie this potentially irreversible iatrogenic syndrome, the nature of the neuroleptic-induced neuropathology is unclear. In the present study, we treated rats with either vehicle or fluphenazine decanoate (5 mg/kg, IM) every 2 weeks for 4, 8 or 12 months. Four to nine weeks after the last injection, the animals were sacrificed and the density of cells in the central part of the striatum was measured with a computerized image-analysis system. The control and experimental animals did not differ in body weight with 4 and 8 months of treatment, but the rats treated with fluphenazine for 12 months had significantly lower body weights than comparable controls. Four months of neuroleptic use produced no significant neuropathologic changes. The animals treated with fluphenazine for 8 months had a significantly lower density of the large neurons. In the 12-month-treated group, there was no significant difference between the control and experimental animals, probably because of a 'floor effect': the density of the large neurons was significantly lower in the 12-month-treated compared to the 8-month-treated control rats.

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