Limbic Nuclei Research Articles

Intrahypothalamic Implantation of Progesterone in Castrated Male Whiptail Lizards (Cnemidophorus inornatus) Elicits Courtship and Copulatory Behavior and Affects Androgen Receptor- and Progesterone Receptor-mRNA Expression in the Brain

A primary tenet of behavioral neuroendocrinology is that gonadal steroid hormones act on limbic nuclei to activate mating behavior in vertebrates. Traditionally, research has focused on the regulation of male-typical sexual behavior by testicular androgens and female-typical sexual behavior by ovarian estrogen and progesterone. Indeed, progesterone generally is regarded as an antiandrogen, acting centrally to inhibit sexual behavior in males. However, experiments with lizards, and more recently with rats, have challenged this paradigm. For example, exogenous progesterone induces mating behavior in some, but not all, castrated male whiptail lizards. The present study determined that implantation of progesterone into the anterior hypothalamus preoptic area of castrated, progesterone-sensitive males completely restored sexual behavior but failed to elicit sexual activity in castrated, progesterone-insensitive males. Further, androgen receptor -and progesterone receptor-mRNA expression in specific brain regions was significantly different in progesterone-sensitive versus progesterone-insensitive animals. Progesterone-sensitive males showed significantly higher relative abundance of androgen receptor-mRNA in the preoptic area, amygdala, and lateral septum, as compared with progesterone-insensitive animals receiving the same treatment. In contrast, progesterone receptor-mRNA abundance was lower in preoptic area of progesterone-sensitive males than in progesterone-insensitive males. No differences were found in the baseline abundance of androgen receptor-or progesterone receptor-mRNA in these nuclei between control groups of progesterone-sensitive and progesterone-insensitive males who were castrated but not implanted. This suggests that progesterone differentially regulates its own receptor as well as androgen receptor in areas of the brain involved in the control of sexual behavior of males and that the nature of this regulation shows individual variability.

Neurotensin induces Fos and Zif268 expression in limbic nuclei of the rat brain

The endogenous tridecapeptide neurotensin exerts a wide range of behavioral, electrophysiological and neurochemical effects when administered directly into the brain. These effects are thought to result from the activation of distinct populations of neurotensin receptors distributed throughout the central nervous system. We have mapped the sites of functional change in the rat brain associated with the central administration of neurotensin using the induction of the nuclear protein products of the immediate early genes c-fos and zif268 as markers of cellular activation. The administration of neurotensin into the lateral ventricle of rats produced an increase in the number of nuclei positive for Fos and Zif268 immunoreactivity in the central and basolateral nuclei of the amygdala and the paraventricular and supraoptic nuclei of the hypothalamus. Neurotensin also produced an increase in serum corticosterone concentration and decrease in body temperature. The intraperitoneal administration of SR48692, a non-peptide neurotensin receptor antagonist, blocked the neurotensin-induced corticosterone secretion and significantly reduced the number of neurotensin-induced Fos-positive and Zif268-positive neurons in the amygdaloid complex. A significant positive correlation wash found between the number of Fos-positive nuclei in the central or basolateral nucleus of the amygdala and the serum corticosterone concentration. A significant positive correlation was also found between the number of Zif-positive cells in the paraventricular nucleus of the hypothalamus and change in body temperature following treatment. Our findings indicate that the central role of neurotensin in increasing serum corticosterone involves the induction of Fos in the central and basolateral nuclei of the amygdala. In contrast, the neurotensin-induced hypothermia, which was unaffected by pretreatment with SR48692, involves Zif induction in the paraventricular nucleus of the hypothalamus. These data support further the existence of central neurotensin receptor subtypes which may regulate distinct immediate early genes.

Pattern of brain destruction in Parkinson's and Alzheimer's diseases.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related degenerative disorders of the human brain. Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities which gradually develop in only a small number of neuronal types. In AD, susceptible neurons produce neurofibrillary tangles (NFTs) and neuropil threads (NTs), while in PD, they develop Lewy bodies (LBs) and Lewy neurites (LNs). The specific lesional pattern of both illnesses accrues slowly over time and remains remarkably consistent across cases. In AD, six developmental stages can be distinguished on account of the predictable manner in which the neurofibrillary changes spread across the cerebral cortex. The pathologic process commences in the transentorhinal region (clinically silent stages I and II), then proceeds into adjoining cortical and subcortical components of the limbic system (stages III and IV - incipient AD), and eventually extends into association areas of the neocortex (stages V and VI - fully developed AD). During the course of PD, important components of the limbic system undergo specific lesions as well. The predilection sites include the entorhinal region, the CA2-sector of the hippocampal formation, the limbic nuclei of the thalamus, anterior cingulate areas, agranular insular cortex (layer VI), and - within the amygdala - the accessory cortical nucleus, the ventromedial divisions both of the basal and accessory basal nuclei, and the central nucleus. The amygdala not only generates important projections to the prefrontal association areas but also exerts influence upon all non-thalamic nuclei which in a non-specific manner project upon the cerebral cortex and upon the nuclei regulating endocrine and autonomic functions. All these amygdala-dependent structures themselves exhibit severe PD-specific lesions. In general, the extranigral destructions are in themselves not sufficient to produce overt intellectual deterioration. Similarly, AD-related pathology up to stage III may be asymptomatic as well. Fully developed PD with concurring incipient AD, however, is likely to cause impaired cognition. Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD.

Adrenocortical Response to Open-field Test in Rats with Anterodorsal Thalami Nuclei Lesion

The influence of limbic anterodorsal thalami nuclei (ADTN) on adrenocortical activity and on emotional reactivity were investigated in male and female rats. The emotional reactivity was evaluated by means of the open-field test and the corticoadrenal function by means of plasma and adrenal corticosterone concentration. The results demonstrate that ADTN lesion does not affect the behavioural patterns in the open-field test on the 29th and 30th day after lesion nor adrenal response when animals are exposed to a novel situation.

Neuropeptide Y in hamster limbic nuclei: lack of colocalization with substance P.

The medial nucleus of the amygdala (Me), bed nucleus of the stria terminalis (BNST), and medial preoptic area (MPOA) regulate copulation in the male hamster. The present study identified neuropeptide Y-immunoreactive (NPY-IR) neurons in the BNST and Me with the greatest concentration in the posteromedial and posteriordorsal subdivisions of these nuclei, respectively. NPY-IR filters are found in all three nuclei with dense plexi of NPY-IR varicosities in the most medial subdivisions. Substance P neurons are also densely concentrated in the posterior BNST and Me; however, no neurons contained both peptides. Thus, NPY and substance P neurons comprise two distinct populations within the BNST and Me of the hamster.

Pancreatic polypeptide receptors in the rat brain localize to autonomic control areas of the hypothalamus and brainstem, limbic nuclei and the olfactory system: AM Puccio, GE Hoffman and DC Whitcomb, Depts of Medicine, Neurobiology, Cell Biology and Physiology, Univ. Pittsburgh, Pittsburgh, PA 15261 and VAMC Pittsburgh 15240

Pancreatic polypeptide receptors in the rat brain localize to autonomic control areas of the hypothalamus and brainstem, limbic nuclei and the olfactory system: AM Puccio, GE Hoffman and DC Whitcomb, Depts of Medicine, Neurobiology, Cell Biology and Physiology, Univ. Pittsburgh, Pittsburgh, PA 15261 and VAMC Pittsburgh 15240

Emotional response and corticoadrenal function in anterodorsal thalami nuclei lesioned rats.

In male and female rats, the effect of limbic anterodorsal thalami nuclei lesions (ADTN) on the emotional reactivity and their relationship with corticoadrenal function were studied. The emotional reactivity was evaluated by means of the open-field test and the corticoadrenal function by means of plasma anol adrenal corticosterone concentration. The results demonstrate that, on the 8th or 9th day after the lesion, the male rats show lack of habituation and the female ones, an increase in emotional reactivity. They also indicate that the lesion of ADTN does not affect the corticoadrenal response to exposure to novel situations.

Distribution of NMDAR1 receptor subunit mRNA and [125I]MK-801 binding in the hypothalamus of intact, castrate and castrate-DHTP treated male rats.

This study examines NMDAR1 receptor subunit mRNA expression and [125I]MK-801 binding in hypothalamic and limbic nuclei of intact, castrate and castrate-dihydrotestosterone propionate (DHTP)-treated male rats. In intact rats, the highest levels of NMDAR1 mRNA were observed in the supraoptic, suprachiasmatic, ventromedial and arcuate nuclei. Low levels of hybridization were observed in the bed nucleus of the stria terminalis, lateral preoptic area, lateral hypothalamic area and lateral septum. In castrated rats both NMDAR1 mRNA and [125I]MK-801 binding are significantly decreased in the lateral septum compared to castrate rats treated with DHTP, a non-aromatizable androgen. NMDAR1 mRNA was also significantly decreased in the supraoptic nucleus of castrate rats when compared to castrate rats treated with DHTP. These data suggest that androgens may modulate NMDA receptor function in some parts of the central nervous system.

Antidepressant treatment and limbic serotonergic mechanisms regulating rat locomotor activity

The effects of chronic administration of desipramine, citalopram, and electroconvulsive shocks (ECS) on changes in rat motility after intraaccumbens (NAS) injections of selective serotonergic drugs were studied in intact and 5.7-DHT lesioned animals. It was shown that local injections of 8-OHDPAT and DOI-HCl depressed rat locomotor activity. Their effects appeared to be mediated postsynaptically, and could be antagonized by NAN-190 and ritanserin, respectively. Chronic but not acute pretreatment of rats with antidepressants (21 days long; the experiment was performed 24 h after the last dose) as well as repeated ECS (shocks were applied five times every second day), antagonized behavioral depression after 8-OHDPAT and DOI-HCl. The influence of antidepressant treatment was prevented by serotonergic lesions. Chronic administration of antidepressants and ECS did not equivocally affect the levels or metabolism of 5-HT, dopamine, and noradrenaline in the rat limbic forebrain. It is concluded that the present data indicate diminished activity of 5-HT systems related to the 5-HT1A and 5-HT2 receptors in the limbic nucleus, after chronic antidepressant treatment. This effect of drugs and ECS concerns nervous processes linked with the function of postsynaptically localized 5-HT receptor subtypes, and it probably depends on intact presynaptic 5-HT innervation.

Distribution and steroid dependence of aromatase enzyme immunoreactivity in limbic nuclei of the female musk shrew brain

In the female musk shrew ( Suncus murinus) neural aromatization of testosterone to estradiol is critical for the expression of sexual behavior. To localize the brain regions capable of aromatization, we used immunocytochemistry to map the distribution of aromatase enzyme. Aromatase immunoreactivity (AROM-ir) has a discrete distribution primarily limited to the lateral septum (LS), central nuclei of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST). In these nuclei the intensity of immunoreactivity varies with hormonal status. Ovariectomy (OVX) significantly reduces the optical density of AROM-ir neurons in all nuclei as compared with brains of normal females. Combined OVX and adrenalectomy (ADX) further reduces optical density readings in AROM-ir cells in the LS and BST, as compared with readings from the brains of OVX animals. Normal and ovariectomized females implanted with testosterone had qualitatively equivalent AROM-ir. High levels of aromatase activity have been measured in the preoptic area and hypothalamus in a number of mammals, including the musk shrew. However, in this experiment AROM-ir was absent in these areas. We present several hypotheses to account for this discrepancy between previously reported biochemical data and these histological data. In summary, these data suggest that limbic nuclei may play a role in the expression of sexual behavior in female musk shrews.

Seasonal fluctuations in brain nuclei in the red-sided garter snake and their hormonal control

In many vertebrates, breeding seasons are protracted and mating behavior is temporally associated with gonadal growth and increased sex steroid hormone secretion. In the red-sided garter snake (Thamnophis sirtalis parietalis), mating behavior is restricted to the 2-4 weeks immediately following emergence from winter dormancy. During this period mating behavior is sex-specific: chin-rubbing is exhibited only by males and receptivity to chin-rubbing is exhibited only by females. It is remarkable that mating occurs when the gonads are small and circulating concentrations of gonadal hormones are low. As in other vertebrate species, limbic nuclei are involved in the mediation of mating behaviors. To determine if limbic nuclei are sexually dimorphic and, further, whether they fluctuate in size with the seasons, the volume of brain areas was measured in both sexes at different times of the year (spring, fall, hibernation) and after hormone manipulation (gonadectomy and gonadectomy plus hormone treatment). The areas of interest were the preoptic area (POA), ventromedial hypothalamus (VMH), and the nucleus sphericus (NS or amygdala); control areas included the external nucleus of the optic tract (a cell-rich area) and medial forebrain bundle (a fiber-rich area). Comparisons according to season and manipulation revealed only two instances of sexual dimorphism: the POA of females was significantly smaller than that of males during hibernation and the NS of females was significantly smaller than that of males in those animals not subjected to hibernation. This general lack of sexual dimorphisms in the brain despite the sex-specificity of the behavior patterns and their marked seasonality may reflect the dissociated reproductive pattern characteristic of this species.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of the 5-ht 3 receptor antagonists

The roles of hippocampus (HP) and the nucleus accumbens septi (NAS) in the anxiolytic activity of two 5-HT 3 receptor antagonists were studied in two animal models of anxiety, in rats. Injection of tropisetron (0.005 and 0.01 μg) or ondansetron (1.0 and 2.5 μg) into the hippocampus increased punished consumption of water in the Vogel conflict test. In the open field test neither 5-HT 3 receptor antagonists had anxiolytic-like effects. Tropisetron (0.01 and 0.025 μg) injected into the NAS caused a marked increase in punished drinking, while ondansetron (0.01–15.0 μg) had no effect. In the open field test, tropisetron (0.001, 0.005 and 0.01 μg) and ondansetron (1.0 and 2.5 μg) given to the NAS increased the number of entries into the central part of the open-field, and the time spent in the central sector of the arena. Depletion of 5-HT significantly enhanced the anxiolytic-like effect of intra-NAS-injected tropisetron in the open field, at the dose of 0.005 μg. Moreover, 5,7-DHT lesions produced a tendency to increase motor activity in tropisetron-treated rats. Both hippocampal and accumbens 5-HT 3 receptors seem to contribute to the anxiolytic-like effects of 5-HT 3 antagonists in the Vogel test. It also appears that this effect of 5-HT 3 receptor antagonists is related to their action on postsynaptic 5-HT 3 receptors within the NAS, and depends on the functional state of the 5-HT innervation ascending from the raphe nuclei. Thus, the present data add more arguments for the more specific involvement of this limbic nucleus in emotional control.

(D-Ala2)deltorphin II: D1-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens

In order to investigate the relative role of central delta- and mu-opioid receptors in behavior, the effects of (D-Ala2)deltorphin II, a natural delta-opioid peptide, and PL017, a beta-casomorphin derivative specific for mu receptors, were compared after local intracerebral and intraventricular administration. Intracerebral infusion of the two peptides was done bilaterally in the limbic nucleus accumbens and in the ventral and dorsal caudate putamen of freely moving rats through chronic intracerebral cannulas. After intra-accumbens infusion, the two peptides elicited marked but opposite behavioral effects: while (D-Ala2)deltorphin II evoked dose-dependent motor stimulation characterized by locomotion, sniffing, and oral stereotypies, PL017 elicited motor inhibition with rigidity and catalepsy. These effects were site specific because they could not be evoked from the ventral or from the dorsal caudate. Low doses of naloxone (0.1 mg/kg, s.c.) blocked the effects of PL017 but not those of (D-Ala2)deltorphin II, which instead were reduced by high doses of naloxone (1.0 mg/kg) and by the putative delta-antagonist naltrindole; this drug failed to affect the catalepsy induced by PL017. Therefore, while (D-Ala2)deltorphin II effects were delta-mediated, PL017 effects were mu-mediated. Blockade of dopamine D1 receptors by SCH 23390 abolished (D-Ala2)deltorphin II effects, while blockade of dopamine D2 receptors by raclopride or by haloperidol was without effect. Local application by reverse dialysis of (D-Ala2)deltorphin II (5 microM) to the accumbens resulted in a naloxone-sensitive increase of extracellular dopamine concentrations; these effects could not be evoked from the caudate, nor by PL017 in the accumbens. Intracerebroventricular administration of (D-Ala2)deltorphin II or of PL017 elicited behavioral effects qualitatively similar to those obtained from the accumbens.

Distribution of estrogen receptor‐immunoreactive cells in the forebrain of the female guinea pig

We mapped the distribution of estrogen receptor-containing cells in the forebrain of the adult female guinea pig. Cellular estrogen receptor content was detected using monoclonal antibody H222, directed against the estrogen receptor, and the avidin-biotin method with nickel-intensified diaminobenzidine as the chromagen. A complete set of deletion, titration, and adsorption controls established the specificity of the staining. The most dense collections of estrogen receptor-immunoreactive cells were found in medial preoptic, medial hypothalamic, and limbic nuclei (amygdala, bed nucleus of the stria terminalis, lateral septum). Numerous estrogen receptor-immunoreactive cells were also found in additional, specific subregions of the remainder of the preoptic area, hypothalamus, and limbic system, and also in the midbrain (central gray). Elsewhere, estrogen receptor-immunoreactive cells were present in smaller numbers or were absent. This map confirms and extends previous maps based on estrogen binding. The majority of estrogen receptor-immunoreactive cells are found in areas known to be involved in some aspect of reproduction. In addition, many estrogen receptor-immunoreactive cells are found in areas not typically considered to have a primary role in reproductive behavior or neuroendocrine function.

Alzheimer's disease affects limbic nuclei of the thalamus

Sensitive silver techniques for amyloid and neurofibrillary changes were applied to examine the pathological changes revealed by limbic nuclei of the thalamus in Alzheimer's disease. Large numbers of extracellular amyloid deposits occurred in almost all thalamic nuclei. The antero-ventral nucleus harbored numerous large globular patches, other areas contained more densely packed and smaller deposits, while narrow zones of gray matter subjacent to the ependymal lining of the third ventricle remained virtually devoid of amyloid. Intraneuronal neurofibrillary changes were encountered in the form of distended argyrophilic processes covering the medial convexity of the antero-ventral nucleus. Similar structures, although in considerably lesser density, occurred in the laterally adjoining reticular nucleus. The anterior nuclear complex, the latero-dorsal nucleus, portions of the intralaminar complex, the paraventricular and reuniens nucleus contained numerous neurofibrillary tangles and neuropil threads. The antero-dorsal nucleus showed the most severe involvement. At first glance, the thalamus appeared to be only mildly affected by Alzheimer's disease. Closer inspection revealed that severe changes were confined to only a few limbic nuclei. These changes were virtually identical in amount, type and location in all cases of severe Alzheimer's disease studied. It is assumed that these changes considerably hamper the transport of information through limbic circuits.

Characterisation and autoradiographic localisation of 5-HT 3 receptor recognition sites identified with [ 3H]-(S)-zacopride in the forebrain of the rat

The pharmacological characterisation and topographical distribution of [ 3H]-(S)-zacopride recognition sites in the forebrain of the rat was studied using homogenate and autoradiographic radioligand binding techniques. [ 3H]-(S)-Zacopride labelled a single, saturable, specific binding site (defined by 10.0 μM granisetron) in homogenates prepared from the entorhinal cortex of the rat (p K D = 9.5 l ±0.08; B max = 104 ± 7 fmolmg −1 protein; mean ± SEM, n = 8). Pharmacological characterisatio of the recognition site, within the entorhinal cortex, suggested that [ 3H]-(S)-zacopride selectively labelled the recognition site of the 5-HT 3 receptor. Specific binding of [ 3H]-(S)-zacopride (defined by 1.0 μM granisetron) was differentially distributed throughout the forebrain of the rat; highest densities were located within sub-nuclei of the amygdala (cortical amygdaloid nucleus, amygdalohippocampal area, posterior medial cortical amygdaloid nucleus, posterior lateral amygdaloid nucleus), cortical areas (primary olfactory cortex, entorhinal cortex) and hippocampus. Non-specific binding was distributed homogeneously, although lower in myelinated structures. It is concluded that [ 3H]-(S)-zacopride selectively labels 5-HT 3 receptor recognition sites within the forebrain of the rat; the topographical distribution of these sites, within the limbic nuclei, is consistent with the behavioural actions in animal models of the selective 5-HT 3 receptor antagonists.

Anatomical investigation of projections from thalamus to posterior parietal cortex in the rhesus monkey: A WGA‐HRP and fluorescent tracer study

The parietothalamic projections have been shown to be heterogeneous and appear to be a reflection of the detailed architectonic parcellation of the parietal lobe. In the present study WGA-HRP injections were placed in the different subdivisions of the posterior parietal cortex of the rhesus monkey to determine whether a similarly complex pattern also exists in the thalamocortical pathway. Additionally, in an attempt to determine whether there is an intranuclear specificity of projections from individual thalamic nuclei to different subdivisions of the parietal lobe, multiple retrograde fluorescent tracers were injected into the rostral to caudal sectors of the parietal lobe of the same animal. Different subdivisions of the parietal lobe appear to receive different sets of thalamic input. Thus the superior parietal lobule (SPL) projections are derived from more lateral regions in the thalamus, arising predominantly from the lateral posterior (LP) and pulvinar oralis (PO) nuclei, with additional contributions from the pulvinar lateralis (PL) and pulvinar medialis (PM) nuclei. The inferior parietal lobule (IPL), by contrast, receives its projections from more medial thalamic regions, its main thalamic input originating from PM, and aided by LP, PL, and PO. Both the SPL and IPL also receive projections from the mediodorsal (MD), ventroposterior, ventrolateral, intralaminar, and limbic nuclei, albeit from different components within these nuclei. A topographical arrangement also exists in the thalamic projections to the rostral versus the caudal subdivisions of both the SPL and the IPL. Thus, in the SPL, the ventral posterolateral nucleus, pars oralis (VPLo), ventral lateral nucleus, pars oralis (VLo), and ventral lateral nucleus, pars medialis (VLm) project to rostral regions, whereas the PM and limbic nuclei, anteroventral (AV), and anteromedial (AM), project to area PGm on the medial convexity of the SPL. With respect to projections to the IPL, the ventral posteromedial (VPM) and PO nuclei project to rostral regions, whereas the limbic nuclei lateral dorsal (LD), AM and AV project only to the caudal most area, Opt. A rostrocaudal difference is reflected also within certain nuclei (LP, PO, and PM) that project to the SPL or IPL. Thus rostral parietal subdivisions receive projections from ventral regions within these thalamic nuclei, whereas caudal parietal afferents arise from the dorsal parts of these nuclei. Intervening cortical levels receive projections from intermediate positions within the nuclei. It therefore seems that the increasing architectonic and functional complexity as one moves from rostral to caudal in the SPL and IPL appear to be reflected in the thalamic afferents.(ABSTRACT TRUNCATED AT 400 WORDS)

Maternal thermal stimulation changes metabolic activity in fetal hypothalamus

To study whether the central nervous system in the perinatal fetal rat can operate during maternal cooling and warming, we examined the 2-deoxy- d-[ 14C]glucose ([ 14C]DG) uptake in the fetal brain. Full-term pregnant rats were placed at three different ambient temperatures of 35–37 °C, 24–25 °C and 0–10 °C. Saline containing 20 μCi/100 g of [ 14C]DG was injected into the superior caval vein in the pregnant rats. Forty-five min after the injection, the mother rats were decapitated and the fetal brains were taken out for autoradiography. The [ 14C]DG uptake was significantly influenced by maternal thermal stimulation in the hypothalamus and not in other brain regions examined such as the cerebral cortex, the basal ganglia and the limbic nuclei. Glucose utilization in the fetal anterior hypothalamus, paraventricular hypothalamus and dorsomedial hypothalamus significantly increased when the mother rat was exposed to heat compared to when the mother rat was in the thermoneutral condition. During maternal cooling, glucose utilization in the ventromedial hypothalamus and dorsomedial hypothalamus significantly decreased. There was no area activated by cooling and/or inhibited by warming. Compared to a similar study in adult rats ( Am. J. Pysiol., 248 (1985) R84–92), the present results suggest that although the perinatal fetal brain does not respond to thermal stimulation in terms of glucose utilization as fully as the adults, a few hypothalamic nuclei have already acquired thermal responses, which might be a possible neuronal basis for the thermoregulatory responses just after birth in rats.

Three‐dimensional distribution of 3H‐Naloxone binding to opiate receptors in the human fetal and infant brainstem

Despite the putative role of opioids in disorders of the developing human brainstem, little is known about the distribution and ontogeny of opioid-specific perikarya, fibers, terminals, and/or receptors in human fetuses and infants. This study provides baseline information about the quantitative distribution of opiate receptors in the human fetal and infant brainstem. Brainstem sections were analyzed from three fetuses, 19-21 weeks gestation, and seven infants, 45-68 postconceptional weeks, in whom the postmortem interval was less than or equal to 12 hours. Opiate receptors were localized by autoradiographic methods with the radiolabelled antagonist 3H-naloxone. Computer-based methods permitted quantitation of 3H-naloxone binding in specific nuclei, as well as three-dimensional reconstructions of binding patterns. High 3H-naloxone binding corresponds primarily to sensory and limbic nuclei, and to nuclei whose functions are known to be influenced by opioids, e.g., trigeminal nucleus (pain), nucleus tractus solitarii and nucleus parabrachialis medialis (cardio-respiration), and locus coeruleus (arousal). The regional distribution of opiate receptors as determined by 3H-naloxone binding is similar in human infants to that reported in human adults and animals and corresponds most closely to that of mu receptors. We found, however, that opiate receptor binding is high in the fetal and infant inferior olive, in comparison to low binding reported in this site in adult humans, primates, and rodents. In addition, opiate receptors are sparse in the fetal and infant substantia nigra, as in reports of the adult human substantia nigra, compared to moderate densities reported in primates and rodents. By midgestation, the regional distribution of 3H-naloxone binding in human fetuses is similar, but not identical, to that in infants. Highest 3H-naloxone binding occurs in the inferior olive in fetuses at midgestation, compared to the interpeduncular nucleus in infants. Tritiated naloxone binding quantitatively decreases in virtually all nuclei sampled over the last trimester, but not to the same degree. The most substantial binding decrease (two- to fourfold) occurs in the inferior olive and may reflect programmed regressive events, e.g., neuronal loss, during its development. Definitive developmental trends in 3H-naloxone binding are not observed in the postnatal period studied. The heterogeneous distribution of opiate binding in individual brainstem nuclei underscores the need for volumetric sampling in quantitative studies.

Morphine-induced alterations of local cerebral glucose utilization in the basal ganglia of rats

The actions of various doses of morphine on the local cerebral glucose utilization (LCGU) were studied by means of the autoradiographic [ 14C]2-deoxyglucose technique. Morphine (1–15 mg/kg i.p.) decreased LCGU in most areas of the basal ganglia (caudate nucleus, globus pallidus, nucleus accumbens), but not in the substantia nigra pars compacta. LCGU was also decreased in limbic nuclei, such as septum, hippocampus and amygdala, and in most thalamic areas. In most cortical regions, a decrease was found as well. Findings in some efferent nuclei seemed of particular interest, namely in the substantia nigra pars reticulata, anteroventral and lateral nucleus of the thalamus and the subthalamic nucleus, where decrease in LCGU were found after administration of 7.5 mg/kg or sometimes lower doses, but not after 15 mg/kg of morphine. The decreases seem to reflect a general depressory effect of morphine on neuronal activity which is known from electrophysiological studies. Part of these effects might be, in addition, due to an activation of dopaminergic neurons, since dopamine mainly acts as an inhibitory neurotransmitter. This dopaminergic activation leads to characteristic behavioral effects after lower doses of morphine. The largest dose used (15 mg/kg) produces muscular rigidity, probably by a direct action on the striatum. This effect antagonizes and masks the dopaminomimetic effects. The results suggest that it also antagonizes the functional alterations in some efferent nuclei of the basal ganglia manifest after lower doses of morphine. Local injections of morphine (15 μg) led to decreases of LCGU in the various parts of the striatum, but to increases in lateral and anteroventral thalamus. These increases in LCGU in two thalamic areas seem to support the above hypothesis that the rigidity is accompanied, at least in part of the efferent nuclei of the basal ganglia, by increases in LCGU antagonizing the inhibitory effects described above.