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.     

Stimulation and destruction of the locus coeruleus: opposite effects on 3-methoxy-4-hydroxyphenylglycol sulfate levels in the rat cerebral cortex

The effect of electrical stimulation or electrothermic destruction of the locus coeruleus on cortical (including hippocampus) levels of 3-methoxy-4-hydroxyphenylglycol sulfate (MHPG-sulfate) was studied in rats. The locus coeruleus, which consists of norepinephrine (NE-containing nerve cell bodies, projects to the cerebral cortex and the hippocampus. 10 days after unilateral destruction of the locus coeruleus NE was decreased 78% and MHPG-sulfate, a central NE metabolite, was lowered by 69% in these areas. No alterations in levels of norepinephrine or MHPG-sulfate were observed on the contralateral side.Stimulation of the locus coeruleus induced a frequency-dependent increase in MHPG-sulfate. The most effective frequency was 20 pulses per sec. After 15 min of stimulation the MHPG-sulfate had reached a new steady state level of about 80% over the contralateral side.These findings indicate that MHPG-sulfate levels are dependent upon the integrity of NE neurons and that the level of rate of formation of MHPG-sulfate in the brain can be a reflection of the physiological activity of these neurons.     

Effects of central norepinephrine depletion on the initiation and maintenance of maternal behavior in the rat

The catecholaminergic neurotoxin, 6-hydroxydopamine (6-OHDA), was used to test the hypothesis that increased transmission across selected noradrenergic synapses is involved in the initiation of maternal behavior. Specifically, 6-OHDA was infused intraventricularly either two days before parturition or four days after parturition. Control animals were infused with the vehicle alone. Among prepartum animals, NE depletion of more than 30 percent of control levels interfered with the initiation of maternal behavior. Among lactating animals, similar degrees of NE depletion had no significant effect on the maintenance of maternal behavior. Thus, NE appears to be involved in the initiation of maternal behavior, but not in the maintenance of the behavior once that behavior is established.     

Chronic norepinephrine injection into the hypothalamic paraventricular nucleus produces hyperphagia and increased body weight in the rat

A single injection of norepinephrine (NE) into the paraventricular nucleus (PVN) is known to elicit a feeding response in the satiated rat. Through repeated NE injections, the present study set out to determine whether chronic noradrenergic stimulation of the PVN is effective in producing changes in total daily food intake, as well as in body weight gain. The results indicate that repeated injections of NE (20 nmoles/injection given 4 times/day) cause a stimulation of eating with each injection and consequently produce a significant increase in total daily food intake. This stimulatory effect on feeding behavior occurs under food-restricted conditions, where food is available only at times (in the daytime) when NE is injected, and also under food-satiated conditions were food is available essentially ad lib. This hyperphagia results in a gradual increase in body weight which develops over the course of a 5-day sequence of repeated NE injections. There is some evidence to suggest that the overeating produced by NE throughout the day may be attributed specifically to an increase in meal size rather than to a change in meal frequency. This evidence suggests that medial hypothalamic NE, particularly within the PVN, may play a role in long-term feeding behavior and body weight regulation.     

Effects of carbamazepine on noradrenergic mechanisms in affectively ill patients

Noradrenergic mechanisms have been postulated to account for the anticonvulsant and psychotropic effects of carbamazepine. In order to assess this possibility in man, cerebrospinal fluid (CSF) was obtained from affectively ill patients before and during treatment with carbamazepine (average duration 29 days) at doses averaging 860 mg/day, achieving blood levels of 8.86 g/ml. Neither plasma nor CSF norepinephrine (NE) nor CSF 3-methoxy-4-hydroxyphenylgycol (MHPG) was significantly altered by carbamazepine. Baseline medication-free values in 21 depressed patients were not predictive of the degree of subsequent clinical antidepressant response. CSF NE decreased in four manic patients treated with carbamazepine. The many effects of carbamazepine on noradrenergic mechanisms in animals are discussed in relationship to these first studies of carbamazepine in man.     

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serotonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after alpha-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma MHPG and AMDP depression relations,evolution and drug effect in a follow-up study of depressed patients

Plasma MHPG levels and AMDP rating score were measured in depressed patients before treatment, and a follow-up study was performed during the next 3 months of drug therapy to detect possible relationships between the parameters. Before treatment, MHPG levels were moderately lower in depressed than in age- and sex-matched normal subjects. Bipolar depressed patients presented the lowest values. In the three diagnostic groups (DSM-III), antidepressant treatment resulted in a significant decrease of mean levels in unipolar and dysthymic depressed, but not in bipolar depressed patients. When the type of antidepressant was considered, imipramine (IMI)- or desipramine (DMI)-treated patients, but not fluvoxamine (FLU)-treated, also decreased their mean values of MHPG, with minor difference between improved and non-improved patients. However, when patients were grouped according to their pattern groups (low (LL), high (HL), or normal (NL) baseline MHPG levels), interesting information emerged: improvement of clinical state of patient (i.e. 60 per cent of AMDP baseline reduction) resulted in ‘normalization’ of erratic values (HL and NL) whatever the treatment, while in non-improved patients such evolution was not observed. In the latter group, change in MHPG levels was only drug-related (decrease in IMI–DMI-treated and no change in FLU-treated values). Results suggest that mechanisms of buffering NA activity were lost in endogenous depression and restored in patients responding to treatment.     

Phenylethylamine, norepinephrine and mounting behavior in the male rat

Phenylethylamine, which induces mounting behavior in naive adult male rats when administered chronically, was shown to selectively raise brain norepinephrine levels in the medial preoptic nucleus, a region known to be implicated in the regulation of sexual behaviors. It is suggested that the catecholamine alteration is a secondary response to the primary influence of phenylethylamine on the preoptic nucleus.     

Further studies on the effect of p-hydroxynorephedrine (PONE) on norepinephrine metabolism in the rat brain

Rats pretreated i.c. with 10 μg of PONE were administered d-amphetamine and the effect of the combination of these drug treatments on behavior and the formation of ³H-norepinephrine from ³H-tyrosine was measured. PONE pretreatment blocked the d-amphetamine-induced increase in exploratory activity but enhanced the production of d-amphetamine-induced stereotyped behaviors. PONE pretreatment caused a 43% decrease in brain norepinephrine (NE) levels and this effect was potentiated by d-amphetamine. The in vivo formation of ³H-NE was decreased in animals administered d-amphetamine alone or PONE + d-amphetamine. However, these groups differed in the following respects: (a) d-amphetamine decreased the rate of disappearance of ³H-NE formed from ³H-tyrosine while PONE + d-amphetamine enhanced disappearance; (b) d-amphetamine decreased the formation of ³H-3-methoxy-4-hydroxyphenylglycol (MOPEG) while PONE + d-amphetamine enhanced ³H-MOPEG formation; (c) d-amphetamine enhanced ³H-NE release but decreased ³H-NE synthesis in a tissue slice preparation but PONE + d-amphetamine only enhanced ³H-NE release. The relevance of these findings to the effect of PONE pretreatment on d-amphetamine-induced behavior is discussed.     

Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: effects on urinary catecholamine metabolites and behavior

The purpose of this study was to determine: 1) whether 6-hydroxydopamine (6-OHDA), previously shown to deplete brain catecholamines (CA) in rodents, depletes brain CA in rhesus monkeys; 2) whether depletion of brain CA produces changes in behavior; and, 3) whether urinary output of 3-methoxy-4-hydroxyphenylglycol (MHPG) reflects brain norepinephrine (NE) depletions.Repeated intracerebroventricular (ICV) injection of 6-OHDA (N=20; 15.5–73.3 mg/subject) produced chronic changes in social behavior and, at higher dosages, reduced output of urinary MHPG. However, 4 weeks after the last ICV 6-OHDA injection, urinary MHPG excretion returned to baseline values and whole brain CA content was not reliably different from control.A single treatment with 6-OHDA microinjected into the substantia nigra (SN) (N=12; 120–240 g/subject) produced chronic whole brain depletions of brain CA without depleting serotonin. Reductions in brain CA were associated with a specific set of motor behaviors, aphagia, and adipsia. SN 6-OHDA produced greater brain NE depletions than ICV 6-OHDA, but urinary MHPG output was not reduced. SN 6-OHDA treated subjects showed chronic changes in social behavior and were more sensitive to the operant response rate decreasing effects of alpha-methyl-para-tyrosine (AMPT) than control subjects. Subjects with the largest depletions of brain dopamine (DA) (>90%) were hypokinetic, rigid, and had a distal limb tremor.These results show that SN but not ICV injection of 6-OHDA can deplete brain CA in the rhesus monkey. The most prominent behavioral changes were characterized bydisturbances in motor function. Urinary MPHG output does not reflect depletions of brain NE in this species.     

Methyl bromide alters catecholamine and metabolite concentrations in rat brain

The effects of inhalation exposure of rats methyl bromide (MB) on dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA) concentrations of various brain regions (striatum, hypothalamus, frontal cortex, midbrain, and medulla oblongata) were investigated. Rats received a single 8 hr exposure to MB, and amines and metabolites were separated by a reverse-phase HPLC, and were quantified via native fluorescence. An exposure to 100 ppm MB decreased tissue levels of DA and NE in all brain areas at 0 or 2 hr following exposure. HVA and MHPG contents were significantly increased in almost all brain regions. In a second study, rats were exposed to four concentrations of MB ranging from 31-250 ppm, and monoamine and metabolite levels in brain regions measured immediately after the exposure. Again, there were dose-dependent decreases of DA and NE, and increases in HVA and MHPG. Less clear changes in 5 HT and 5HIAA contents were observed. These data suggest that alterations of catecholamine metabolism may be a factor in MB-induced neurotoxicity.     

DSP-4-induced depletion of brain norepinephrine produces opposite effects on exploratory behavior 3 and 14 days after treatment

Exploratory behavior of a complex novel environment was examined 3 and 14 days following treatment with the noradrenergic-selective neurotoxin, DSP-4. This toxin significantly decreased norepinephrine concentrations in neocortex and hippocampus but not hypothalamus. DSP-4 significantly increased exploratory behavior in animals tested 3 days after treatment. In contrast, exploratory behavior was decreased in animals tested 14 days after treatment. The effect of DSP-4 at 3 days is similar to treatments that act to inhibit noradrenergic function such as administration of the ₁-antagonist, prazosin, or the ₂-agonist, clonidine. The effect of DSP-4 at 14 days resembles that observed following treatment with the ₁-agonist, phenylephrine, or the ₂-antagonist, idazoxan. These data provide additional support for a role of noradrenergic systems in exploratory behavior. The simplest explanation for the time dependent effects of DSP-4 on exploratory behavior is the occurrence of the slow development of a supersensitivity of cerebral systems affected by norepinephrine.     

Comparison of the effect of prostaglandin E1 and norepinephrine injected into the brain on ingestive behavior in the rat

Norepinephrine hydrochloride (NE) in doses of either 5 or 25 μg and prostaglandin E₁ (PGE₁) in doses of either 5 or 50 ng were made directly into the substance of the hypothalamus as well as other limbic structures of the unrestrained, unanesthetized rat. The animals had free access to food and water at all times. NE injected into the perifornical area of the hypothalamus, the hippocampus and the amygdala elicited vigorous eating. PGE₁ did not produce eating which differed from that observed following control injections of a physiological control solution. Drinking was not observed following injections of either NE or PGE₁ at the dose used. These data indicate that PGE₁ does not play a direct role in the hypothalamic and limbic control of ingestive behavior.     

Initiation of maternal behavior in the rat: possible involvement of limbic norepinephrine

The dorsal norepinephrine (NE) fiber system was manipulated in pregnant female rats. Brainstem lesions of the dorsal bundle, depleting NE in cortex and hippocampus, resulted in deficits in maternal-behavior onset in primiparous rats. Similarly, fornix-bundle transections, depleting only hippocampal NE, were associated with an absence of pup care. Hypothalamic NE levels, as well as dopamine and serotonin concentrations in cortex, hippocampus and hypothalamus, were not significantly affected by these manipulations. The data are discussed in terms of behavioral specificity, possible hormonal involvement and interactions with diencephalic mechanisms controlling the onset of maternal behavior in the female rat.     

Time-dependent changes in hypothalamic dopamine metabolism during feeding in the rat

The accumulation of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), but not the serotonin metabolite 5-hydroxyindoleacetic acid, in the hypothalamus is increased in rats during the second, third and fourth hours of a four hour period of access to food following a 20 hour period of food deprivation. This metabolic change does not correlate with duration of access to food or with amount of food consumed. These results suggest that increased hypothalamic dopamine metabolism during feeding is not related in any simple way to either the onset or termination of feeding.     

Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal

Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 μg/μl) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.     

Effect of theophylline on monoamine metabolism in the rat brain

The effect of theophylline on brain monoamine metabolism was studied in rats. Single doses of theophylline caused a striking and dose-related increase in the levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO₄) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. The level of brain homovanillic acid was only slightly affected. No appreciable change occurred, however, in the levels of brain norepinephrine, serotonin and dopamine. The increased level of brain MOPEG-SO₄ or 5-HIAA after theophylline does not appear to result from its interference with the transport system for the acids in the brain since the rate of decline of the acid levels following pargyline was not affected. Under the conditions of brain monoamine oxidase inhibition, theophylline enhanced the increase in brain normetanephrine level without causing any change in 3-methoxytyramine level. The enhancement of brain normetanephrine level by theophylline became more pronounced when rats were pretreated with imipramine in addition to pargyline.These results suggest that, in the brain, theophylline may cause a release of serotonin leading to its increased turnover. The results also confirm the previous conclusion that the methylxanthine causes a release of norepinephrine and a concomitant increase in its turnover in the brain.     

The effects of lithium salts on the turnover and metabolism of norepinephrine in rat brain

Summary Acute or chronic administration of lithium chloride increased the disappearance of intracisternally administered norepinephrine-H³ from rat brain. Tritiated deaminated catechol metabolites and free deaminated-O-methylated metabolites represented a larger fraction of the radioactivity present in the brain in animals treated with lithium chloride than in control animals. Statistically significant changes in the uptake of norepinephrine-H³ into brain were not observed after the chronic administration of lithium chloride. The findings suggest that chronic, as well as acute administration of lithium salts may increase norepinephrine turnover in brain and possibly increase the deamination of this amine.This work was supported, in part, by United States Public Health Service General Research Grant 5 S01 Fr-05555, awarded to the Massachusetts Mental Health Research Corporation.     

Long-term behavioural and biochemical effects following prolonged treatment with a neuroleptic drug (flupenthixol) in rats

The effects of long-term treatment (36 weeks) with a neuroleptic drug (flupenthixol) were investigated behaviourally and biochemically in rats. Sixteen rats were trained on a DRL (differential reinforcement of low rate) 15-s schedule until stable responding was obtained. During the following 36 weeks 9 rats were injected weekly with flupenthixol dissolved in Viscoleo® [4 mg/kg (i.m.)] and seven rats received Viscoleo® alone. During this perod the animals were not run on the DRL schedule. Retesting on DRL 7 weeks after the last drug injection yielded highly significant differences between the flupenthixol-treated animals and the controls. Thorough neurological examinations of the animals just preceding the retesting period also revealed some deficits in the flupenthixol-treated animals. At sacrifice, 14–18 weeks after the last drug injection, levels of homovanillic acid (HVA) were measured in the corpus striatum and total 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rest of the forebrain. The results indicate a nonsignificant increase of 25% in the dopamine metabolite HVA, while the noradrenergic metabolite MOPEG was significantly decreased by 14% in experimental animals. The possibility of persistent functional and biochemical effects produced by prolonged treatment with a neuroleptic drug is highlighted in the results presented here.     

Cafeteria behavior in the rat after hypothalamic cholinergic and adrenergic stimulation.

Norepinephrine, carbachol, or placebo was micro-injected into the perifornical region of the rat hypothalamus, via stereotaxically implanted cannulas. Ingestive behavior was observed in the hour after injection in a cafeteria situation in which water, milk, mash, powdered food, and lab chow were all freely available. After adrenergic stimulation, animals ingested significant amounts of mash only; after cholinergic stimulation, animals ingested significant amounts of water and milk, but water was significantly preferred to milk. These findings are seen as providing further support for the behavioral specificity of direct chemical stimulation of the brain, and as casting serious doubts on the interpretation of milk-ingestion as eating behavior.