Lesions Of Dorsal Noradrenergic Bundle Research Articles

Binge-Like Eating Attenuates Nisoxetine Feeding Suppression, Stress Activation, and Brain Norepinephrine Activity

Stress is often associated with binge eating. A critical component of the control of stress is the central norepinephrine system. We investigated how dietary-induced binge eating alters central norepinephrine and related behaviors. Young male Sprague Dawley rats received calorie deprivation (24 h) and /or intermittent sweetened fat (vegetable shortening with sucrose; 30 min) twice a week for 10 weeks. The groups were Restrict Binge (calorie deprivation/sweetened fat), Binge (sweetened fat), Restrict (calorie deprivation), and Naive (no calorie deprivation/no sweetened fat). Dietary-induced binge eating was demonstrated by Restrict Binge and Binge, which showed an escalation in 30-min intake over time. Feeding suppression following nisoxetine (3 mg/kg; IP), a selective norepinephrine reuptake inhibitor, was not evident in Restrict Binge (Restrict Binge: 107±13, Binge: 52±9, Restrict: 80±8, Naive: 59±13% of saline injection at 1 h). In subsequent experiments with Restrict Binge and Naive, Restrict Binge had reduced corticosterone (Restrict Binge: 266±25; Naive: 494±36 ng/ml) and less feeding suppression (Restrict Binge: 81±12, Naive: 50±11% of non-restraint intake at 30 min) following restraint stress (1 h). Dietary-induced binge eating in Restrict Binge was not altered by a dorsal noradrenergic bundle lesion caused by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), but frontal cortex norepinephrine was positively correlated with the average 30-min intake post-lesion (0.69; p<0.01). In a separate set of animals, single-unit in vivo electrophysiological recording of locus coeruleus–norepinephrine neural activity demonstrated reduced sensory-evoked response as a consequence of the Restrict Binge schedule (Restrict Binge: 8.1±0.67, Naive: 11.9±1.09 Hz). These results, which suggest that a consequence of dietary-induced binge eating is to attenuate the responsiveness of the brain norepinephrine system, will further our understanding of how highly palatable foods dampen the stress neuraxis.

Selective serotonin reuptake blockade increases extracellular dopamine in noradrenaline‐rich isocortical but not prefrontal areas: dependence on serotonin‐1A receptors and independence from noradrenergic innervation

The present study investigated the effects of two serotonin (5-HT) uptake inhibitors, citalopram and paroxetine, and of a non-selective noradrenaline (NA) and 5-HT uptake blocker, imipramine, on extracellular NA and dopamine (DA) in the prefrontal cortex (PfCX), parietal cortex (ParCX) and occipital cortex (OccCX). Citalopram, the most selective 5-HT uptake blocker, increased dialysate DA in the OccCX and ParCX but not in the PfCX and this effect was prevented in the OccCX by WAY-100635, an antagonist of serotonin-1A (5-HT(1A)) receptors, but not by dorsal noradrenergic bundle (DNAB) lesions that reduced to unmeasurable levels basal dialysate NA but did not affect dialysate DA. Paroxetine, a less selective 5-HT uptake inhibitor than citalopram, at the dose of 5 mg/kg, increased DA in the OccCX but not in the PfCX; however, at doses of 10 mg/kg, which increase PfCX NA, paroxetine increased DA also in this area. Imipramine increased dialysate DA and NA both in the PfCX and in the OccCX and this effect was abolished by DNAB lesions and was reduced but not abolished by WAY-100635. Administration of doses of reboxetine and citalopram that do not increase DA release in the OccCX if given separately, markedly increased DA when combined. These results indicate that endogenous 5-HT, raised by selective blockade of the 5-HT carrier, can increase extracellular DA in the OccCX and in the ParCX by stimulating 5-HT(1A) receptors independently from the presence of NA terminals, although blockade of 5-HT and NA carrier can strongly interact to raise extracellular DA in this area. These observations are consistent with the existence of DA neurons separate from the NA ones contributing to extracellular DA even in NA-rich/DA poor isocortical areas.

Effects of Dorsal Noradrenergic Bundle Lesions on Recovery After Sensorimotor Cortex Injury

Several lines of evidence suggest that the recovery of the ability of rats to traverse a narrow beam after unilateral injury to the sensorimotor cortex is noradrenergically mediated. We tested the hypotheses that the influence of norepinephrine on beam-walking recovery occurs, at least partially, through effects in the contralateral and/or ipsilateral cerebral cortex. Rats had either a selective left or right 6-hydroxydopamine lesion or sham lesion of the dorsal noradrenergic bundle (DNB) 2 weeks before suction-ablation or sham injury of the right sensorimotor cortex. The rats’ abilities to perform the beam-walking task were measured over the 10 days following cortex surgery. DNB lesions did not affect the initial severity of the beam-walking deficit and had no effect on the performance of the task in rats with sham cortex injuries. Lesions of the contralateral but not ipsilateral DNB significantly impaired recovery. Further, in cortically lesioned rats with contralateral DNB lesions, norepinephrine content in the cerebral cortex opposite to the sensorimotor cortex lesion was significantly correlated with recovery. These data suggest that the effect of norepinephrine on recovery of beam-walking ability may be partially exerted in the cerebral cortex contralateral to the injury.

Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance.

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.

Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance.

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.

Comparison of the effects of single and combined neurotoxic lesions of the nucleus basalis magnocellularis and dorsal noradrenergic bundle on learning and memory in the rat

Groups of rats received bilateral destruction of either the nucleus basalis magnocellularis (NBM) by infusion of ibotenic acid, the dorsal noradrenergic bundle (DNB) by infusion of 6-hydroxydopamine, or both NBM + DNB (COMB). These lesion groups along with sham operated controls were trained on a food reinforced spatial delayed conditional discrimination task in a T-maze. All four groups were able to attain a criterion of 85% correct responses despite significant group differences in the number of trials to criterion and number of correct responses during training. Performance of the DNB and NBM groups on acquisition trials was significantly lower than controls, significantly higher than the COMB group, but not significantly different from each other. When tested at delays of 30–300 s, all groups demonstrated parallel rates of decline in performance. On reversal learning trials, the NBM and COMB groups were significantly impaired, whereas the performance of the DNB group was better than controls. No significant interaction between the DNB and NBM lesions was observed on any of the behavioral measures. Biochemical analyses demonstrated significant reductions of choline acetyltransferase (ChAT) activity in cortex but not hippocampus of the NBM and COMB groups, and a significant reduction of norepinephrine (NE) in cortex and hippocampus of the DNB and COMB but not the NBM group. The concentration of other monoamine and amino acid neurotransmitters in the lesion groups were unchanged from controls. These results suggest that DNB and NBM lesions produce separate and independent cognitive impairments that do not severely disrupt retention of trial independent (reference memory) and trial dependent (working memory) information on this T-maze task.

Behavioral effects of concurrent lesions of the nucleus basalis magnocellularis and the dorsal noradrenergic bundle

The effects of separate and concurrent lesions to the cholinergic and noradrenergic (NE) systems were assessed in two water mazes. Lesion of the nucleus basalis magnocellularis (NBM) decreased performance in a spatial memory task (Morris water maze) while lesions of the dorsal NE bundle (DNB) enhanced the acquisition of this task independent of the NBM effects. Both lesions impaired performance on a water-escape motivated T-maze; however, the deficits induced by the combined lesion did not differ from the effects of either lesion alone. Neither lesion, nor their combination, had significant effects on open field activity. Biochemical analyses revealed almost total loss of NE in the cortex and hippocampus after DNB lesion, with relatively minor changes in other catecholamines or metabolites. Choline acetyltransferase activity was not significantly altered by the DNB lesion but was decreased in the cortex by the NBM lesion. These results suggest a task-specific effect of DNB lesion that is detectable under conditions of mild stress when floor effects are minimized.

Long latency event related potentials in rats: The effects of changes in stimulus parameters and neurochemical lesions

Animal models of event related potentials (ERPs) have recently been developed in order to gain further understanding of the psychobiological variables which may underlie these brain potentials. In the present study, unanaesthetized rats were utilized in order to evaluate the effects on rat ERP morphology of changes in the auditory stimulus parameters used to elicit these potentials such as tone probability and intensity. In addition, the consequences of reductions in norepinephrine (NE) produced by six-hydroxydopamine (6-OHDA) lesions to the area of the dorsal noradrenergic bundle in ERP wave forms were evaluated. Forty, experimentally naive, male rats chronically implanted with electrodes were used in this study. The results of these studies showed that in all electrode sites (frontal cortex, ventral thalamus, dorsal hippocampus, locus coeruleus) a series of large amplitude potentials in the 10-200 msec latency range could be recorded, some of which were sensitive to changes in the auditory stimulus parameters such as probability and tone intensity. Late positive potentials in the 300-400 msec range could be identified in recordings from the dorsal hippocampus and were found to be sensitive to probability independent of tone intensity. Dorsal noradrenergic bundle lesions were also found to produce significant changes in these rat ERP components. Lesioned animals were found to have increases in amplitude to the early negative potentials (in the 50-100 msec range) in response to frequent tones in cortical leads and decreases in the amplitude of the late positive potentials (in the 300-400 msec range) recorded in hippocampal leads in response to infrequent tones. These findings are consistent with a role for NE in the forebrain in the processing of novel or "selective" stimuli.

Memory following cholinergic (NBM) and noradrenergic (DNAB) lesions made singly or in combination: Potentiation of disruption by scopolamine

Groups of rats were trained on either delayed matching or nonmatching to position tasks, then divided into four subgroups and given the following bilateral lesions: (a) SHAM [vehicle injection into the nucleus basalis magnocellularis (NBM) and dorsal noradrenergic bundle (DNAB)], (b) DNAB (6-hydroxydopamine lesion of the DNAB, vehicle into the NBM), (c) NBM (quisqualic acid lesion of the NBM, vehicle into the DNAB) and (d) DUAL (neurotoxin lesions of both DNAB and NBM). Following postoperative recovery, the DUAL lesion subjects were slightly impaired, but by the seventh day of testing all groups were performing at similar levels. This strongly suggests that quisqualate lesions of the NBM are not sufficient to produce severe and lasting mnemonic disorders resembling those seen in Alzheimer's disease (AD). These data also indicate that the noradrenergic system may not be of critical importance with respect to cognition. It was reasoned that an additional anticholinergic treatment might exacerbate an underlying deficiency. All groups were injected, peripherally, with the cholinergic antagonist scopolamine (0-0.5 mg/kg). This drug dose-dependently disrupted performance in all groups. Moreover, the highest dose had a marked effect in the DUAL group, impairing performance even when no mnemonic burden was present (at zero delay). The results suggest that cholinergic NBM and noradrenergic DNAB lesions produce only transient mnemonic deficiencies. A combination of the two can be disruptive, but longer term task (or reference) memory is the primary process affected, and only under certain conditions. The implication of these findings to research concerning animal models relating to Alzheimer's disease is discussed.

The effects of dorsal noradrenergic bundle lesions on spatial learning, locomotor activity, and reaction to novelty

The dorsal noradrenergic bundle (DNB) of male Wistar rats was lesioned bilaterally using intracerebral injections of 6-hydroxydopamine neurotoxin. Some of the rats were trained in a water maze using an "alternation" strategy, where the two positions of the hidden platform in the pool were changed between successive trials in the daily tests, and other rats in a water maze, where the temperature of the water was lowered to about 11 degrees C. The rats trained in the cold-water maze were also tested in open-field and saccharin neophobia tests. No differences were found between the two groups in learning of water maze tasks or in locomotor activity in the open-field tests. However, the saccharin neophobia test revealed an increased neophobia in the DNB-lesioned rats.

Disinhibition by propranolol and chlordiazepoxide of nonrewarded lever-pressing in the rat is unaffected by dorsal noradrenergic bundle lesion

Ten male Sprague-Dawley rats received 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle and 10 others underwent control operations. The lesion depleted levels of noradrenaline in the hippocampus to 2% of those in the controls. All rats were then trained for 16 sessions to lever-press in a Skinner box on a variable interval 18 sec schedule of food-reinforcement, then for 42 days on a successive discrimination between periods of variable interval (VI 18 sec) food-reinforcement and periods of extinction. This report describes the effects of chlordiazepoxide (CDP; 5 mg/kg) and propranolol (5 and 10 mg/kg) injected intraperitoneally in both groups on modified ABBA designs after this training. Both drugs increased the response rates in extinction periods. The effect of propranolol was similar at each dose and smaller than that of CDP. Although CDP and propranolol (5 mg/kg) increased variable interval response rates also, this could not account for the effect on extinction response rates. Responding did not differ between the lesioned and control animals and the effects of drugs were similar in each group. It is unlikely that CDP or propranolol release nonrewarded responding by disrupting transmission in the dorsal noradrenergic bundle.

Effects of lesions of the dorsal noradrenergic bundle on conditioned suppression to a CS and to a contextual background stimulus

The aim of the experiment was to determine whether the dorsal noradrenergic bundle (DB) plays a role in conditioning to context. Rats received either bilateral lesions of the DB by local injection of 6-hydroxydopamine, vehicle injections only, or sham operations. All animals were then trained to barpress for food on a variable interval (VI) schedule. Two 5-min intrusion periods were superimposed on the VI baseline during each session. An ‘envelope’ stimulus (flashing light) was on throughout each intrusion period. In addition, embedded in the two intrusion periods of each session, there occurred 8 presentations of a ‘punctate’ conditioned stimulus (CS) (a 15-s clicker), and 8 presentations of a 0.5-s footshock. Within each surgical condition rats were randomly allocated to one of three conditioning groups, receiving 100%, 50% or 0% temporal association between CS and shock. Conditioning to the punctate CS and to the context provided by the envelope stimulus was assessed by the degree of suppression of the barpress response relative to the VI baseline. Responding was most suppressed in the punctate CS in the 100 and 50% conditions, and most suppressed in the envelope stimulus in the 0% condition. DB lesions released response suppression to the punctate CS, had no effect on suppression to the envelope stimulus, and reduced sensitivity to CS-shock probability as measured by response suppression during the punctate CS. These results confirm previous reports that DB lesions alleviate response suppression to shock-associated cues, identify some of the parameters that affect this phenomenon, but fail to support a role for the DB in contextual conditioning.

On the role of the dorsal noradrenergic bundle in learning and habituation to novelty

In Experiment 1, the performance of vehicle control rats and rats with 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DB) was examined in acquisition and extinction of bar pressing and in spontaneous and food-reinforced alternation in a T-shape maze. Plasma corticosterone levels in basal conditions, after chronic food restriction, after transportation to a novel environment, and after sessions of either rewarded or nonrewarded bar pressing were assayed. DB lesions produced a significant decrease of spontaneous alternation and a significant but small resistance to extinction, without reliably altering either corticosterone responses or instrumental spatial alternation. In Experiment 2, bar-press extinction and instrumental alternation were reexamined in new groups of control rats and rats with DB lesions without any blood collection procedures. The DB lesions did not reliably alter either behaviors on any measures. Taken together, these data indicate no consistent effects of forebrain noradrenaline depletion on either extinction or spatial memory or pituitary-adrenocortical function. However, the impairment of spontaneous alternation found in a previous study was confirmed. These findings are discussed in terms of the proposed roles of the dorsal noradrenergic bundle in learning and habituation to novelty.

Noradrenaline- and time-dependent changes in neocortical α 2- and β 1-adrenoceptor binding in dorsal noradrenergic bundle-lesioned rats

A 6-hydroxydopamine-induced lesion of the dorsal noradrenergic bundle (DNB) in rats markedly decreased neocortical noradrenaline concentration (NNC) by 72–100% as measured 1, 3 and 13 months after the lesioning procedure. The concomitant assessment of neocortical α 2- and β 1-adrenoceptor binding (NAAB and NBAB, respectively) usually indicated significant increases of 25–74% for these two variables. There were, however, cases of unchanged NAAB and NBAB which presumably reflected an incomplete DNB lesion and a consequent time-related, partial recovery of NNC. The results emphasize the potential for long-term sequelae of the DNB lesion, and the existence of a critical NNC threshold (∼10–30% of control NNC values) which modulates postsynaptic α 2 and β 1-adrenoceptor density.

Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions.

A series of experiments examined the effects of lesions of the dorsal noradrenergic bundle (DNAB), induced by 6-hydroxydopamine (6-OHDA), on the behavioural response to systemic and intra-accumbens amphetamine, using a rat analogue of Leonard's 5-choice serial reaction time task for humans. Although the 6-OHDA DNAB lesion produced a profound depletion of cortical noradrenaline (NA) (to around 5% of control levels) it did not impair any aspect of performance on this task. Both systemic and intra-accumbens amphetamine increased behavioural measures of impulsivity of responding, but neither impaired discriminative accuracy in the sham-operated control rats. However, the DNAB lesioned rats did show a discriminative impairment following both low doses of systemic amphetamine, and intra-accumbens amphetamine. The latter effect was antagonised by systemic administration of the specific dopaminergic (DA) antagonist alpha-flupenthixol. The DNAB lesion did not alter the effect of amphetamine on any other behavioural measure, including speed and impulsivity of responding. These results suggest that although DA and NA participate in qualitatively different behavioural processes, the effects of DNAB lesions on attentional processes depend on the level of DA activity within the nucleus accumbens.

Effects of lesions to the dorsal noradrenergic bundle on counterconditioning of punished barpressing

The possible contribution of the dorsal noradrenergic bundle (DB) to the development of a simple form of counterconditioning (an associative mechanism leading to behavioural tolerance for stress) was assessed by comparison of the performance of animals with 6-hydroxydopamine-induced lesions of the DB to that of sham-operated (SH) animals. Animals engaging in barpressing for food reward on a random-interval (RI) 64 sec schedule were presented with a stimulus signalling the concurrent operation of an RI-64 sec schedule of response-contingent shock. In the control condition (punishment), shock and reward never occurred as a result of the same barpress. In the experimental condition (counterconditioning), the frequency of shock and reward were the same as for the punishment condition but the two events always occurred in succession, with food following shock, as a consequence of the same barpress. DB lesions had no effect on the acquisition of rewarded barpressing or on the initial acquisition of the discrimination between the shock-free and shock-containing (signalled) components of the schedule. However, once performance on the discrimination had reached asymptote, DB animals in the punishment control group showed significantly less suppression to the signal than SH animals. The counterconditioning schedule used was effective, leading to significantly reduced response suppression in the SH animals in comparison to the SH group subjected to punishment. The pattern of findings in the DB groups was consistent with a blockade by the lesion of the development of counterconditioning. These results suggest, therefore, that the DB is involved in at least one associative mechanism leading to tolerance for stress.

Central noradrenaline depletion attenuates amphetamine-induced locomotor behavior

Male rats were given 6-hydroxydopamine-induced lesions of the locus coeruleus (LC) or the dorsal nor-adrenergic bundle (DNAB), prior to the measurement of locomotor and rearing activity induced by d-amphetamine. The increased locomotor activity induced by d-amphetamine (1.8 mg/kg) was significantly attenuated by both the LC and the DNAB lesions. The stimulatory effect of the 7.2 mg/kg dose of amphetamine was attenuated by the LC lesion, whereas the DNAB lesion potentiated this effect. The LC lesion also attenuated rearing induced by the 7.2 mg/kg dose of amphetamine. These results suggest some involvement of central noradrenergic neurons in the activity induced by amphetamine in the rat.

Brain norepinephrine depleting lesions selectively enhance behavioral responsiveness to novelty

The noradrenergic innervation of the forebrain by cells from the locus coeruleus (LC) was interrupted by either electrolytic lesions of the LC or 6-hydroxydopamine (6-OHDA) lesions of the dorsal noradrenergic bundle (DB). Animals so treated were then tested in a modified open field test designed to measure responsiveness to environmental novelty and also tested for food consumption in their home cages. In addition, DB lesioned animals were tested in photocell activity cages for both their initial locomotor response to the novel cages as well as their activity level after habituation. The DB lesioned animals were also tested for rates of acquisition and extinction of an operant response. The DB lesion produced no deficits in either the acquisition or the extinction of a food rewarded operant response. The DB lesion did reduce the initial amount of locomotor activity in response to introduction to the activity cages but did not alter the rate of habituation of the locomotor response nor the “basal” level of activity at the end of two hr of exposure. Neither lesion affected the amount of food eaten by 24 hr-fasted animals in their home cages during the first 15 min. When fasted prior to being given access to food in a novel open field, however, both lesions resulted in decreased food consumption and decreased amounts eaten per approach to the food pedestal. The DB lesion, but not the LC lesion, resulted in decreased rearing and grooming in this setting. These data are consistent with previous reports of NE depletion producing enhanced responsiveness to novelty and suggests that this effect results from destruction of the locus coeruleus forebrain system. As there was no change in direct measures of extinction of an operant response or the habituation of a locomotor response to novelty, these results suggest that the observed enhanced response to novelty was not due to a resistance to extinction to the novel elements in the environment or a decreased rate of habituation to those elements per se, but may be more related to the stressful nature of the situation.

A comparative study of the behavioral effects of the locus coeruleus and the dorsal noradrenergic bundle lesions in the rat

The effects of bilateral lesions of the dorsal noradrenergic bundle (DB) or of the locus coeruleus (LC) on the rat's behavior in different anxiogenic behavioral situations have been studied. The DB rats defecate less but ambulate more than shams in the open-field (O.F.); these data suggest a decrease in the reactivity of these animals to novelty. Furthermore, the LC rats have a behavior identical to that of shams in the O.F. We note moreover that the DB rats do not habituate to a novel stimulus. During the Henderson test, the behavioral inhibition of all lesioned animals seems to be less important than that of shams. These results are discussed in relation to existing hypotheses of the DB function. The lesions of DB induce a decrease in the noradrenaline (NA) cortical level and in the catecholamines level in hypothalamus. The lesions of LC produce 30% loss of forebrain NA. These results reveal a discrepancy between the effects induced by the lesioning of DB fibers and those produced by lesions of LC, which originate in the DB. The presence of non-noradrenergic elements, fibers of passage, which do not travel with the DB fibers or terminals in the LC region may be elements for interpretation.

Deficits in conditioned avoidance responding following adrenalectomy and central norepinephrine depletion are dependent on postsurgical recovery period and phase of the diurnal cycle.

Rats that had undergone combined dorsal noradrenergic bundle lesion (DNBL) and bilateral adrenalectomy were impaired in acquiring a conditioned avoidance response when tested 1 week following surgery. Normal acquisition was observed, however, when testing occurred 3 weeks or more after surgery despite low levels of both plasma corticosterone and brain norepinephrine at that time. Furthermore, neither neonatal systemic administration of 6-hydroxy-dopamine to deplete forebrain norepinephrine, combined with the corticosterone inhibitor metyrapone, nor the pharmacological blockade of noradrenergic receptors, combined with adrenalectomy, disrupted acquisition of the avoidance response. Thus, the combination of forebrain norepinephrine loss and low plasma corticosterone does not inevitably impair avoidance acquisition. Rather, the determining factor for such impairment seems to be the interval between surgery and testing. The impairment at 1 week following DNBL and adrenalectomy occurred only for rats tested during the dark phase of their light cycle. In addition, the DNBL abolished the effect of the light/dark cycle on posttraining plasma corticosterone. These results demonstrate the importance of the phase of the rat's diurnal rhythm on both the hormonal and the behavioral effects of altering the pituitary-adrenal axis and/or forebrain norepinephrine. Because adrenocorticotropin, corticosterone, and vasopressin all show diurnal patterns of release, it cannot be determined at this time which, if any, of these hormones is most important for the behavioral results reported here.