Anterolateral Hypothalamus Research Articles

Deletion of the STOP gene, a microtubule stabilizing factor, leads only to discrete cerebral metabolic changes in mice

In mice, deletion of the STOP protein leads to subtle anatomic changes and induces depleted synaptic vesicle pools, impaired synaptic plasticity, hyperdopaminergy, and major behavioral disorders alleviated by neuroleptics, hence leading to a schizophrenic-like phenotype. In this study, we applied the quantitative autoradiographic [(14)C]2-deoxyglucose technique to study to what extent the basal rate of cerebral glucose utilization in STOP-knockout (STOP-KO) mice occurs in regions where metabolic changes have been reported in schizophrenic patients. Studies were performed on wild-type, heterozygous, and homozygous STOP-KO mice (7-8 per group). Mice were implanted with femoral artery and vein catheters, and cerebral glucose utilization was quantified over 45 min. Compared with that in wild-type mice, glucose utilization in STOP-KO mice was significantly increased in the olfactory cortex, ventromedial and anterolateral hypothalamus, ventral tegmental area, and substantia nigra pars compacta. Nonsignificant increases, ranging between 9% and 19%, were recorded in the whole auditory system, CA1 pyramidal cell layer, and dorsal raphe. Glucose utilization was also significantly increased in heterozygous mice compared with that in wild-type mice in olfactory cortex. These data might reflect hyperdopaminergic activity, olfactory deficits, and sleep disturbances in STOP-KO mice that have also been reported in schizophrenic patients.

Differential distribution of hypocretin (orexin) and melanin‐concentrating hormone in the goldfish brain

The orexigenic peptides hypocretin (orexin) and melanin-concentrating hormone (MCH) are involved in the control of food intake and in other homeostatic functions including sleep and arousal. In this article we study the distribution of these peptides in the brain of the goldfish (Carassius auratus), focusing on those regions particularly related to feeding, sleep, and arousal. Although the general distribution of these peptides in goldfish shows many similarities to those described previously in other species, we observed some noteworthy differences. As in other vertebrates, the peptidergic somata lie in the anterolateral hypothalamus. In goldfish, both hypocretin and MCH immunoreactive cell bodies project fibers to the ventral telencephalon, thalamus, and hypothalamus. At mesencephalic levels fibers reach the deep layers of the optic tectum and also course sparsely through the mesencephalic tegmentum. In contrast to the strong innervation of locus coeruleus and raphe in mammal, the MCH and hypocretin systems in goldfish barely innervate these aminergic populations related to the regulation of sleep and arousal. MCH, but not hypocretin, immunoreactive fibers terminate substantially in the sensory layer of the vagal gustatory lobe of goldfish, while both peptidergic systems distribute to the primary visceral sensory areas of the medulla and pons. The strong involvement of these peptidergic systems with the hypothalamus and general visceral nuclei, but not with locus coeruleus or raphe nuclei support the view that these peptides originally played a role in regulation of energy balance and evolved secondarily to influence sleep-wakefulness systems in amniote vertebrates.

The effect of blocking of medial raphe nucleus Ca+2-channels on pain in male rats using formalin test

Midbrain periaqueductal gray mater area (PAG) receives some afferents from anterolateral system, frontal cortex, and hypothalamus that inhibit pain through its descending pathway that synapses medial raphe nuclus (mrph) and finally terminates on spinal cord enkephalinergic interneurons in layers II and III. In the present study, the role of Ca+2–channels located on medial raphe nucleus neurons was studied. For this purpose, thirty male NMRI rats weighting 185-240 g were used and a stainless steel guide cannula (0.7 mm in diameter) was implanted into mrph nucleus under stereotaxic surgery (AP = -7.8, ML = 0, DV = 8). Then, one microliter of deltiazem(0.1 mg/kg) was injected into mrph. Five minutes after injection, the pain was evaluated using formalin test (50 µl of 2.5% formalin solution was injected into hind paw, s.c.). Every 15 seconds of each 5-minute blocks was scored by 0-3 scores. Sham- treated animals received the same volume of ACSF into mrph nucleus. These results show that intra mrph nucleus administration of diltiazem could not significantly change pain threshold in male rats.

Olfactory projections to the hypothalamus

Electrophysiological recording, together with anterograde and retrograde axonal tracers, was used to provide a comprehensive description of the origin and distribution of the olfactory input to the lateral hypothalamus. This input was much more substantial to the caudal part of the hypothalamus than to the rostral part and originates from several different areas of the olfactory cortex. Positive responses to electrical stimulation of the olfactory bulb were found consistently in the postero-lateral hypothalamus, but only occasionally at more rostral levels. In agreement with this, injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) in the posterior half of the lateral hypothalamus labeled cells in four cortical areas that receive input from the olfactory bulb: the anterior olfactory nucleus, the piriform cortex (in the deepest layer or ventral endopiriform nucleus), the olfactory tubercle (in the deep polymorphic layer), and the anterior cortical nucleus of the amygdala. Injections of WGA-HRP in the anterolateral hypothalamus labeled cells only in the anterior cortical nucleus of the amygdala. Anterograde axonal tracing confirmed these projections. Injections of 3H-leucine in the anterior olfactory nucleus, the piriform cortex, and the olfactory tubercle produced axonal label that was light and confined to the medial forebrain bundle in the rostral hypothalamus but was more substantial and extended throughout the lateral hypothalamic area caudally. Injections in the anterior cortical amygdaloid nucleus labeled axons in the anterior hypothalamus and in the premammillary nuclei as well as in the posterolateral hypothalamic area. In addition, a projection was demonstrated to the nuclei gemini from the polymorphic zone deep to the olfactory tubercle. Injections of two fluorescent retrograde tracers into the mediodorsal nucleus of the thalamus and the posterolateral hypothalamus showed that cells projecting to both diencephalic sites were intermingled in all of the olfactory cortical areas except the anterior olfactory nucleus, where cells were labeled only from the hypothalamus. In the deep layer of the piriform cortex and in the anterior cortical amygdaloid nucleus cells were also double labeled, indicating that they send collateral axons to both parts of the diencephalon.

On the distribution and morpho-functional characteristics of 5-HT-immunoreactive cells in the hypothalamus of fetuses and neonatal rats

This study attempted to visualize serotonin (5-HT)-immunoreactive (IR) neurons in the hypothalamus of intact fetuses (E18) and neonatal rats (P9) as well as after their pretreatment with some drugs interfering with the 5-HT metabolism and uptake in the serotoninergic neurons ( l-tryptophan, pargyline, 5-hydroxytryptophan, fluoxetine). The 5-HT-IR cells were not observed in the hypothalamus of normal, untreated fetuses and neonatal rats. However, two large accumulations of 5-HT-IR neurons appeared in the anterolateral hypothalamus and in the dorsomedial nucleus after the subsequent injections of the monoamine oxidase inhibitor, pargyline, and the amino acid precursor of the 5-HT synthesis, l-tryptophan. A significantly less intensive reaction was observed after injections either of the second precursor of the 5-HT synthesis, 5-hydroxytryptophan instead of l-tryptophan, or pargyline only. Immunostaining, provoked by the pargyline and l-tryptophan pretreatment, was completely blocked by the injection of the specific 5-HT uptake inhibitor, fluoxetine. It means that the 5-HT immunostaining of the hypothalamic neurons may be accounted for by their capacity to take up specifically 5-HT from the environment rather than by its intraneuronal synthesis from l-tryptophan. Nevertheless, the 5-HT synthesis from 5-hydroxytryptophan in these cells cannot be excluded. The uptake of extracellular 5-HT into catecholaminergic neurons can be excluded as nomifensine, the specific inhibitor of the uptake to these neurons, did not modify the immunostaining.

Antagonization of the behavioral activation produced by direct stimulation of forebrain dopamine receptors caused by intraaccumbens injections of neurotensin.

A number of studies have shown that intracisternal, intracerebroventricular, or direct administration of neurotensin (NT) into the nucleus accumbens (ACC) can antagonize the arousal and excitement produced by activation of the mesolimbic dopamine (DA) system of rats. This study investigated where NT acts relative to DA neurons to exert this antagonistic effect. In this study we selectively removed the majority of limbic forebrain DA terminals by bilateral administration of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus of desipramine-pretreated rats. The 6-OHDA-treated rats subsequently developed DA receptor supersensitivity, as evidenced by behavioral supersensitivity to L-DOPA. The L-DOPA dose employed was subthreshold for behavioral excitation in control rats. The behavioral excitation to L-DOPA in 6-OHDA-treated rats consisted of increases in sniffing and increases in locomotion and/or rearing, along with decreases in resting and sleep. Following bilateral intra-ACC injections of NT, L-DOPA-induced sniffing, rearing, and locomotion decreased significantly, and resting and sleep increased significantly. These data suggest that intra-ACC NT, acting in or proximal to the ACC, can antagonize the behavioral effects of limbic DA stimulation and that this antagonism is postsynaptic to DA neurons.

ChemInform Abstract: Drug Design via Pharmacophore Identification. Dopaminergic Activity of 3H‐ Benz[e]indol‐8‐amines and Their Mode of Interaction with the Dopamine Receptor.

AbstractAusgehend von den Aminotetralinen (II) werden gemäß Schema in einer vielstu?‐ gen Reaktionsfolge die im Titel genannten Verbindungen (VIII) synthetisiert.

Troponoids. 7. Chemistry and dopamine agonist activity of ciladopa and related aralkyltroponylpiperazines.

A series of N-aralkyltroponylpiperazine derivatives were synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine (DA) pathway and to suppress elevated serum prolactin levels. The compounds were compared to bromocriptine. Some of the more potent analogues were also assayed for their binding affinity to dopamine (DA) and alpha 1-adrenergic receptors. The results established that the potency of some of the compounds were comparable or superior to that of bromocriptine indicated that potent dopaminergic activity was dependent on the presence of both a substituted phenyl and a troponylpiperazine moiety, and confirmed that the dopaminergic activity depends on relative and absolute stereochemistry.

Comparative effects of infusions of 6-hydroxydopamine into nucleus accumbens and anterolateral hypothalamus induced by 6-hydroxydopamine on the response to dopamine agonists, body weight, locomotor activity and measures of exploration in the rat

Groups of rats received infusions of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens or anterolateral hypothalamus with 6-hydroxydopamine (6-OHDA), or sham operations. Body weight was monitored for 28 days after the infusion, after which rats were first tested in an exploration choice-box and then underwent a series of pharmacological challenges. At this time after the operation, rats which had received 6-OHDA in the nucleus accumbens showed neither loss of body weight, deficit in exploration, nor hypokinesia, but sustained an 80% reduction in dopamine levels in the nucleus accumbens. Locomotion was decreased in response to 1.5 mg/kg (i.p.) of d-amphetamine but increased following 0.1 mg/kg (s.c.) of apomorphine; stereotyped responses to larger doses were unaltered. By contrast, rats which had received 6-OHDA in the anterolateral hypothalamus lesions lost substantial amounts of body weight and were hypoactive. Although both locomotor and stereotypy responses to d-amphetamine were abolished, these responses were enhanced in response to apomorphine. Consistent with this, regional assay using high pressure liquid chromatography (HPLC) snowed profound loss of dopamine in the caudate-putamen as well as in the nucleus accumbens and frontal cortex. It seems unlikely that the reductions in exploration previously reported after lesions of the mesolimbicocortical dopamine system at the level of anterolateral hypothalamus induced by 6-OHDA are either behaviourally specific or result solely from depletion of dopamine with the nucleus accumbens and frontal cortex.

ChemInform Abstract: TROPONOIDS. 6. TROPONYLPIPERAZINES: A NEW CLASS OF DOPAMINE AGONISTS

AbstractTropone wie (VII)‐(IX) werden synthetisiert und an Ratten auf dopaminergische Aktivität untersucht.

Troponoids. 6. Troponylpiperazines: a new class of dopamine agonists.

A series of alkyltroponylpiperazine derivatives was synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine pathway. The compounds were compared to bromocriptine. The results indicate that dopaminergic activity is very sensitive to small changes in the troponylpiperazine moiety.

Lateral hypothalamic mediation of midbrain catecholaminergic influences on preovulatory surges of serum gonadotropin and prolactin in female rats.

To investigate the involvement of the midbrain ascending pathways in the control of ovulation, bilateral coronal transections were produced at three rostro-caudal levels in the lateral hypothalamus as well as in the lateral forebrain on the day of proestrus. Although lateral forebrain transections failed to block spontaneous ovulation, transections in both the anterolateral hypothalamus (ALH) and the midlateral hypothalamus blocked ovulation and the proestrous surges of serum LH, FSH, and PRL. When electrochemical stimulation was applied to the diagonal band of Broca, ovulation could be induced in animals with ALH transections. Moreover, the effects of intraventricular saline, norepinephrine (NE; 40 microgram), or dopamine (40 microgram) on the induction of preovulatory surges of serum gonadotropin and PRL were examined in proestrous rats with ALH transections. Ovulation was restored by the intraventricular injection of NE, but not of dopamine. In ALH-transected animals which ovulated in response to intraventricular NE, serum concentrations of LH, FSH, and PRL were higher than those of ALH-transected animals injected with saline. These results suggest that the lateral hypothalamus plays an important role in the control of preovulatory surges of serum gonadotropin and PRL by mediating the midbrain catecholaminergic innervation of the preoptic-hypothalamic area.

Relationships between selective denervation of dopamine terminal fields in the anterior forebrain and behavioral responses to amphetamine and apomorphine

To investigate the relationship between denervation of dopamine (DA) terminal fields in the anterior forebrain and the behavioral responses to amphetamine (1.5 mg/kg) and apomorphine (1 mg/kg), we injected 6-hydroxydopamine (6-OHDA) bilaterally into the anterolateral hypothalamus (ALH) or into specific mesolimbic and anterior striatal terminal fields after pretreatment with desmethylimipramine to protect noradrenergic axons and terminals from 6-OHDA toxicity. After drug testing was completed, the extent of denervation was determined by fluorescent histochemical analysis. When nearly all of the mesolimbicocortical and anteroventral striatal DA terminal fields were denervated by bilateral ALH 6-OHDA, the locomotor response to amphetamine was abolished, and the locomotor and stereotyped sniffing responses to apomorphine were increased. When fewer DA terminal fields were denervated, different results were obtained: the locomotor response to amphetamine decreased or did not change; stereotyped sniffing elicited by apomorphine did not increase or sniffing was replaced by stereotyped licking and biting. The results suggest a mass action relationship between DA terminal fields in the anterior forebrain and the locomotor response to amphetamine. The relationship between the same DA lesions and responses to apomorphine appears to be more complex.

Supersensitivity to apomorphine in experimentally induced hypokinesia and drug-induced modifications of the apomorphine response.

The development and degree of supersensitivity to the locomotor stimulant effect of apomorphine were studied in rats which had been rendered hypokinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus. Up to 2 days after surgery the effect of apomorphine was comparable in lesioned and normal rats, indicating that dopaminergic supersensitivity did not develop over this short period. As the duration between the 6-hydroxydopamine injections and time of testing with apomorphine increased, the animals became progressively more sensitive to the stimulant effects of apomorphine. Pretreatment with butaclamol reduced the effect of apomorphine in a dose-dependent manner. A high dose of clozapine also antagonized the effect of apomorphine, but a low dose potentiated it. No inhibition was observed following administration of the alpha-adrenergic antagonist, phenoxybenzamine, or the beta-adrenergic antagonist, propranolol. The 5HT antagonist methysergide and the anticholinergic drug, scopolamine potentiated the effects of apomorphine.l These studies suggest that the apomorphine-induced ambulation in hypokinetic rats is primarily mediated through dopaminergic mechanisms but both serotonergic and cholinergic mechanisms exert modulating influences.

Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats

Rats explore a novel open field or novel object less after denervation of mesolimbicocortical dopaminergic terminal fields produced by bilateral 6-hydroxydopamine (6-OHDA) microinjections into the anterolateral hypothalamus after pretreatment with desmethylimipramine (DMI). These behavioral deficits were correlated with complete or nearly complete loss of fluorescent dopaminergic (DA) terminals in the nucleus accumbens, olfactory tubercle, dorsal bed nucleus of the stria terminalis, lateral septal nucleus and the deep layers of the frontal and piriform cortices. There were also fewer A10, medial A9, and A8 DA fluorescent cells after the 6-OHDA-DMI injections; this suggests retrograde degeneration of the cells of origin of the mesolimbicocortical DA system. When the DMI pretreatment was omitted, identical bilateral 6-OHDA microinjections also produced severe loss of norepinephrine (NE) fibers in the neocortex, hippocampus, lateral hypothalamus and ventral bed nucleus of the stria terminalis. The addition of this noradrenergic damage did not change the exploratory deficits observed after mesolimbicocortical DA denervation alone. Systemic administration of the DA agonist apomorphine, but not the adrenergic agonist clonidine, to the 6-OHDA-DMI rats repaired the deficits in exploration of a novel open field or novel object. The increased locomotion in a novel open field and investigation of a novel object produced by apomorphine in 6-OHDA-DMI rats were blocked by the DA antagonist, pimozide. This is evidence that apomorphine restored exploratory responses by stimulating dopaminergic receptors. The exploratory responses produced by apomorphine were also blocked by testing rats in a familiar open field or with a familiar novel object. This is evidence that apomorphine facilitates exploratory responding to novel stimuli by 6-OHDA-DMI rats, but that the same dose of apomorphine does not increase activity when 6-OHDA-DMI rats are confronted by familiar stimuli. We conclude: (1) that mesolimbicocortical dopaminergic terminals are necessary for normal exploratory behavior in rats; and (2) that DA released by these terminals may facilitate optimal sensorimotor integration in these terminal fields during spontaneous exploratory behavior.

Mesolimbic and mesocortical dopaminergic neurons are necessary for normal exploratory behavior in rats

After ablation of mesolimbic and mesocortical dopaminergic neurons produced by 6-hydroxydopamine (6-OHDA) injections in the anterolateral hypothalamus, rats investigate a novel object less. Systemic administration of the dopamine (DA) agonist apomorphine increases investigatory movements in these DA-denervated rats when the object is novel, but not when the object is familiar. Pimozide pretreatment prevents the increased investigation produced by apomorphine in DA-denervated rats. These findings suggest that mesolimbic and mesocortical DA neurons are necessary for normal exploratory behavior in the rat.

Unilateral mesolimbicocortical dopamine denervation decreases locomotion in the open field and after amphetamine

Unilateral denervation of the mesolimbicocortical dopaminergic (DA) system was produced by microinjections of 6-hydroxydopamine (6-OHDA) into the right or left anterolateral hypothalamus after desmethylimipramine pretreatment. Unilateral DA denervation was confirmed by the marked loss of fluorescent fibers in mesolimbic DA terminal fields in brains processed for catecholamine histofluorescence with the glyoxylic acid-paraformaldehyde method. Such unilateral DA denervation significantly decreased the locomotor exploration of an open field and the locomotor response to d-amphetamine (1.5 mg/kg). These results demonstrate that unilateral mesolimbococortical DA denervation is sufficient, and that bilateral denervation of a single mesolimbic terminal field such as the n. accumbens is not necessary, to produce a decrease in the locomotor response to amphetamine or a decrease of locomotion in the open field. The results are consistent with the hypothesis that the mesolimbicocortical DA system energizes behavior, but does not direct it.

Septal stimulation on painful and symbolic stress. Experimental study.

Based on the rewarding effect of septal area, therapeutic stimulation of this region has been applied to surgical management of chronic pain. However some basic problems of this technique remain unsolved. Thus the effect of septal stimulation was tested on an experimental model of painful and symbolic stress, comparing the variations in the pituitary-adrenal axis activity, the peripheral catecholamine levels and the structural changes in gastric mucosa and adrenal glands, between the problem and different control groups. The bioelectrical activity of septal area and anterolateral hypothalamus during stimulation were recorded. A decrease in gastric ulceration and plasma cortisol were observed in the septal stimulation group. No direct influence on the catecholaminic system was noted. A facilitation of septal activity and its influence on hypothalamic rythm were found. All these effects were mainly achieved in the posterior perifornical septal region.

Behavioral effects of stimulating positive reward sites in the central tegmentum of rhesus monkeys

Rhesus monkeys with electrodes chronically implanted in reward sites in central tegmentum were given telemetered brain stimulation while they were free ranging alone or with cagemates. Stimulation seemed to induce a relaxed positive affect as measured by increased huddling, increased lipsmacking, reduced muscle tone, increased solicitation of grooming and increased grooming of other monkeys. Stimulation did not increase dominant/submissive interactions and seemed to have no effect on aggression or fear. These results are very different from those obtained from an anterolateral hypothalamic self-stimulation site and indicate that fibers which provide input from this area to anterolateral hypothalamus are not solely responsible for effects obtained in the anterolateral hypothalamic area.

Effect of brain peptides on hypokinesia produced by anterolateral hypothalamic 6-OHDA lesions in rats

Intraventricular injections of substance P, TRH and somatostatin were administered to rats rendered hypokinetic by bilateral microinjections of 6-hydroxydopamine into the anterolateral hypothalamus. Only substance P in a dose of 0.30 μg/rat significantly increased motor activity as determined by photocell counts in a 5 min test session immediately after administration of the peptide. Behavioral observations indicated that grooming and not locomotion was mainly responsible for the greater activity scores. None of the three peptides at the doses examined potentiated or reduced the increased activity induced by 1 mg/kg apomorphine. Stereotyped behavior was also not affected by previous injections of substance P and somatostatin but was enhanced in animals which had received 5 μg/rat TRH 30 min prior to apomorphine.