Electrophysiological actions of neuropeptide Y and its analogs: new measures for anxiolytic therapy?

Neuropeptide Y (NPY) has neuromodulatory actions on multiple brain functions including endocrine, behavioral, and circadian processes. Behavioral studies suggest that NPY is a potent anxiolytic; however, little is known about how NPY affects general arousal and/or attention states. The present study evaluated the effects of NPY on spontaneous brain activity as well as auditory processing by using electrophysiological measures. Electroencephalographic (EEG) and event-related potentials (ERPs) were obtained in awake animals after intracerebroventricular administration of NPY (1.0, 3.0 nmol) and two of its analogs, active at Y1 (1.0, 3.0 nmol) and Y2 (1.0, 3.0 nmol) receptor sites. NPY was found to produce dose-related effects on electrophysiological measures. Spectral analyses of the EEG revealed that NPY produced slowing of delta activity (1-2 Hz) in the frontal cortex and high frequency theta activities (6-8 Hz) concomitant with a speeding up of low frequency theta (4-6 Hz) in cortex, hippocampus, and amygdala. At higher doses (3.0 nmols) in addition to shifts in frequency, EEG power was also significantly reduced in all frequencies (0.5-50 Hz) in cortex, and in the higher frequencies (8-32 Hz) in the amygdala. The Y1 and Y2 agonists had a somewhat different profile of EEG effects than the parent compound. At the 1 nmol dose both agonists were found to produce selective depressions in power in the hippocampus. The 3.0 nmols dose of the Y1 agonist produced decreases in EEG stability, an effect commonly produced by anxiolytic drugs, whereas the Y2 agonist produced increases in EEG stability in cortex and amygdala. Auditory processing, as assessed by ERPs, was affected most significantly in the frontal cortex where dose-dependent decreases in the N1 component of the ERP, a finding also commonly seen after anxiolytics, was found. Y1 and Y2 agonists were also found to significantly reduce the amplitude of the N1 component of the ERP but less so than the parent compound. The electrophysiological and behavioral profiles of NPY and the Y1 agonist resembles those of anxiolytics such as ethanol and benzodiazepines. Taken together these data suggest that electrophysiological measures of the actions of this peptide system may represent a new potentially useful assay for the development of anxiolytic drugs.