Christine Somes

CRF/NPY interactions: a potential role in sleep dysregulation in depression and anxiety.

Neuropeptide Y (NPY) has neuromodulatory actions on multiple brain functions including endocrine, behavioral, and circadian processes and has been implicated in the pathophysiology of both anxiety and depression. Behavioral studies suggest that NPY is a potent anxiolytic, whereas CRF is anxiogenic, thus it seems that a balance of these two peptides may exert important influences on behavioral state regulation. However, little is known about how the NPY/CRF balance affects general arousal, attention, and/or sleep states. The present study evaluated the effects of CRF alone, and co‐administered with NPY, on spontaneous brain activity as well as on auditory processing using electrophysiological measures. Electroencephalographic (EEG) and event‐related potentials (ERPs) were obtained in rats following intracerebroventricular administration of CRF (0.5 μg) and CRF (0.5 μg)/NPY (5.0 or 15 μg). Auditory processing, as assessed by ERPs, was affected most significantly in the frontal cortex where CRF produced increases in the N1 and P3 components of the ERP, and NPY/CRF co‐administration produced significant decreases. These data are consistent with a role for CRF in hyperarousal, and further suggest that NPY may be capable of reversing such states. Administration of CRF also produced a significant increase in the time to sleep onset and a decrease in the amount of time spent in non‐rapid eye movement (NREM) sleep as quantified by scoring the EEG paper records. Co‐administration of NPY with CRF reversed the effects of CRF on sleep duration and sleep onset in a dose‐dependent fashion. Spectral analysis revealed that CRF produced quantitative changes in the EEG that were similar to what has previously been reported. CRF‐induced increases in fast frequency activity were found to be reversed by co‐administration of NPY. Taken together these data suggest that “dysregulation” of sleep and arousal states in depression and anxiety may be consistent with an upset of the balance between hypothalamic neuropeptide systems. Depression and Anxiety 6:1–9, 1997.

Are some of the effects of ethanol mediated through NPY

Abstract Central administration of neuropeptide Y (NPY) in low concentrations has been shown to produce anxiolysis and suppression of locomotor activity, a behavioral profile not dissimilar to that of ethanol. The present study was conducted to ascertain whether NPY and ethanol have similar electrophysiological profiles and to evaluate the combined actions of NPY and ethanol. Eighty-five Wistar rats were stereotaxically implanted with electrodes aimed at dorsal hippocampus, amygdala, and frontal cortex. Rats were administered NPY [or saline (SAL)] intracerebroventricularly (ICV) whereas the doses of alcohol (or SAL) were given intraperitoneally (IP). Two doses of alcohol (0.75, 1.5 g/kg) and two doses of NPY (1, 3 nmol) were given alone and in combination. Drug effects were assessed using event related potentials (ERP) recorded in response to an auditory ”oddball” plus noise paradigm between 30 and 40 min post-drug. Multivariate analyses of variance (MANOVA) revealed that NPY produced a significant decrease in the amplitude and increase in the latency of the N1 component in cortex and a decrease in the amplitude of the P3 component in amygdala, but no overall effects in hippocampus. Ethanol produced identical effects to NPY on the N1 and P3 components of the ERP in cortex and amygdala. Combined administration of EtOH and NPY (1 nmol) produced effects equivalent to those seen following the higher doses of NPY (3 nmol) or EtOH (1.5 g/kg). These studies demonstrate that NPY and ethanol have a similar electrophysiological profile. In addition, the combined administration of NPY and ethanol produced additive effects.

Neurotensin studies in alcohol naive, preferring and non-preferring rats∗

Neurotensin is a tridecapeptide, present in the central nervous system and the gastrointestinal tract in man and animals. Previous studies in mice selectively bred for differences in hypnotic sensitivity to ethanol have provided data to suggest that neurotensinergic systems may mediate differences in ethanols actions in these animals. The present study sought to determine if brain neurotensin levels differed between two lines of rats which have been selectively bred for alcohol preferring or non-preferring behaviors. In addition, electroencephalographic and event-related potential responses to intracerebroventricular saline and neurotensin (10 or 30 microg) were evaluated between the rat lines. Similar to human subjects at high genetic risk for alcoholism, preferring rats were found to have more electroencephalographic fast frequency activity and lowered amplitude of the P3 component of the event-related potential in cortical sites under the saline condition. Overall, electrophysiological response to neurotensin, in the two rats lines, was substantially similar to what has been reported previously in outbred Wistar rats, and consisted of dose-related decreases in overall electroencephalographic spectral power concomitant with increases in amplitude and decreases in the latency of the N1 component of the event-related potential. However, differences in neurotensin responses between the preferring and non-preferring rat lines were also found. The differences in electroencephalographic high-frequency activity and in P3 amplitude seen between the rat lines under control conditions were eliminated by administration of neurotensin. In addition, preferring rats appeared to be more sensitive to neurotensin-induced increases in N1 amplitude. Brain neurotensin concentrations were also found to differ between the lines. Significantly lower concentrations of neurotensin were found in the frontal cortex of preferring rats when compared to non-preferring rats or outbred Wistars. Taken together, these studies suggest that differences in the regulation of neurotensin neurons may contribute to the expression of behavioral preference for ethanol consumption in selective rat lines. Additionally, drugs targeting the neurotensinergic system may plausibly be of utility in the treatment of alcoholism.

NEUROPHYSIOLOGICAL EFFECTS OF INTRACEREBROVENTRICULAR ADMINISTRATION OF UROCORTIN

The recently isolated Corticotropin Releasing Factor (CRF) related peptide, urocortin, has been reported to elicit a different behavioral profile than that of CRF. CRF is a potent anxiogenic agent and stimulant of motor activity whereas under similar conditions urocortin is a potent anorectic and mild locomotor stimulant. The neurophysiological effects of this newly synthesized peptide have not yet been examined. The present study evaluated the effects of intracerebroventricular administration of 3 doses of urocortin on the electroencephalogram (EEG) and on Event-Related Potentials (ERPs) in rats. Twenty male Wistar rats were implanted with electrodes in the amygdala and dorsal hippocampus, a cannula into the lateral ventricle, and skull surface electrodes over the frontal and parietal cortices. Following recovery from surgery, urocortin (0.01-1.0 microg) was infused into the lateral ventricle 5 min prior to the recording of EEG (10 min) and ERPs (10 min). Urocortin at any of the doses, did not produce any electrographic or behavioral signs of seizure activity. The predominant effect of urocortin infusion on EEG spectral activity was an increase in mean power in the 4-16 Hz range in the frontal cortex and a decrease in EEG stability in the frontal cortex and amygdala. Urocortin administration also decreased the latency of the P3 component of the ERP in the amygdala and hippocampus. These neurophysiological effects, that only partially overlap with those of CRF, are consistent with the behavioral profile described following urocortin administration in rats. Overall, these data further support the assertion that urocortin functions as a mild CNS stimulant enhancing arousal, as measured by EEG, and modulating the speed of stimulus evaluation as measured by ERPs.

Effects of Neonatal Exposure to Nicotine on Electrophysiological Parameters in Adult Rats

In clinical studies and animal models, there is evidence that nicotine exposure during gestation can result in deficits in cognitive performance. The present study examined the effects of two doses of neonatal nicotine exposure on adult brain activity as assessed by the N1 and P3 components of the event-related potential (ERP) and background electroencephalography (EEG). Nicotine (0 mg, 1 mg/kg/day, 4 mg/kg/day) was administered to neonatal rat pups from postnatal day 4 (PN4) through PN12 with an artificial rearing paradigm; suckled rats served as additional control subjects. Nicotine exposure was specifically found to alter responses of the P3 component of the ERP, recorded in dorsal hippocampus, to changes in stimulus parameters. A significant reduction in the response of the P3A component to the noise tone as compared with the level of the frequently presented tone was found. A significant reduction in the response to the noise tone as compared with the level of the infrequently presented tone also was seen in the P3B component. No effects of drug exposure were found on the N1 component in any lead, although artificial rearing produced specific effects on the latency of the N1 component in cortex. No significant differences among treatment groups were found on any of the EEG-dependent variables. Female rats overall were found to have significantly higher EEG amplitudes than the males, a finding previously reported in our laboratory. However, no overall effects of gender were found on any ERP component. These studies suggest that neonatal nicotine exposure specifically reduces the electrophysiological response of the hippocampus to changes in auditory stimuli. Additional studies will be necessary to link these P3 amplitude changes to the effects of nicotine on the developing brain in human and animal subjects.

Effects of prolonged ethanol exposure on neurophysiological measures during an associative learning paradigm

Long-term ethanol exposure has been reported to produce electrophysiological and cognitive impairments in some alcoholics. This study assessed the effects of chronic ethanol exposure on neurophysiological indices of associative learning in rats. Male Wistar rats (46) were exposed to ethanol vapor (EtOH group) or air (control group) for 6 consecutive weeks. After the animals were withdrawn from ethanol, electrodes were implanted in the frontal and parietal cortices and in the amygdala. Following a prolonged abstinence from ethanol (10-15 weeks), rats were exposed to a classical conditioning paradigm in which a food pellet was paired with the presentation of an auditory stimulus. During the first five sessions (conditioning phase), food pellet presentation was paired with the presentation of an infrequently presented tone. During the second five sessions (extinction phase), the association between food pellet presentation and the infrequently presented tone was weakened by no longer presenting food pellets following the infrequent tone. During selected test sessions, event-related brain potentials (ERPs) elicited by each tone (i.e. food-paired tone, non-paired tone) were recorded and analyzed. These analyses revealed differences in ERP responses between the groups. The latency of the N1 and P2 ERP components in the cortex of the control group, but not the EtOH group, increased during sessions when the association between food pellet delivery and tone presentation was being established or extinguished. These data support the hypothesis that chronic ethanol treatment results in a loss of responsivity in ERP components sensitive to changes in food-tone associations, even following a prolonged period of withdrawal from ethanol.

Calcitonin gene-related peptide (CGRP) levels and alcohol

Calcitonin gene-related peptide (CGRP) when administered into the brain exerts stress-like effects such as increased pain sensitivity, anorexia, and potentiation of fear-related behaviours. Since alcohol consumption may be related to alcohols anxiolytic properties, the present study sought to determine if brain CGRP levels were correlated with genetic differences in preference for drinking alcohol and/or affected by alcohol exposure/withdrawal. CGRP-like immunoreactivity (CGRP-LI) was measured by radioimmunoassay (RIA) in amygdala, hippocampus, frontal cortex, hypothalamus, and caudate. In the first experiment, CGRP-LI was compared in alcohol-naive rats [preferring (P) and non-preferring (NP)], lower concentrations were found in the hippocampus (U = 153.5; d.f. = 1,28; p < 0.014) and frontal cortex (U = 183.0; d.f. = 1,28; p < 0.0001) of the P rats. In a second experiment, a group of outbred Wistar rats were exposed to alcohol in vapour chambers, or control conditions. At 7 wk of alcohol exposure there were no differences in exposed rats as compared to controls. However, at 4 wk following ethanol withdrawal, higher concentrations of CGRP-LI were found in the hippocampus (U = 26.5; d.f. = 1,20 p < 0.05), hypothalamus (U = 17.5; d.f. = 1,20; p < 0.009), and caudate-putamen (U = 17.0; d.f. = 1,20; p < 0.009) of the previously exposed animals. These studies suggest that CGRP may modulate alcohol preference and additionally, that exposure/withdrawal from ethanol produces long-lasting effects on CGRP-LI.

LONG LATENCY EVENT-RELATED POTENTIALS IN RATS: EFFECTS OF NUCLEUS BASALIS MAGNOCELLULARIS LESIONS*

The effects of AMPA lesions of the nucleus basalis magnocellularis (NBM) on EEG and event-related potentials (ERPs) generated by an auditory discrimination task were examined. The lesions significantly reduced choline acetyl transferase (ChAT) activity in frontal and parietal cortex. NBM lesions produced significantly more errors in the task. Significant increases in EEG spectral power in the fronto-parietal cortex were found, most predominantly in the higher frequencies (8-32 Hz), suggesting increases in arousal in the lesioned animals. Additionally, the lesion resulted in an increase in the area, the standard deviation of the amplitude of the N1 component, as well as instability in the amplitudes of several other ERP components. These results suggest that NBM lesions may impair ability to correctly respond in a discrimination task by a combination of increased arousal and an inability to maintain stable attentional capacity.