Paraventricular nucleus: a primary site mediating adrenergic stimulation of feeding and drinking

Central injection of norepinephrine (NE) has been found to elicit preprandial drinking and feeding responses in the satiated rat. In the present study, 35 different brain areas, in over 500 rats, were examined to localize the precise region of NE sensitivity. Essentially all sites outside the hypothalamus, as well as in the lateral portion of the hypothalamus, were relatively or totally unresponsive to NE. In the medial hypothalamic area, the paraventricular nucleus (PVN) was clearly distinguished as the most effective site for initiating both feeding and drinking with noradrenergic activation in the satiated animal. Sites greater than 0.5 mm rostral, caudal, dorsal, ventral or lateral to this nucleus yielded significantly smaller effects. In mildly hungry rats, NE was found to potentiate the ongoing feeding response, and anatomical analyses of this phenomenon showed the PVN to be most responsive, with a smaller but reliable potentiation occurring along the periventricular hypothalamus adjacent to the third ventricle. Norepinephrine injected into the lateral perifornical hypothalamic area actually produced a suppression of feeding in these hungry animals. These findings, together with results from other studies, converge on the medial PVN region as being a key link in the process of increased food and water consumption associated with increased noradrenergic activity.     

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.     

Sulpiride antagonizes the biphasic locomotor effects of quinpirole in weanling rats

Low doses of dopamine (DA) agonists such as the D₂ receptor subfamily agonist quinpirole are thought to stimulate DA autoreceptors selectively, thereby inhibiting locomotor activity. High doses of quinpirole initially suppress and later activate locomotion during a single test session; the activation is presumably due to stimulation of postsynaptic receptors. The aim of this study was to investigate whether pretreatment with a selective DA D₂ receptor antagonist, sulpiride, could block the putative autoreceptor-mediated inhibition at a lower dose than was required to block the postsynaptically mediated activation. Male and female 30-day-old rats were injected SC with one of eight doses of sulpiride (0.313–40 mg/kg) or the vehicle. Sixty minutes later, rats were injected SC with 0.2 mg/kg quinpirole or the vehicle. Five minutes after the second injection, rats were placed in automated activity monitors which recorded locomotor behavior for 60 min at 5-min intervals. Quinpirole at this dose first suppressed and later increased locomotor activity. Sulpiride pretreatment dose-dependently reversed both the early inhibition and later activation of quinpirole-induced locomotion. However, sulpiride did not block the quinpirole-induced early suppression at a lower dose than was required to block the later activation. Thus, there was no evidence that the locomotor suppression elicited by quinpirole is mediated by a more sensitive subset of DA receptors.     

In vivo release of newly synthesized catecholamines from the hypothalamus by amphetamine

Summary The posterior hypothalamus of cats immobilized with gallamine was superfused through a push-pull cannula with artificial cerebrospinal fluid. Addition of³H-tyrosine into the superfusing fluid led to synthesis of³H-catecholamines which were released spontaneously. Separation of the³H-catecholamines by column chromatography or their acetylation and separation by paper chromatography revealed that both³H-noradrenaline and³H-dopamine were released. In most experiments³H-noradrenaline represented about 10 to 25% of total³H-catecholamines. Superfusion of the hypothalamus with amphetamine (1×10^–5 M) enhanced the release of total³H-catecholamines, the release of³H-noradrenaline being relatively more enhanced than that of³H-dopamine. Determination of the readioactive compounds in the hypothalamus at the end of the experiments showed that total³H-catecholamines represented 3% of³H-tyrosine. About 15% of the total³H-catecholamines were due to³H-noradrenaline and 85% to³H-dopamine.     

Release of endogenous catecholamines from rat hypothalamus in vivo related to feeding and other behaviors

The release of endogenous noradrenaline (NA) and dopamine (DA) from various sites in the hypothalamus was determined in unanesthetized, freely moving rats by means of a push-pull perfusion technique in combination with a sensitive radiochemical assay. The perfusate was collected continuosly over 10-min periods for 4 to 8 hr. Patterns of feeding, drinking, grooming, and locomotor activity were recorded during the perfusion experiments. Release patterns and behavior recordings were analysed by tests of serial correlation. Although significant variations in catecholamine release over time were observed, they did not reflect a fixed autonomic periodicity. Release from the medial hypothalamus was measured in rats which had been deprived of food for 16 hr and were subsequently given free access to food. Before food presentation, mean NA release over 10-min periods was consistently higher than during satiety. Mean NA and DA release over 10-min periods before, during and after the occurence of feeding, drinking or grooming were calculated for the dorsomedial, perifornical, subfornical, and anterolateral hypothalamus of freely feeding rats. During feeding, NA (but not DA) release from the dorsomedial and perifornical areas was significantly elevated (40–50%) when compared with pre- or postfeeding values. An increase in catecholamine release was not observed during drinking or grooming. In addition, NA release from the anterolateral area correlated with locomotor activity. The enhancement of NA release from the perifornical area during feeding is considered to be specific as no change in release was observed even during the drinking vigorous response induced by angiotensin.     

Increase in dopamine release from the nucleus accumbens in response to feeding: a model to study interactions between drugs and naturally activated dopaminergic neurons in the rat brain

The aim of the present study was to investigate the interactions between the in vivo release of dopamine and certain drugs, during conditions of increased dopaminergic activity. Dopaminergic neurons in the nucleus accumbens were activated by feeding hungry rats.48–96 h after implantation of a microdialysis probe 30 min food ingestion by hungry rats induced an immediate eating response that was accompanied with a reproducible and long-lasting increase in extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC).The effect of various drugs (infused into the nucleus accumbens via the microdialysis probe), on the extracellular levels of dopamine and DOPAC were recorded, and the effect of eating was determined.Infusion of 5 mol/l nomifensine and 3.4 mmol/l calcium increased dopamine release respectively 5.4 and 2-fold but did not modify the eating related increase in dopamine and DOPAC release. Infusion (1 mol/l) as well as intraperitoneal administration (20 mg/kg) of sulpiride induced an increase in basal dopamine release to 220 and 195% of controls, respectively. Both routes of sulpiride pretreatment enhanced the eating related increase in extracellular dopamine and DOPAC.The results of the sulpiride experiments indicate that a behaviorally induced stimulation of dopamine release is modified by autoinhibition. Correspondence to: B. H. C. Westerink at the above address     

Catecholamines in discrete areas of the hypothalamus of obese and castrated male rats

Levels of norepinephrine (NE) and dopamine (DA) were measured in eight discrete regions of the hypothalamus in three groups of male rats; genetically obese (fafa), non-obese (FaFa) and castrated non-obese (FaFa). DA levels showed no significant differences among the groups in any of the regions. NE levels in the paraventricular nucleus (PVN) were significantly lower in the obese and castrated animals than in the normal animals. In the median eminence (ME), NE levels were significantly decreased for the castrated group. None of the other regions sampled showed significant differences in NE levels.     

The effects of amphetamine and scopolamine on adjunctive drinking and wheel-running in rats

Two groups of rats were exposed to a fixed-interval 90 s schedule of food reinforcement. One group had access to a drinking tube containing water and the second had access to a running wheel. Amphetamine (0.3–10.0 mg/kg) and scopolamine (0.1–3.0 mg/kg) were assessed for their effects on lever-pressing, adjunctive drinking and adjunctive wheel-running. Low to moderate doses of amphetamine increased overall rates of lever-pressing, whereas the highest dose decreased them. Scopolamine decreased overall lever-pressing rates in a dose-dependent manner. Both drugs changed the within-interval pattern of lever-pressing from one of increasing probability through the interval to almost constant probability throughout. Overall rates of adjunctive drinking and adjunctive wheel-running were decreased by amphetamine and scopolamine. Amphetamine failed to alter the within-interval patterns of either drinking or wheel-running in any substantial manner. The effect of scopolamine was to make the probabilities of each adjunctive behaviour more even through the interval. Although the two drugs had different actions, there was little difference in the way drinking and wheel-running were affected by each.     

Is the noradrenergic “feeding circuit” in hypothalamus really an olfactory system?

Since the act of feeding releases catecholamines from certain areas of the rat's hypothalamus, we have examined the possibility of a sensory component underlying this release. An individual diencephalic site in the unanesthetized rat was radiolabeled by microinjection of 1.0–2.0 μCi of ¹⁴C-NE, in a volume of 0.5–1.0 μ1, through a permanently implanted guide cannula. Then 30 min later, the labeled site was perfused by means of push-pull cannulae, with an osmotically balanced CSF solution at a rate of 25 μl/min. The interval of perfusion was 5 min with 10 min intervening. In the midpoint of a sequence of 7 perfusions, either the rat was allowed to consume food, or one of two odoriferous substances was placed beneath its cage floor, i.e., peanut butter or pyridine. During the presentation of either of the two olfactory stimuli to the animal, the efflux of ¹⁴C-NE was enhanced from the same circumscribed site of perfusion in which feeding augmented similarly the release of the ¹⁴C-NE isotope. An analysis of selected hypothalamic perfusates by TLC verified quantitatively the alteration in the profile of ¹⁴C-NE and its labeled metabolites. Our results thus support the view that the changes in the catecholamine release within the hypothalamus reflect synaptic activity of the sensory pathways which mediate the olfactory input to this diencephalic structure.     

Possible mechanism for the effect of anorexic agents on feeding and hoarding behaviour in rats

Amphetamine, fenfluramine, and chlorphentermine were tested for their effect on feeding and hoarding activity in rats, and the results interpreted according to a hypothalamic model for the regulation of motivated behaviour. All three compounds inhibited both feeding and hoarding, and the degree of inhibition was dose-dependent. Since feeding and hoarding are both influenced by activity in the lateral hypothalamus while feeding alone is modified by ventromedial hypothalamic activity, the result is consistent with a direct (inhibitory) action of the drugs on the lateral hypothalamus, rather than on the ventromedial region.     

Repeated injections of sulpiride into the medial prefrontal cortex induces sensitization to cocaine in rats

Rationale Recent studies have suggested that the medial prefrontal cortex (mPFC) plays an important role in the development of sensitization to cocaine. In particular, a recent report proposed that sensitization is associated with a decreased dopamine D₂ receptor function in the mPFC. The present study was designed to further examine the involvement of mPFC dopamine D₂ receptors in cocaine sensitization.Objectives The experiments described below sought to determine the effects of acute or repeated intra-mPFC injections of the dopamine D₂ antagonist sulpiride on subsequent motor-stimulant and nucleus accumbens dopamine responses to cocaine.Methods Rats received bilateral cannulae implants above the ventral mPFC for microinjections and above the nucleus accumbens for in vivo microdialysis. Initial studies examined the effects of intra-mPFC sulpiride pretreatment on the acute motor-stimulant and nucleus accumbens dopamine responses to cocaine. Follow-up studies determined the effects of repeated intra-mPFC sulpiride injections on subsequent behavioral and nucleus accumbens dopamine responses to a cocaine challenge.Results Intra-mPFC sulpiride enhanced the cocaine-induced increases in motor activity and dopamine overflow in the nucleus accumbens. Repeated intra-mPFC sulpiride induced behavioral and neurochemical cross-sensitization to cocaine.Conclusions The data support previous findings that sensitization is associated with a decrease in dopamine D₂ receptor function in the mPFC.     

Pulsatile release of catecholamines in the hypothalamus of conscious rats

Summary To investigate the patterns of catecholamine release in the brain, the hypothalamus of conscious, freely moving rats was superfused through a push-pull cannula with artificial cerebrospinal fluid and the catecholamines dopamine, noradrenaline and adrenaline were determined in the superfusate radioenzymatically. Superfusate was continuously collected in time periods of 20 min for at least 20h. Dopamine, noradrenaline and adrenaline release rates fluctuated according to an ultradian rhythm with a frequency of 1 cycle/92 min (dopamine and noradrenaline) or 99 min (adrenaline). Additionally, the three catecholamines were released according to an ultradian rhythm with the following frequencies: noradrenaline and adrenaline 1 cycle/ 12 h, dopamine 1 cycle/8 h. The release rates of dopamine and adrenaline were similar during light and dark periods, while the release rate of noradrenaline in the dark period was slightly lower than that during the light period. It is concluded that in the hypothalamus of the conscious rat the release rates of dopamine, noradrenaline and adrenaline fluctuate according to two ultradian rhythms with different frequencies.This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds zur Förderung der wissenschaftlichen ForschungParts of this work have been presented at the 29th Spring Meeting of the German Society of Pharmacology and Toxicology, 1988 and at the 12th Annual Meeting of the European Neuroscience Association, 1989Correspondence to H. Prast at the above address     

Post-session sulpiride infusions within the perifornical region of the lateral hypothalamus enhance consolidation of associative learning

Whilst neurons within the lateral hypothalamus are well known to be responsive to the presentation of previously learned associative stimuli, the consolidation of a Pavlovian association is thought to depend in large part upon other brain regions, including the amygdala. The present study addressed this assumption directly, by examining the effect of post-session infusions of sulpiride within the lateral hypothalamus upon the acquisition of a conditioned approach response in an appetitive differential conditioning task. Subjects were exposed to an initially neutral stimulus (CS⁺), which immediately preceded the availability of a 10% sucrose reward (US). A second, control stimulus (CS⁻) was also presented, but never in close temporal proximity to the US. The number and duration of alcove approaches were recorded. Immediately following each training session, subjects were infused bilaterally with sulpiride (0, 0.5, 5 μg) in the vicinity of the perifornical region of the lateral hypothalamus. Sulpiride dose-dependently enhanced the rate of acquisition of a conditioned approach response to presentation of the CS⁺, but was without affect upon approach behaviour during CS⁻ or US presentations. Thus, 0.5 μg sulpiride facilitated at an early stage (session 2 onwards) the number of alcove approaches to the CS⁺, while 5 μg sulpiride enhanced to a greater extent the duration of conditioned approach, particularly during later sessions. A subsequent locomotor test using 0.5 mg/kg d-amphetamine indicated that repeated infusions of the higher dose sulpiride (5 μg), but not the lower dose (0.5 μg), resulted in behavioural sensitisation to administration of the psychomotor stimulant. Acquisition of a novel conditioned instrumental response was not affected by previous exposure to sulpiride. These data suggest that dopamine-sensitive neurons within the lateral hypothalamus may play a significant role in the acquisition of appetitive Pavlovian associations. Received: 2 January 1998/Final version: 16 April 1998     

Intrahypothalamic and intrastriatal dopamine and norepinephrine injections in relation to motor hyperactivity in rats

High doses of dopamine (59 g) and norepinephrine (65 g) injected directly into the striatum and hypothalamus induced motor hyperactivity in rats. The motor activity recorded on the Animex for a period of 60 min after injection of 65 g of norepinephrine into the hypothalamus, showed a significant increase (p<0.005) in comparison with the controls. The increase in motor activity after dopamine (intrahypothalamic) and norepinephrine and dopamine (intrastriatal) was distinctly lower, although there was an initial large increase of motor activity after intrastriatally injected dopamine. Pre-treatment with reserpine or parachlorophenylalanine (intraperitoneal injection) to lower the serotonin level in the brain, followed by intracerebral injection of norepinephrine or dopamine failed to produce fighting or mounting behaviour.     

Noradrenergic feeding system in monkey hypothalamus is altered by localized perfusion of glucose,insulin, 2-DG and eating

Hypothalamic sites in the monkey were labelled by micro-injections of ³H-NE and successive push-pull perfusions were carried out at a rate of 25 μl/min. When the monkey was fed, ³H-NE within the perifornical region increased. When 2-deoxy-D- glucose (2-DG) was added to the perfusate, ³H-NE release was also enhanced, whereas insulin perfused at the same rate caused a delayed increase in catecholamine levels as reflected by increased radioactivity. Glucose supressed the release of ³H-NE, suggesting overall that the noradrenegic feeding system in the hypothalamus of the monkey is modulated by the regional level of glucose as well as the local concentration of insulin.     

Effects of stimulation of putative dopamine autoreceptors on electroencephalographic power spectrum in comparison with effects produced by blockade of postsynaptic dopamine receptors in rats

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D₂ blocker) or SCH 23390 (0.2 mg/kg i.p., D₁ blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D₁ or D₂ postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D₁ and D₂ receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.     

Effects of manipulations of peripheral serotonin on feeding and drinking in the rat

Rats injected peripherally with serotonin showed a dose dependent increase in water intake which was maximal at 2-hours. This effect, along with a dose dependent anorexia was also observed in animals eighteen hour food deprived overnight. In rats maintained on a 6-hour feeding schedule there was a significant anorectic effect of 5-HT that could be reversed by pretreatment with methysergide but not metergoline. However the hyperdipsia was not apparent in these animals due to prandial drinking by control animals. The optimal dose of 5-HT for producing an anorexic response produced only a transient conditioned taste aversion to a novel solution in a sensitive 2-bottle choice test. On the other hand a high dose of 5-HT, and 3 mg/kg fenfluramine produced sustained aversions. These results are discussed with regard to a possible peripheral role for 5-HT in the control of food intake.     

Relationship of adrenergic and electrical brain stimulation induced feeding responses

Electrical and adrenergic brain stimulation can induce eating in satiated animals. This report explores the interrelationship of brain feeding systems mediating eating in response to norepinephrine and electrical stimulation of the hypothalamus in rats. It was found that simultaneous adrenergic and electrical brain stimulation resulted in a significant increase in food intake as compared to each stimulation condition alone. Furthermore, pharmacological blockade of the alpha-adrenergic receptors in the hypothalamus attenuated feeding in response to adrenergic, but not electrical brain stimulation. Results are interpreted to suggest that these feeding systems are independent at the level of the diencephalon. The role of the vagus nerve as an efferent link through which these brain systems may influence feeding behavior is discussed.     

Automatic measurement of drinking in rats: Effects of hypophysectomy

A new apparatus for the continuous measurement of drinking in the rats was assembled. The principle of the device is as follows: a cartridge which makes water drops (0.05 ml) is inserted between a water tank and a drinking spout. When a rat drinks, water falls into the cartridge drop by drop and the number of drops is electrically counted. The total count of drops per day, as well as counts at definite intervals, can be automatically printed out. To test apparatus reliability and applicability, drinking behavior in hypophysectomized rats was investigated in the light and dark phases, alternating every 12 hr. Activity and feeding in these phases were also observed. In the sham-operated rats, the total daily water intake was 30–40 ml, which corresponded to 10–15% of the body weight, and 85–95% of the total daily drinking counts were recorded in the dark phase. In the hypophysectomized rats, a large amount of water was drunk immediately after the operation. However, the high rate of drinking rapidly returned to near the normal level within a few days. Drinking in the dark phase decreased to about 75% of the total daily, but synchronization with the light-dark cycle was still maintained. The daily patterns of activity and eating ran nearly parallel with the drinking behavior. These results indicate that our drinkometer could have extensive applications within many fields of research.     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.