Posterior Hypothalamic Region Research Articles

Update on hemicrania continua.

Hemicrania continua (HC) is a rare primary headache syndrome, characterized by unilateral pain and an absolute response to indometacin. Since the term was first coined in 1984, more than 100 cases have been described worldwide. Most recently, detailed case series that provide more detailed information concerning the sometimes complex clinical presentation of HC have been reported. Functional imaging studies suggest a unique pattern of subcortical involvement in HC: contralateral to the pain posterior hypothalamic region, ipsilateral dorsal pons and ipsilateral ventral midbrain, which, along with the particular effect of indometacin, probably justifies its classification as a unique entity. Increasing the awareness of this primary headache form among clinicians will aid in its diagnosis while further work is being undertaken to characterize the syndrome.

Endothelin-1 and -3 modulate the neuronal norepinephrine transporter through multiple signalling pathways in the rat posterior hypothalamus

We have previously reported that endothelin-1 and -3 modulate different steps of noradrenergic transmission in the hypothalamus. We showed that endothelins modify neuronal norepinephrine transport activity through the regulation of the kinetic constant and internalization. In the present work we sought to define the endothelin receptors and intracellular mechanisms involved in the down-regulation of neuronal norepinephrine uptake induced by endothelin-1 and -3 in the rat posterior hypothalamic region. Results showed that endothelin-1 reduced norepinephrine uptake through ET B receptors, whereas endothelin-3 through a non-conventional or atypical endothelin receptor. In both cases, the effect on norepinephrine uptake was coupled to protein kinase A and C as well as nitric oxide pathways. However, neither protein kinase G nor intracellular or extracellular calcium and calcium/calmodulin-dependent protein kinase II were involved. In addition, the same intracellular mechanisms participated in the reduction of nisoxetine binding (norepinephrine transporter internalization index) induced by both endothelins. Present findings reveal the underlying mechanisms involved in the regulation of the neuronal norepinephrine transporter by endothelins and further support the role of these peptides in the modulation of noradrenergic transmission at the presynaptic nerve endings in the posterior hypothalamus.

Intracellular signaling mechanisms underlying the activity and internalization of the neuronal norepinephrine transporter by endothelin‐3 in the rat posterior hypothalamus

Brain norepinephrine (NE) is involved in relevant physiological functions regulated by the hypothalamus. We previously reported that endothelins (ET) participate in the short term regulation of NE uptake in the anterior and posterior hypothalamus by changing the kinetic and internalization of the neuronal NE transporter (NET). In the present work we studied the mechanisms involved in the regulation of NET by ET‐3 in the rat posterior hypothalamic region (PHR). Experiments were performed in vitro and neuronal NE uptake and nisoxetine binding were used as indexes of activity and internalization of NET, respectively. Results showed that ET‐3 reduced neuronal NE uptake through the activation of a non conventional ET receptor involving PKC, PKA and PKG pathways. Furthermore ET‐3 enhanced NET internalization. However incubation with inhibitors of PKC (GF‐109203x), PKA (H‐89) or PKG (KT5823) inhibited ET‐3 response on NET internalization. Present findings suggest that the effect of ET‐3 on NET in the rat PHR is mediated by a non‐conventional ET receptor coupled to various intracellular pathways including PKC, PKA and PKG.(UBACyT B079, CONICET‐PIP 5929, ANPCyT PICT‐38333)

MICROELECTRODE RECORDING IN THE POSTERIOR HYPOTHALAMIC REGION IN HUMANS

Deep brain stimulation of the posterior hypothalamic region (PHR) is an emerging technique for the treatment of medically intractable cluster headache. Few reports have analyzed single unit neuronal recordings in the human PHR. We report properties of spontaneous neuronal discharge in PHR for 6 patients who underwent DBS for cluster headaches. Initial target coordinates, determined by magnetic resonance imaging stereotactic localization, were 2 mm lateral, 3 mm posterior, and 5 mm inferior to the midpoint of the anterior commissure-posterior commissure plane. A single microelectrode penetration was performed beginning 10 mm above the anatomic target, without systemic sedation. Single units were discriminated off-line by cluster cutting in principal components space. Discharge rates, interspike intervals, and oscillatory activity were analyzed and compared between ventromedial thalamic and hypothalamic units. Six patients and 24 units were evaluated. Units in the PHR had a slow, regular spontaneous discharge with wide, low-amplitude action potentials. The mean discharge rate of hypothalamic neurons was significantly lower (mean +/- standard deviation, 13.2 +/- 12.2) than that of medial thalamic units (28.0 +/- 8.2). Oscillatory activity was not detected. Microelectrode recording in this region caused no morbidity. The single-unit discharge rate of neurons in the PHR of awake humans was 13.2 Hz and was significantly lower than medial thalamic neurons recorded dorsal to the target. The findings will be of use for microelectrode localization of the cluster headache target and for comparison with animal studies.

Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats

The histamine-containing posterior hypothalamic region (PH-TMN) plays a key role in sleep-wake regulation. We investigated rapid changes in glutamate release in the PH-TMN across the sleep-wake cycle with a glutamate biosensor that allows the measurement of glutamate levels at 1- to 4-s resolution. In the PH-TMN, glutamate levels increased in active waking (AW) and rapid eye movement (REM) sleep compared with quiet waking and nonrapid eye movement (NREM) sleep. There was a rapid (0.6 +/- 1.8 s) and progressive increase in glutamate levels at REM sleep onset. A reduction in glutamate levels consistently preceded the offset of REM sleep by 8 +/- 3 s. Short-duration sleep deprivation resulted in a progressive increase in glutamate levels in the PH-TMN, perifornical-lateral hypothalamus (PF-LH), and cortex. We found that in the PF-LH, glutamate levels took a longer time to return to basal values compared with the time it took for glutamate levels to increase to peak values during AW onset. This is in contrast to other regions we studied in which the return to baseline values after AW was quicker than their rise with waking onset. In summary, we demonstrated an increase in glutamate levels in the PH-TMN with REM/AW onset and a drop in glutamate levels before the offset of REM. High temporal resolution measurement of glutamate levels reveals dynamic changes in release linked to the initiation and termination of REM sleep.

Regulation of the neuronal norepinephrine transporter by endothelin-1 and -3 in the rat anterior and posterior hypothalamus

We previously reported that endothelin-1 and endothelin-3 modulate norepinephrine neuronal release and tyrosine hydroxylase activity and expression in the hypothalamus. In the present study we sought to establish the role of endothelin-1 and -3 in the regulation of norepinephrine uptake in the anterior and posterior hypothalamus. Results showed that in the anterior hypothalamus endothelin-3 increased neuronal norepinephrine uptake whereas endothelin-1 decreased it. Conversely, in the posterior hypothalamic region both endothelins diminished the neuronal uptake of the amine. Endothelins response was concentration dependent and maintained at all studied times. Endothelins also modified the kinetic and internalization of the NE neuronal transporter. In the anterior hypothalamic region endothelin-3 increased the V max and the B max whereas endothelin-1 decreased them. However, in the posterior hypothalamic region both endothelins diminished the V max as well as B max. Neither endothelin-1 nor endothelin-3 modified neuronal norepinephrine transporter K d in the studied hypothalamic regions. These findings support that in the posterior hypothalamic region both endothelins diminished neuronal norepinephrine transporter activity by reducing the amine transporter expression on the plasmatic membrane. Conversely, in the anterior hypothalamic region endothelin-3 enhanced neuronal norepinephrine transporter activity by increasing the expression of the transporter on the presynaptic membrane, whereas endothelin-1 induced the opposite effect. Present results permit us to conclude that both endothelins play an important role in the regulation of norepinephrine neurotransmission at the presynaptic nerve endings in the hypothalamus.

Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and 1-year results in four patients

Cluster headache (CH) is the most severe of the primary headache disorders. Based on the finding that regional cerebral blood flow is increased in the ipsilateral posterior hypothalamic region during a CH attack, a novel neurosurgical procedure for CH was recently introduced: hypothalamic deep brain stimulation (DBS). Two small case series have been described. Here, the authors report their technical approach, intraoperative physiological observations, and 1-year outcomes after hypothalamic DBS in four patients with medically intractable CHs. Patients underwent unilateral magnetic resonance (MR) imaging-guided stereotactic implantation of a Medtronic DBS (model 3387) lead and Soletra pulse generator system. Intended tip coordinates were 3 mm posterior, 5 mm inferior, and 2 mm lateral to the midcommissural point. Microelectrode recording and intraoperative test stimulation were performed. Lead locations were measured on postoperative MR images. The intensity, frequency, and severity of headaches throughout a 1-week period were tracked in patient diaries immediately prior to surgery and after 1 year of continuous stimulation. At the I-year follow-up examination, DBS had produced a greater than 50% reduction in headache intensity or frequency in two of four cases. Active contacts were located 3 to 6 mm posterior to the mammillothalamic tract. Neurons in the target region showed low-frequency tonic discharge. In two previously published case series, headache relief was obtained in many but not all patients. The results of these open-label studies justify a larger, prospective trial but do not yet justify widespread clinical application of this technique.

Microinjection of carbachol in the supramammillary region suppresses CA1 pyramidal cell synaptic excitability

Previous studies have established that the posterior hypothalamus-supramammillary (SUM) region is involved in the control of the hippocampal theta rhythm and also modulates the synaptic excitation of hippocampal neurons. Particularly, the medial but not lateral SUM region mediates reticular stimulation-induced suppression of CA1 pyramidal cell synaptic excitation to Schaffer collateral stimulation. In the present study using urethane anesthetized rats, we have investigated the effect of direct chemical stimulation of the posterior hypothalamus-SUM region on CA1 pyramidal cell excitability. It was observed that microinjection of the cholinergic muscarinic receptor agonist, carbachol (0.1 microl, concentration of either 0.0052, 0.156, or 0.625 microg/microl), evoked concentration-dependent suppression of CA1 pyramidal cell excitability that was dissociated from theta activation. Further, carbachol microinjection preferentially recruited the lateral SUM region when compared with the medial SUM and the posterior hypothalamic regions. In this context, the shortest latencies to suppression at the lowest concentration of carbachol and the strongest suppression at higher concentrations were observed with lateral microinjections. The carbachol-induced suppression was attenuated by inactivation of the medial septal region by microinjection of procaine (0.5 microl, 20% w/v). These results underscore a possible role for cholinergic mechanisms in the lateral SUM region in modulation of CA1 pyramidal cell synaptic excitation via the medial septal region. Furthermore, the present findings when juxtaposed with the medial SUM mediation of reticularly-elicited suppression suggest a medial-lateral topographic organization of the SUM region in modulation of CA1 excitability.

Comparative anatomy of α2 and β adrenoceptors in the adult and developing brain of the marine teleost the red porgy (Pagrus pagrus, Sparidae): [3H]clonidine and [3H]dihydroalprenolol quantitative autoradiography and receptor subtypes immunohistochemistry

The present study aimed to determine the anatomic distribution and developmental profile of alpha(2) and beta adrenoceptors (AR) in marine teleost brain. Alpha 2 and beta adrenoceptors were studied at different developmental stages by using [(3)H]clonidine and [(3)H]dihydroalprenolol, respectively, by means of in vitro quantitative autoradiography. Furthermore, immunohistochemical localization of the receptor subtypes was performed to determine their cellular distribution. Saturation studies determined a high-affinity component of [(3)H]clonidine and [(3)H]dihydroalprenolol binding sites. High levels of both receptors were found in preglomerular complex, ventral hypothalamus, and lateral torus. Dorsal hypothalamus and isthmus included high levels of alpha(2) AR, whereas pretectum and molecular and proliferative zone of cerebellum were specifically characterized by high densities of beta AR. From the first year of life, adult levels of both AR were found in most medial telencephalic, hypothalamic, and posterior tegmental areas. Decreases in both receptors densities with age were prominent in ventral and posterior telencephalic, pretectal, ventral thalamic, hypothalamic, and tegmental brain regions. Immunohistochemical data were well correlated with autoradiography and demonstrated the presence of alpha(2A), alpha(2C), beta(1), and beta(2) AR subtype-like immunoreactivity. Both the neuronal (perikaryal or dendritic) and the glial localization of receptors was revealed. The localization and age-dependent alterations in alpha(2) and beta AR were parallel to plasticity mechanisms, such as cell proliferation in periventricular thalamus, hypothalamus, and cerebellum. In addition, the biochemical characteristics, distribution pattern, and neuronal or glial specificity of the receptors in teleost brain support a similar profile of noradrenergic transmission in vertebrate brain evolution.

Rewarding effects of AMPA administration into the supramammillary or posterior hypothalamic nuclei but not the ventral tegmental area.

We examined whether injections of the excitatory amino acid AMPA are rewarding when injected into the posterior hypothalamus and ventral tegmental area. Rats quickly learned to lever-press for infusions of AMPA into the supramammillary or posterior hypothalamic nuclei but failed to learn to lever-press for similar injections into the ventral tegmental areas. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, induced conditioned place preference. The rewarding effects of AMPA appear to be mediated by AMPA receptors, because coadministration of the AMPA antagonist CNQX blocked the rewarding effects of AMPA, and administration of the enantiomer R-AMPA did not mimic the rewarding effects. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, also increased extracellular dopamine concentrations in the nucleus accumbens. Pretreatment with the D1 dopamine antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] led to extinction of AMPA self-administration. These findings implicate posterior hypothalamic regions in reward function and suggest that reward mechanisms localized around the ventral tegmental area are more complex than has been assumed recently.

Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo

Orexin-A (Hypocretin-1) has been localized in the posterior and lateral hypothalamic perifornical region. Orexin containing axon terminals have been found in hypothalamic nuclei and many other parts of the brain; for example, the hippocampus. Two types of orexin receptors have been discovered. Orexin 1 type of receptors have been described and been shown to be widely distributed in the rat brain including the hippocampus. Subsequently Orexin-A was found to impair both water maze performance and hippocampal long term potentiation (LTP). Leptin is expressed in adipose tissue and released into the blood where it affects food intake and can also produce widespread physiological changes mediated via autonomic preganglionic neurons, pituitary gland, and cerebral cortex. Immunoreactivity for leptin receptors has been found in various hypothalamic nuclei including the lateral hypothalamic area as well as the hippocampus especially in the dentate gyrus and CA1. Leptin receptor deficient rats and mice also show impaired LTP in CA1 and poor performance in the water maze. The present study was conducted to determine the effects of 0.0, 30, 60, 90, and 100 nM, orexin-A, and leptin, 0.0, 1.0, 100 nM, 1, and 10 μM, in 1.0 μl of ACSF, applied directly into the dentate gyrus, on LTP in medial perforant path dentate granule cell synapses in urethane anesthetized rats. Orexin-A specifically enhanced LTP at the 90 nM dose; and it was possible to block the enhancement by pretreating the animals with SB-334867, a specific orexin 1 receptor antagonist. Leptin enhanced normal LTP at 1.0 μM but inhibited LTP at lower and higher doses. These results and previous data indicate that the same peptide could possibly have different modulatory post synaptic effects in different hippocampal synapses dependent upon different types of post synaptic receptors.

The effect of posterior hypothalamic injection of cholinergic agents on hippocampal formation theta in freely moving cat

The effect of intra-hypothalamic micro-injection of muscarinic (atropine sulphate, pirenzepine and gallamine) and nicotinic (hexamethonium) antagonists on spontaneous, sensory and electrically-induced hippocampal formation (HPC) theta EEG activity was investigated in the freely behaving cat. Administration of hexamethonium and gallamine failed to elicit a detectable effect on HPC theta activity. However, the injection of atropine sulphate and pirenzepine abolished the theta rhythm recorded from HPC. This effect was reversible. A substantial difference in the recovery time course between frequency versus amplitude (μV) and power (μV 2) of hippocampal theta was observed. While theta frequency exhibited a rapid reappearance with a shallow slope, the power and amplitude showed a gradual recovery with a steeper slope. The injection of carbachol into posterior hypothalamus (PH) produced almost a continuous HPC theta with increased power. These results demonstrate that cholinergic (M1) receptors localised in the posterior area of the hypothalamus are engaged in mechanisms responsible for generating hippocampal theta oscillations in the freely behaving cat. The contribution of posterior hypothalamic region to HPC theta frequency and amplitude is discussed.

Reticular stimulation evokes suppression of CA1 synaptic responses and generation of theta through separate mechanisms.

The induction of hippocampal theta by reticular stimulation involves a relay to the hippocampus via the posterior hypothalamic-supramammillary region and then the medial septum. Interestingly, sensory- or behaviour-induced theta is accompanied by suppression of hippocampal field CA1 synaptic responses. In the present study, performed on anaesthetized rats, we observed that reticular stimulation also induced a suppression of the CA1 pyramidal cell population spike and the corresponding dendritic field excitatory postsynaptic potential evoked by field CA3 stimulation. This suppression was observed at stimulation intensity below the threshold for generation of CA1 theta and was maximal at stimulation intensities at the threshold for theta. The frequency and amplitude of theta waves, by contrast, increased further with increasing reticular stimulation voltage. Neural inactivation by microinjection of the local anaesthetic procaine (20% w/v, 0.1-0.2 microL) or the inhibitory ligand gamma aminobutyric acid (0.8 m, 0.5 micro L) in the posterior hypothalamic regions, especially the ipsilateral medial supramammillary region, or the medial septum attenuated both the suppression of CA1 pyramidal cell synaptic excitability and theta generation. However, the effects of microinjection on suppression and theta were not always in parallel. Furthermore, the effect of microinjection of gamma aminobutyric acid on reticularly elicited suppression was observed from relatively fewer sites in the posterior hypothalamus as compared with that on theta activation. These results suggest that reticular stimulation evokes an inhibition of CA1 pyramidal cell excitability that (i) is mediated, at least in part, via medial supramammillary and septal regions, but (ii) involves a separate neural pathway from theta generation.

Total monoamine oxidase activity in the hypothalamus, ovary and uterus of rats with an extreme number of ovarian corpora lutea

The activity of total monoamine oxidase (MAO) in the rat ovary and uterus fluctuates significantly under various physiological conditions. We analyzed total MAO activity in the hypothalamus, uterus and ovary in adult rats, having an extreme number of corpora lutea (hyperluteinized ovaries) resulting from the mechanical lesions in the posterior hypothalamic region of neonatal rats. Total MAO activity in the hypothalamus (30.21 +/- 1.53 pmol/mg tissue/min) and uterus (3.16 +/- 0.61 pmol/mg tissue/min) of rats with hyperluteinized ovaries did not show a significant difference as compared to that of intact controls (31.09 +/- 1.72 and 2.90 +/- 0.40 pmol/mg tissue/min, respectively). In contrast, in the ovaries of hyperluteinized rats, total MAO activity (21.16 +/- 1.70 pmol/mg tissue/min) was significantly higher (p<0.01) when compared to that of intact controls (13.61 +/- 1.30 pmol/mg tissue/min). The increased MAO activity in the hyperluteinized ovaries may be attributed to the increased number of transformed and accumulated corpora lutes as a consequence of diminished luteolysis.

Melanin-concentrating hormone system in the brain and skin of the cichlid fish Cichlasoma dimerus: anatomical localization, ontogeny and distribution in comparison to alpha-melanocyte-stimulating hormone-expressing cells.

Distribution and development of the melanin-concentrating hormone (MCH) system were examined by immunocytochemistry of the brain, pituitary gland and skin of the South American cichlid fish Cichlasoma dimerus. In adults, the most prominent group of MCH-ir perikarya was located in the nucleus lateralis tuberis (NLT). Outside the NLT, in the posterior hypothalamic region, a group of small neurons was found between the third ventricle and the lateral ventricular recess with delicate immunoreactive fibers that did not seem to contribute to the pituitary innervation. MCH-ir perikarya were identified at day 4 after hatching (AH) in a proliferating zone of the hypothalamic floor. Pituitary innervation could be detected at this stage. Another group of small MCH-ir neurons, only detected in pre-juvenile stages, originated close to the third ventricle in the medial hypothalamic region by day 6 AH. alphaMSH-ir neurons were localized in similar regions of the NLT and in the nucleus periventricularis posterior (NPP). Free MCH-ir neuromasts were detected in the ventral and dorsal skin of larval heads. These epidermal sensory organs were in close association with blood vessels and dermal melanocytes, suggesting that MCH synthesized in larval skin might act in an endocrine way reaching different targets and/or in a paracrine mode regulating melanin concentration in dermal melanocytes.

CNS Expression Pattern of Lmx1b and Coexpression with Ptx Genes Suggest Functional Cooperativity in the Development of Forebrain Motor Control Systems

In the central nervous system, acquisition of regional specification is an important developmental process. The regional specification is reflected by restricted and overlapping expression of homeobox genes, which are regulators of this event. Here, we detail the expression pattern of Lmx1b during late embryonic brain development and show that this gene is expressed in multiple regions and diverse sets of neurons. Noteworthy, the Lmx1b expression domain is shared by Ptx2 in posterior hypothalamic regions and by Ptx3 in the dopaminergic neurons of the ventral midbrain. In addition, the mutual cofactor Ldb1 is expressed in these regions. The expression of these gene sets is maintained in the adult brain. The subthalamic nucleus, where Lmx1b is coexpressed with Ptx2, and the substantia nigra/ventral tegmental area, where Lmx1b is coexpressed with Ptx3, are both ancillary nuclei of the motor control circuitry, but use different neurotransmitters. These data point to a combinatorial gene network that allows Lmx1b to diversify its regulatory actions by cooperation with specific Ptx genes.

Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons

The lateral hypothalamic area (LHA) and the ventromedial hypothalamic nucleus (VMH) have historically been implicated in ingestive behavior, energy balance and body mass regulation. The LHA is more closely associated with the initiation of eating; whereas the VMH mediates the cessation of eating. The parvocellular part of the paraventricular nucleus (pPVN) is also included in the suppressing mechanism. Recently, two hypothalamic peptides, orexin-A and orexin-B, localized in the posterior and lateral hypothalamic perifornical region were discovered in the rat brain and they increase food intake. Leptin, a protein encoded by an obesity gene, expressed in adipose tissue and released into the blood also affects food intake. Orexin and leptin receptors have been localized in the LHA, pPVN, and VMH. The purpose of this study was to measure food intake in the rat in response to leptin and orexin-A; and to determine their electrophysiological effects on feeding related hypothalamic neurons. Results clearly show that leptin suppresses food intake whereas orexin-A increases food intake. These differences are associated with leptin and orexin-A modulatory effects on LHA, pPVN, and VMH glucose responding neurons. In the LHA, leptin inhibits a larger proportion of both glucose-sensitive neurons (GSNs) and non-GSNs. In the pPVN, leptin increases more GSNs in comparison to non-GSNs. Whereas in the VMH, leptin increases the activity of glucoreceptor neurons (GRNs) in comparison to non-GRNs. Orexin-A had opposite effects: increases activity of GSNs more than the non-GSNs in the LHA and significantly suppresses GRNs in the VMH. In the pPVN, orexin-A had no observable effects on neurons that have a low density of orexin 2 receptors. Results are discussed in terms of hypothalamic neural circuits that are sensitive to endogenous food intake inducing and reducing substances.

Interaction of the monoaminergic and opioidergic brain systems in the course of nociceptive and antinociceptive reactions in cats

Nociceptive responses were evoked in cats by electrical transcutaneous stimulation of the forepaw or electrical stimulation of respective brain structures; these responses could be modulated (intensified or suppressed) by combined electrical stimulation of different brain structures or by neurochemical influences upon these structures. Intensification of nociceptive responses was observed after stimulation of the noradrenergic orP-ergic systems localized in the ventral zone of the central gray (vl SGC) and the structures monosynaptically connected with the latter: the posterior and lateral hypothalamic nuclei (Hp andHl) and preoptic region (RPO). Similar effects were induced by suppression of the serotoninergic system concentrated within the dorsolateral central gray (dl SGC), dorsal raphe nucleus (Rd), and closely related structures: the ventromedial, dorsomedial, and paraventricular hypothalamic nuclei (Hvm, Hdm, andHpv), septum (Sep), basolateral amygdalar nucleus (Am bl), fields 3–4 of the hippocampus (CA3–4), and cingular cortex (GC). Suppression of the serotoninergic system resulted in a decrease in the levels of functioning of the met-enkephalin- and β-endorphinergic systems and facilitation of theP-ergic system. Moderation of nociceptive responses, i.e., an analgesic effect, was observed after either stimulation of the serotonin-, met-enkephalin-, and β-endorphinergic systems localized in thedl SGC, Rd, Hvm, Hdm, Sep, Am bl, CA3–4, andGC, or suppression of the noradrenergic system. The latter influence resulted in inhibition of theP-ergic system and a rise in the functional activity of the met-enkephalin- and β-endorphinergic systems. The composition of two antagonistic brain systems, nociceptive and antinociceptive, is considered. The antinociceptive system includes serotonin-, met-enkephalin-, and β-endorphinergic elements. Leu-enkephalin is a nonspecific activator of the met-enkephalin-, β-endorphin-, andP-ergic systems. The nociceptive system consists of thevl SGC, Hp, Hl, andRPO, while the antinociceptive system includes thedl SGC, Rd, Hvm, Hdm, Hpv, Sep, Am dl, CA3–4, andGC.

Anxiolytic-like behavior after lesion of the tuberomammillary nucleus E2-region

The tuberomammillary nucleus (TM), located in the posterior hypothalamic region, consists of five subgroups and is the only known source of brain histamine. In the present experiment, rats received bilateral ibotenic acid or sham lesions in the rostroventral part of the TM (E2-region). Three weeks later they were tested on the elevated plus-maze test of fear and anxiety. Lesions in the tuberomammillary E2-region elevated the time spent on the open arms, as well as excursions into the end of the open arms, increased scanning over the edge of an open arm, and decreased risk-assessment from an enclosed arm. Thus, partial destruction of TM intrinsic neurons can induce anxiolytic-like effects which are possibly related to a lesion-induced reduction of histaminergic activity.

Circadian Rhythms in Adenohypophysial Hormone Levels and Hypothalamic Monoamine Turnover in Mycobacterial-Adjuvant-Injected Rats

The effect of Freund’s adjuvant injection on 24-hour variation in circulating ACTH, prolactin, growth hormone (GH) and thyroid-stimulating hormone (TSH) levels, and of hypothalamic norepinephrine (NE) content and dopamine (DA) and serotonin (5HT) turnover was examined in adult rats. In control rats, serum ACTH and prolactin exhibited peak values at the light-dark transition while the maximum in TSH was found in the late afternoon. GH levels did not vary on a 24-hour basis. In Freund’s-adjuvant-injected rats, 24-hour variations in TSH levels became blunted while 24-hour variations in prolactin and ACTH persisted. Freund’s adjuvant treatment augmented serum ACTH and prolactin levels, and decreased GH and TSH levels. Hypothalamic NE content, and turnover of DA and 5HT varied on a 24-hour basis in rats receiving adjuvant’s vehicle. The NE content of the anterior, medial and posterior hypothalamus peaked at 04.00 h, while that of the median eminence attained its maximum at 16.00–20.00 h. Maxima in hypothalamic DA and 5HT turnover occurred at 04.00 h regardless of the region examined. In Freund’s-adjuvant-injected rats, reduced amplitude of daily variations of NE content in the median eminence and anterior and medial hypothalamus, as well as a phase advance in the 24-hour rhythm of the posterior hypothalamic NE content were seen. Mycobacterial adjuvant injection also reduced the amplitude of circadian rhythm in hypothalamic 5HT turnover, shifted the maximum in median eminence DA turnover towards light-dark transition, and decreased the amplitude of DA turnover rhythm in the anterior, medial and posterior hypothalamus. Administration of the immunosuppressant drug cyclosporine restored the augmented ACTH and prolactin levels and the depressed GH and TSH levels found in Freund’s-adjuvant-injected rats. Cyclosporine was also effective to restore 24-hour rhythmicity of serum ACTH and TSH, but not of prolactin levels. Immunosuppression restored rhythmicity of NE content and of DA and 5HT turnover in anterior, medial and posterior hypothalamic regions. Cyclosporine did not modify the effect of Freund’s adjuvant on median eminence but in was able to counteract the changes in the DA and 5HT turnover in the median eminence found after immunization. The results are in accord with a significant effect of immune-mediated inflammatory response at an early phase after Freund’s adjuvant injection on ACTH, GH, prolactin and TSH release mechanisms, which was partially sensitive to immunosuppression induced by cyclosporine.