Central Noradrenergic Activation Research Articles

Transcutaneous Vagus Nerve Stimulation (tVNS) Improves High-Confidence Recognition Memory but Not Emotional Word Processing.

Previous clinical research found that invasive vagus nerve stimulation (VNS) enhanced word recognition memory in epileptic patients, an effect assumed to be related to the activation of brainstem arousal systems. In this study, we applied non-invasive transcutaneous auricular VNS (tVNS) to replicate and extend the previous work. Using a single-blind, randomized, between-subject design, 60 healthy volunteers received active or sham stimulation during a lexical decision task, in which emotional and neutral stimuli were classified as words or non-words. In a subsequent recognition memory task (1 day after stimulation), participants' memory performance on these words and their subjective memory confidence were tested. Salivary alpha-amylase (sAA) levels, a putative indirect measure of central noradrenergic activation, were also measured before and after stimulation. During encoding, pleasant words were more accurately detected than neutral and unpleasant words. However, no tVNS effects were observed on task performance or on overall sAA level changes. tVNS also did not modulate overall recognition memory, which was particularly enhanced for pleasant emotional words. However, when hit rates were split based on confidence ratings reflecting familiarity- and recollection-based memory, higher recollection-based memory performance (irrespective of emotional category) was observed during active stimulation than during sham stimulation. To summarize, we replicated prior findings of enhanced processing and memory for emotional (pleasant) words. Whereas tVNS showed no effects on word processing, subtle effects on recollection-based memory performance emerged, which may indicate that tVNS facilitates hippocampus-mediated consolidation processes.

Effects of propiverine hydrochloride, an anticholinergic agent, on urethral continence mechanisms and plasma catecholamine concentration in rats

Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats. Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested. Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased. Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.

Increased psychological and attenuated cortisol and alpha-amylase responses to acute psychosocial stress in female patients with borderline personality disorder

Borderline personality disorder (BPD) is characterized by increased self-reported stress and emotional responding. Knowledge about the psychological and physiological mechanisms that underlie these experiences in BPD patients is scarce. The objective was to assess both psychological and endocrinological responses to a standardized psychosocial stressor in female BPD patients and healthy controls. A total of 15 female BPD patients and 17 healthy control subjects were included in a case-control study. All subjects were free of any medication, had a regular menstrual cycle, and were investigated during the luteal phase of their menstrual cycle. Co-occurring current major depression, current substance abuse/dependence, and lifetime schizophrenia or bipolar I disorder were excluded. Psychological measures of stress, salivary cortisol, salivary alpha-amylase, plasma ACTH, plasma norepinephrine and epinephrine concentrations were measured before, during, and after exposure to a standardized psychosocial stress protocol. BPD patients displayed maladaptive cognitive appraisal processes regarding the upcoming stressor as well as significantly higher subjective stress, coupled with a substantial cortisol and alpha-amylase hyporeactivity to the stressor in comparison to the controls. No significant differences for ACTH and catecholaminergic responses were observed, while the ACTH:cortisol ratio was higher in BPD patients than in controls. Attenuated cortisol responsiveness in BPD patients might in part be explained by decreased adrenal responsiveness to endogenous ACTH and altered central noradrenergic activation as reflected by alpha-amylase.

Substantial role of locus coeruleus-noradrenergic activation and capsaicin-insensitive primary afferent fibers in bee venom's anti-inflammatory effect

Several lines of evidence indicate significant interactions between the immune and nervous systems. Our recent study reveals that ‘bee venom (BV) induced anti-inflammatory effect’ (BVAI) was produced by sympathetic preganglionic neuronal activation and subsequent adrenomedullary catecholamine release in a zymosan-induced inflammation model. However, the specific peripheral input and the supraspinal neuronal systems that are involved in this BVAI remain to be defined. Here we show that subcutaneous BV injection into left hind limb significantly reduces zymosan-induced leukocyte migration and that this effect is completely inhibited by denervation of the left sciatic nerve. This BVAI was not affected by the destruction of capsaicin-sensitive primary afferent fibers using either neonatal capsaicin or resiniferatoxin (RTX) pretreatment. BV injection into the left hind limb significantly increased Fos expression in the contralateral locus coeruleus (LC) in non-inflamed mice. In zymosan-inflamed mice, BV injection produced a further increase in LC Fos expression as compared with non-inflamed mice. This BV-induced Fos increase in the LC was not affected by RTX pretreatment. Pharmacological blockage of central noradrenergic activity by either central chemical sympathectomy (i.c.v. 6-hydroxydopamine) or alpha2 adrenoceptor antagonism (i.c.v. idazoxan) completely blocked BVAI. Taken together, these results suggest that BVAI is mediated by peripheral activation of capsaicin-insensitive primary afferent fibers and subsequent central noradrenergic activation including the LC.

Pathophysiology and Treatment of Menopausal Hot Flashes

Hot flashes are the most common symptom of menopause. Although the appearance of hot flashes coincides with estrogen withdrawal, this does not entirely explain the phenomenon because estrogen levels do not differ between symptomatic and asymptomatic women. Luteinizing throughout? hormone pulses do not produce hot flashes nor do changes in endogenous opiates. Recent studies suggest that hot flashes are triggered by small elevations in core body temperature (T(c)) acting within a reduced thermoneutral zone in symptomatic postmenopausal women. This narrowing may be due to elevated central noradrenergic activation, a contention supported by observations that clonidine and some relaxation procedures ameliorate hot flashes. Because hot flashes are triggered by T(c) elevations, procedures to reduce T(c), such as lowering ambient temperature, are beneficial. Estrogen ameliorates hot flashes by increasing the T(c) sweating threshold, although the underlying mechanism is not known. Recent studies of hot flashes during sleep call into question their role in producing sleep disturbance.

Differential sensitivity of intranuclear and systemic oxytocin release to central noradrenergic receptor stimulation during mid- and late gestation in rats.

A number of changes occur in the oxytocin (OT) system during gestation, such as increases in hypothalamic OT mRNA, increased neural lobe and systemic OT, and morphological and electrophysiological changes in OT-containing magnocellular neurons, suggestive of altered neuronal sensitivity, which may be mediated by ovarian steroids. Because central norepinephrine (NE) and histamine (HA) are potent stimulators of OT release during parturition and lactation, the present study investigated the effects of central noradrenergic and histaminergic receptor activation on systemic (NE, HA) and intranuclear (NE) OT release in pregnant rats and in ovariectomized rats treated with ovarian steroids. Plasma OT levels in late gestation were significantly higher compared with all other groups, and neither adrenergic nor histaminergic receptor blockade decreased these elevated levels. Furthermore, the alpha-adrenergic agonist phenylephrine, but not histamine, stimulated systemic OT release to a significantly greater extent in late gestation than in midpregnant, ovariectomized, or steroid-treated females. Although basal extracellular OT levels in the paraventricular nucleus, as measured with microdialysis, were unchanged during pregnancy or steroid treatment, noradrenergic receptor stimulation of intranuclear OT release was significantly elevated in midgestation females compared with all other groups. These studies indicate that sensitivity of intranuclear and systemic OT release to noradrenergic receptor activation differentially varies during the course of gestation.

Blockade of Stress-Induced But Not Cocaine-Induced Reinstatement by Infusion of Noradrenergic Antagonists into the Bed Nucleus of the Stria Terminalis or the Central Nucleus of the Amygdala

Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of β-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5–7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the β₁- and β₂-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 μl) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.

Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala.

Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of beta-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5-7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the beta(1)- and beta(2)-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 microliter) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.

Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes

Objective: To determine if increases in core body temperature preceding most hot flashes are caused by increased metabolic rate, peripheral vasoconstriction, or central noradrenergic activation. Design: Laboratory physiological study. Setting: University medical center. Patient(s): Fourteen healthy, postmenopausal women reporting frequent hot flashes. Intervention(s): Data were recorded for 3 hours in a temperature- and humidity-controlled room. Main Outcome Measure(s): Core body temperature, mean skin temperature, respiratory exchange ratio, sternal skin conductance, plasma 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid. Result(s): Twenty-nine physiologically defined hot flashes were recorded. Increases in core body temperature, measured with an ingested radiotelemetry capsule, preceded 76% of the flashes. Increased metabolic rate began after increased core temperature. Peripheral vasoconstriction did not occur. Plasma levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of brain norepinephrine, increased significantly, whereas vanillylmandelic acid, a peripheral metabolite, did not. Conclusion(s): Core body temperature elevations preceding menopausal hot flashes are not driven by peripheral vasoconstriction or increased metabolic rate, but probably by a central noradrenergic mechanism.

Stressor-Specific Activation of Catecholaminergic Systems: Implications for Stress-Related Hypothalamic-Pituitary-Adrenocortical Responses

Responses of central catecholaminergic systems as well as the Hypothalamic-Pituitary-Adrenocortical (HPA) axis vary during exposure to different stressors. Extracellular norepinephrine (NE) levels in the paraventricular nucleus (PVN) increase markedly with immobilization (IMMO) or with formalin (FORM)-induced pain and relatively little with insulin (INS)-induced hypoglycemia, cold (COLD) stress, or hemorrhage (HEM). Levels of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, increase in the locus ceruleus with IMMO or ether but are unchanged during INS-induced hypoglycemia. These and other findings have led to the hypothesis of the existence of stressor-specific central noradrenergic pathways participating in regulation of the HPA axis. In the study described in this chapter, conscious rats have been exposed to one of several stressors-HEM, i.v. INS, s.c. FORM, COLD, or IMMO. Fos immunoreactivity of the immediate early gene c-fos was used to investigate changes in the activity of brain stem neurons. The results were correlated with previous findings about stress-induced central noradrenergic activation in the PVN using in vivo microdialysis and simultaneous measurements of plasma adrenocorticotropic hormone (ACTH) levels. The present results indicate that the magnitude of activation of c-fos in brain catecholaminergic regions and of PVN corticotrophin releasing hormone (CRH) neurons varies widely across stressors. The findings support the notion of stressor-specificity of responses of central catecholaminergic systems and the HPA axis and indicate that different central pathways regulate HPA reactivity.

Norepinephrine release in the rat frontal cortex under treadmill exercise: a study with microdialysis

Cortical norepinephrine (NE) release and metabolism were studied by using chronic microdialysis in rats performing a treadmill exercise at 25 m/min with a 3% slope. Cortical microdialysates and peripheral blood were collected at rest, during 1- or 2-h treadmill running, and for 1 h after exercise. Microdialysate NE and its main metabolites, 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol, and plasma epinephrine (Epi) and NE were determined by high-performance liquid chromatography with electrochemical detection. The results show that treadmill running is able to stimulate concomitantly peripheral catecholamine secretion and central noradrenergic activity, i.e., NE turnover and release. The duration of the central activation and its prolongation over recovery period increases as the duration of the running increases. A positive correlation was found between the central noradrenergic activation and peripheral Epi secretion but not peripheral NE. These findings confirm and extend our previous observations in exercising men and give support to the hypothesis that the elevation of circulating Epi can be a relevant factor mediating, directly or indirectly, the exercise-induced central neurochemical, psychological, and cognitive changes.

Physical conditioning in rats influences the central and peripheral catecholamine responses to sustained exercise.

We have investigated the effect of treadmill running in rats (25m.min-1 using a 3% gradient; for 1 h or 2 h) on the cortical extracellular concentrations of noradrenaline (NA) and its main metabolites-3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol- and the plasma adrenaline (A) and NA concentrations in relation to prior physical conditioning (1 or 2-h running.day-1 for 12 days). Cortical microdialysates and peripheral blood were collected during 1-h resting, 1-h or 2-h running and for 1 h after exercise. Catecholamines and their metabolites were quantitated using high performance liquid chromatography with electrochemical detection. Treadmill running stimulated concomitantly peripheral catecholamine secretion and central noradrenergic activity, i.e. NA turnover and release. The effect extended into the recovery period even more as the duration of the run increased. Prior physical conditioning greatly influenced the central and peripheral catecholamine responses: the 1-h trained rats experienced the 2-h run as a stressful new event eliciting great long-lasting catecholamine responses, whereas the 2-h trained rats exhibited a progressive sustained catecholamine increase with an earlier onset of the central NA release. The data are discussed in relation to the psychological and intellectual effects of exercise and physical fitness in humans. In addition, the positive correlation found between the central noradrenergic activation and peripheral A secretion confirmed and extended our previous observations in exercising men and gave support to the hypothesis that the elevation of circulating A can be a relevant factor mediating--directly or indirectly--the exercise-induced central effects.

Noradrenergic mechanisms and the cardiovascular actions of nitroglycerin

In this article we review noradrenergic activities of nitroglycerin in the central and peripheral nervous systems. Nitroglycerin may cause paradoxical bradycardia and occasional life threatening hypotension in patients. Intracisternal injections and microinjections of nitroglycerin into nucleus tractus solitarii produce hypotension and bradycardia, effects which mimic the baroreflex and may involve central noradrenergic mechanisms. The drug also triggers an α 2-adrenoceptor-mediated sympatho-inhibition reflex through vagal afferents. Nitroglycerin mimics biological responses associated with sympathetic neuronal activity, e.g., increase in outflow of norepinephrine and its metabolites from perfused guinea pig atria, medulla-pons tissue and cerebrospinal fluid. The sympathomimetic effects of nitroglycerin are antagonized by pre-treatment with yohimbine or rauwolscine. Clinical studies and animal experiments show that hemodynamics of nitroglycerin and sodium nitroprusside are different. Nitroglycerin is lipophilic and the compounds readily enters cells to form nitric oxide, but sodium nitroprusside is very hydrophilic and the compound has difficulty crossing membranes. Thus, intravenous nitroglycerin-induced increases in central noradrenergic activation and inhibitory reflexes may account for at least some of the therapeutic actions and side effects of the drug. In contrast, minimal central responses are produced by intravenous administration of sodium nitroprusside.

Modification by 6-hydroxydopamine (6-OHDA) of the inhibition of extrinsic rumen contractions in sheep produced by beta-endorphin.

In sheep, beta-endorphin (1 and 2 micrograms/kg) administered into the third cerebral ventricle caused a significant inhibition of the frequency of rumen contractions. The amplitude of the first rumen contractions, following immediately after the end of infusion, and the average amplitude of primary rumen contractions, were inhibited. Beta-endorphin caused general psychomotor excitability. These results suggest that an inhibitory mu and delta opioid system is involved in the control of forestomach motility and general behaviour in sheep. All effects of beta-endorphin were completely prevented by i.c.v. 6-hydroxydopamine (6-OHDA, 18.2 micrograms/kg) pre-treatment. These results suggest that beta-endorphin-induced inhibition of rumen motility is due to central noradrenergic system activation. The exact location of this noradrenergic system remains to be determined.

Auditory-evoked response of the cortex after yohimbine administration: Phase advance effect of central noradrenergic activation

The effects of central noradrenergic activation on an auditory-evoked cortical response were studied using systemic administration of yohimbine (2 mg/kg intravenously. IV), a noradrenergic stimulant, in 13 anesthetized rats. To analyze changes of the response, surface and intracortical evoked potentials (EP) as well as extracellular single-unit recordings with tungsten microelectrodes were employed. It was noted that the initial-positive wave of the surface EP corresponded to unit firing responses in a restricted area of the auditory cortex, where the surface EP was largest and a polarity inversion of the intracortical EP was observed. The following effects were produced by yohimbine: 1) The initial-positive surface potential (n = 10) and corresponding intracortical potential with inverted polarity (n = 6) both showed an increase in amplitude and a decrease in peak latency; 2) the unit firing response (n = 10) tended to show an increase in peak frequency and a decrease in peak firing latency and 3) yohimbine produced an earlier ending of the firing period and in paired stimulation experiments (n = 7) it prolonged the period during which the second response was suppressed, indicating an augmentation of postexcitation inhibition. Later histological examination suggested that most of the units recorded were pyramidal cells. These findings indicate that chemical stimulation of the central noradrenergic system by yohimbine enhances both the initial excitatory and following inhibitory' processes in the auditory-evoked response of the cortical units (probably pyramidal cells), resulting not only in amplification of the response but also in advancement of the response phase. We proposed that this phase advance effect is an important aspect of noradrenergic function that contributes to an acceleration of information processing in the alert state.

Effect of the anesthetic agent propofol on hormonal responses to ECT

Propofol is a new anesthetic induction agent that reduces electroconvulsive therapy (ECT) seizure duration. To indirectly investigate the effect of propofol on ECT-induced acute central neurotransmitter changes, we studied neuroendocrine responses in 25 primary depressed subjects treated with ECT under either propofol or thiopentone anesthesia. Blood samples were taken prior to ECT, and then at regular intervals for 2 hr. Only the prolactin response correlated significantly with seizure duration (r = 0.52, p < 0.01). Subjects given propofol had significantly reduced adrenocorticotropin (ACTH) (p < 0.01) and cortisol (p < 0.05) responses compared to thiopentone, which were independent of seizure duration. There was a trend towards a reduction in the prolactin response with propofol compared to thiopentone, but this was dependent upon the diminished seizure duration. The results indicate that propofol effects endocrine responses to ECT by two distinct mechanisms: decreasing prolactin by reducing the seizure duration and decreasing ACTH and cortisol by another process, possibly via a reduction in central noradrenergic activation.

Body temperature and plasma prolactin and norepinephrine relationships during exercise in a warm environment: effect of dehydration.

The effects of euhydration (Eh) and light (Dh1) and moderate (Dh2) dehydrations on plasma prolactin (PRL) levels were studied in 5 young male volunteers at rest and during exercise to exhaustion (50% of VO2max) in a warm environment (Tdb = 35 degrees C, rh = 20-30%). Light and moderate dehydrations (loss of 1.1 and 1.8% body respectively) were obtained before exercise by controlled hyperthermia. Compared to Eh, time for exhaustion was reduced in Dh1 and Dh2 (p less than 0.01) and rectal temperature (Tre) rose faster in Dh2 (p less than 0.05). Both venous plasma PRL and norepinephrine (NE) increased during exercise at any hydration level (p less than 0.05). Plasma PRL reached higher values after 40 and 60 min in Dh2 and Dh1 (p less than 0.05). Plasma NE values were higher in Dh2 at rest and at the 40th min during exercise (p less than 0.05). Plasma PRL was linearly correlated to Tre and plasma NE (p less than 0.001) but unrelated to plasma volume variation and osmolality. Our results provide further evidence for the major effect of body temperature in exercise-induced PRL changes. Moreover, the plasma PRL-NE relationship suggests that these changes may result from central noradrenergic activation.

Lactate provocation of panic attacks. II. Biochemical and physiological findings.

Thirty-one of 43 patients with panic disorder or agoraphobia with panic attacks and none of 20 normal controls panicked in response to infusions of sodium lactate. Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation. During lactate infusion, patients who did not panic, nevertheless, developed higher lactate and pyruvate levels and greater ionized calcium and pH changes than controls. Lactate-induced panic attacks were regularly accompanied by biological changes consistent with hyperventilation and central noradrenergic activation and irregularly by elevation of plasma norepinephrine and cortisol levels. Panic attacks were not associated with changes in epinephrine or calcium levels or pH. Baseline arousal increased the likelihood of panic during lactate infusion. It is hypothesized that lactate-induced panic primarily involves central noradrenergic discharge with inconsistent peripheral manifestations.

Catecholamine metabolism during clonidine withdrawal.

Abrupt cessation of clonidine treatment in hypertensive patients may precipitate a withdrawal syndrome. Since this drug is likely to be more widely prescribed to normotensive patients with neuropsychiatric diseases, we studied neurochemical, cardiovascular, and behavioral changes upon placebo substitution in seven patients receiving clonidine (6 micrograms/kg/day for 3 weeks) for treatment of alcohol amnestic disorder. Urinary excretion of all major catecholamine metabolites returned to pretreatment levels 3-5 days after discontinuing clonidine, without significant overshoot. The percentage increase during clonidine withdrawal of the norepinephrine metabolite normetanephrine was greater than were those of vanillylmandelic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the epinephrine metabolite metanephrine. Excretion of the dopamine metabolites homovanillic acid and 3-methoxytyramine did not change. Total plasma MHPG, heart rate, and mean arterial pressure were significantly elevated above pretreatment values 72 h after the last dose of clonidine. There was an enhancement of episodic memory compared to predrug values but no other behavioral changes were noted during clonidine withdrawal. These findings are consistent with augmented catecholamine release and central noradrenergic activation which may produce psychopathology in some psychiatric patients during clonidine withdrawal.

Feeding behavior induced by central norepinephrine injection is attenuated by discrete lesions in the hypothalamic paraventricular nucleus

Extensive brain-cannula mapping studies in the rat have demonstrated that th hypothalamic paraventricular nucleus (PVN) is the most sensitive brain site for elicitingeating behavior with central norepinephrine (NE) injection. The present experiments examined the impact of lesions aimed at the PVN on this NE-elicited eating responses. In rats with NE injection cannulas aimed at the lateral ventricle, bilateral lesions of the PVN significantly attenuated, by 60 to 70%, the eating effect induced by NE, at doses ranging from 20 to 160 nmoles. PVN lesions which extended ventrally to damage tissue lying within the periventricular region were more effective in abolishing the NE response than were lesions that remained confined to the dorsal aspects of the PVN. Large lesions located just dorsal to the PVN had no impact on the NE response. This evidence supports the primary role of the PVN in mediating the eating behavior elicited by central noradrenergic activation.