Hippocampal asymmetry in exploratory behavior to vasoactive intestinal polypeptide

The effects of vasoactive intestinal polypeptide (VIP) microinjected uni- or bilaterally into the CA1 hippocampal area of male Wistar rats at a dose of 10, 50 and 100 ng on exploratory behavior were examined. VIP microinjected bilaterally at a high dose (100 ng) significantly decreased the horizontal movements, while at low doses (10 and 50 ng) had no effect on the exploratory activity. Microinjections of VIP into the left hippocampal CA1 area at doses 50 and 100 ng suppressed the exploratory activity, while right-side VIP administration at a dose 100 ng significantly increased horizontal movements compared to the respective controls. Vertical activity was stimulated only by VIP administered into the right hippocampal CA1 area at the three doses used. Neither bilateral nor left injections of VIP induced changes in the vertical movements. The main finding was the presence of hippocampal asymmetry in exploratory behavior to unilateral microinjections of VIP depending on the dose and the microinjected hemisphere.     

Lateralized learning and memory effects of angiotensin II microinjected into the rat CA1 hippocampal area

The effects of angiotensin II (ANG II) microinjected unilaterally (left or right) and bilaterally (left and right) at a dose of 0.5 microg (0.5 nmol) into the CA1 hippocampal area of male Sprague Dowley rats on learning and memory (shuttle box) were studied. Bilateral microinjections of ANG II improved learning, i.e. increased the number of avoidances during the two training days as compared to the respective controls microinjected with saline. ANG II facilitated learning and memory, especially when microinjected into the left CA1 hippocampal area as compared to the respective controls microinjected with saline. Left-side microinjection of ANG II increased the number of avoidances on the first and second training day as compared to the right-side microinjection of ANG II. These findings suggest asymmetric effects of ANG II on cognitive processes in hippocampus.     

Antinociceptive effect of somatostatin microinjected into caudate putamen.

The effects of somatostatin microinjected bilaterally and unilaterally (left or right) at a dose of 10, 50 and 100 ng into the caudate putamen of male Wistar rats on nociception (analgesy-meter test) were studied. Somatostatin injected into caudate putamen resulted in analgesia. Bilateral microinjections of somatostatin significantly increased the pain threshold in a dose-dependent manner, i.e. somatostatin exerted antinociceptive effect. The pain threshold after left-side microinjections was significantly higher than that after injections into right-side. These findings suggest antinociceptive and asymmetric effects of somatostatin on pain in the caudate putamen.     

Cerebroventricular administration of somatostatin (SRIF): effect on central levels of cyclic AMP

The changes in cAMP levels in the hippocampus, cerebral cortex and the neostriatum were investigated at different times after the cerebroventricular administration of SRIF. An early significant increase in cAMP levels (at 5 minutes) in the hippocampus induced by SRIF was eliminated by pretreatment with sotalol. However, the overall behavioral response to SRIF was not affected by sotalol. Sotalol itself significantly reduced cAMP levels in control experiments. In cerebral cortex, an SRIF-induced increase in cAMP levels was significantly lowered by sotalol pretreatment at both 5 and 15 minutes post-SRIF. In neostriatum, a sustained elevation in cAMP levels was observed at 5 and 15 minutes after the intraventricular infusion of SRIF. Sotalol pretreatment failed to reduce the cAMP levels although it lowered its increase at 15 min. post-SRIF. The results appear to show a beta adrenergic involvement in the cAMP response to SRIF and an apparent independence of the behavioral response from cAMP changes.     

Time courses of amnesia development in two areas of the chick forebrain

The roles of different forebrain structures in stages of memory formation were investigated by injecting agents into either the left medial hyperstriatum ventrale (MHV) or right lateral neostriatum (LNS) close to the time of one-trial taste-avoidance training. Withl-glutamate injected into either the left MHV or right LNS 5 minutes pretraining, retention was good 1 minute posttraining but significantly impaired at 5 minutes and each subsequent time point. With emetine injected into either area, retention was still good 60 minutes posttraining but significantly impaired at 90 minutes. With ouabain, retention declined more slowly following injection into the right LNS (at 45 minutes) compared to injection in the left MHV (at 30 minutes). A second experiment confirmed the regional difference in amnesia development produced by ouabain. These results indicate that the duration of short-term memory is longer following inhibition of intermediate-term memory (ITM) in the right LNS, compared to inhibition of ITM in the left MHV.Special Issue dedicated to Prof. Holger Hydén.     

Comparison of metabolic and hormonal effects of calcitonin and somatostatin (SRIF) in the course of oral glucose tolerance test (OGTT)

A comparison is presented of the effect of two therapeutic doses of synthetic somatostatin (250 and 500 micrograms) and salmon calcitonin (50 and 100 U) on the blood levels of sugar, insulin (IRI), somatotropin (HGH) and cortisol in healthy volunteers following peroral administration of 75 g of glucose. Calcitonin was responsible for a significant change in glycaemia as well as IRI levels: following a retarded enhancement glycaemia as well as insulinaemia through out the first 15-30 minutes of OGTT, increased levels of both indicators were persistent at minute 120 and 180, so that the course of both curves was almost parallel. The effect was similar after SRIF had been administered, with the exception of insulin secretion being more pronounced, so that at a later stage of OGTT no hyperinsulinaemia was seen. The HGH levels tended to decrease due to both hormones, the tendency being more marked after SRIF, though statistically insignificant. There was a marked difference between the hormones as regards their effect on adrenocortical secretion. While the latter was constantly stimulated throughout OGTT under calcitonin infusion, the influence of SRIF was not significant. The metabolic and hormonal changes were found after both a lower and higher dose of both hormones, the only differences being that the inhibitory effect on the initial increase in glycaemia following a lower dose of SRIF was of no statistical significance. Hence, the metabolic and hormonal effects of calcitonin and SRIF in an acute experiment display many similarities, however, they do differ in some aspects; these effects do not depend on the doses demonstrated for both lower and higher doses of the above hormones.     

The pancreatic glucagon and C-peptide secretion during hyperinsulinemia in euglycemic glucose clamp with or without somatostatin infusion in normal man

6 normal subjects received two times of 2 hr euglycemic glucose clamp studies (insulin infusion rate 40 mU/M2/min) one with and the other without somatostatin (SRIF) infusion (500 microgram/hr). Serum C-peptide and glucagon levels were measured during clamp to study the sensitivity of pancreatic alpha and beta cells to the suppressive effects of exogenous hyperinsulinemia during normoglycemia in normal subjects and to find whether SRIF had any modulative effects on endocrine pancreas secretion at the status of hyperinsulinemia. The results showed that in normal man the degree of suppression of pancreatic glucagon secretion by hyperinsulinemia (approximately 100 uU/ml) during euglycemic glucose clamp without SRIF infusion was less than that of C-peptide with mean value of 62 +/- 4% of basal glucagon remained at the end of clamp study; while only about 30 +/- 2% of basal C-peptide concentrations remained. But during SRIF infused glucose clamp studies (SRIF was infused from 60 to 120 min), 32 +/- 2% of mean basal C-peptide concentrations and 38 +/- 6% of mean basal glucagon concentrations left at the end of 2 hr clamp studies when serum insulin level was about 100 uU/ml. For the glucose infusion rate (M value), it was significantly greater in our normal subjects in response to insulin + SRIF as compared to insulin alone (12.0 + 0.9 vs 8.8 +/- 1.4; P less than 0.01). We concluded: during hyperinsulinemia (100 uU/ml), the sensitivity of pancreatic alpha cells to insulin seems less than that of beta cells in normal man at normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neostriatal administration of somatostatin:differential effect of small and large doses on behavior and motor control

The administration of small doses of somatostatin (SRIF) (0.01 and 0.1 microgram) into the neostriatal complex of unrestrained, freely moving rats induced general behavioral excitation associated with a variety of stereotyped movements, tremors, and a reduction of rapid eye movements (REM) and deep slow wave sleep (SWS). In contrast, the higher doses of SRIF (1.0 and 10.0 microgram) caused movements to be uncoordinated and frequently induced more severe difficulties in motor control such as contralateral hemiplegia-in-extension which restricted or completely prevented the expression of normal behavioral patterns. As a result, the animals appeared drowsy and inhibited. Analysis of the sleep-waking cycle revealed prolonged periods of a shallow SWS while REM sleep and deep SWS were markedly reduced; electroencephalogram recordings revealed periods of dissociation from behavior. The administration of endocrinologically inactive as well as the active analogues of SRIF failed to induce effects comparable with those observed after the administration of the same dose of the native hormone (10.0 microgram).     

Pancreatic polypeptide, microinjected into the dorsal vagal complex, potentiates glucose-stimulated insulin secretion in the rat

Specific binding sites for circulating pancreatic polypeptide (PP) have been found within the dorsal vagal complex (DVC) in the caudal medulla oblongata. Therefore, the effects of rat PP on pancreatic hormone secretion upon its microinjection into the DVC in halothane-anesthetized rats at doses of 0.4–40 pmol were investigated. At this range of doses, the changes in plasma concentrations of insulin, glucagon and glucose over basal levels did not differ from those after vehicle microinjection. In a separate series of experiments, vehicle and PP at doses of 0.4 and 4 pmol were microinjected into the right DVC 40 min after the continuous infusion of -glucose had been started. In animals receiving continuous infusion of -glucose, PP microinjected into the DVC (4 pmol), resulted in markedly higher insulin levels at corresponding time points compared to those with vehicle microinjected into the DVC. These data indicate, for the first time, that microinjection of PP into the DVC may potentiate glucose-stimulated insulin secretion in halothane-anesthetized rats.     

Somatostatin-dependent adenylyl cyclase activity in nonactivated and mitogen-activated human T cells: evidence for uncoupling of sst3 receptor from adenylyl cyclase

Neuropeptide somatostatin (SRIF) has been shown to modulate interleukin-2 (IL-2) secretion by mitogen-activated T cells. In this study, we further analyzed the transduction pathways underlying SRIF actions on human Jurkat T cells and compared SRIF signaling between nonactivated and mitogen-activated cells. SRIF effects on adenylyl cyclase activity in the absence and presence of mitogens were addressed by using three different analogs: SRIF14, SRIF28, and SMS 201-995. In semipurified membrane preparations obtained from nonactivated cells, all analogs inhibited adenylyl cyclase. However, in membrane preparations obtained from mitogen-activated cells, the maximal inhibition of adenylyl cyclase mediated by SRIF14 and SRIF28 equaled only one third of that measured in the absence of mitogens, whereas SMS 201-995 was completely inactive. To assess the relevant mechanisms associated with different effects of SRIF on adenylyl cyclase activity in nonactivated and mitogen-activated T cells, we performed binding assays by using iodinated SRIF as a radioligand. These experiments suggested that both the number of receptors and their affinities were almost identical in either nonactivated or activated cells. RT-PCR analysis of the pattern of SRIF receptor expression showed that nonactivated as well as activated Jurkat cells expressed only mRNA corresponding to the sst3 receptor subtype. Altogether, these data point to a functional activation-associated uncoupling of sst3 receptors from adenylyl cyclase in human T cells, indicating a T-cell activation-induced alteration in the sst3 receptor transduction pathway.     

Effect of somatostatin in the Syrian hamster bearing a transplantable islet-cell tumor.

The influence of somatostatin (SRIF) on blood glucose, plasma insulin and plasma glucagon was studied in hamsters bearing a transplantable islet-cell tumor secreting insulin and glucagon as well as in normal controls. Fed anesthetized animals were infused intraperitoneally either at a dose of 10 microgram in 15 min or of 150 microgram in 30 min, and intravenously at a dose of 250 microgram in 30 min. Blood was withdrawn from the jugular vein before and after infusion. Before the infusions, tumor bearing animals (TB) had lower blood glucose, markedly elevated plasma glucagon and slightly lower plasma insulin by comparison with normal hamsters (N). Both doses of somatostatin infused by the intraperitoneal route produced a slight but significant hypoglycemia in TB hamsters but not in normals. Ten microgram SRIF did not affect insulin and plasma glucagon levels whereas 150 microgram SRIF significantly depressed plasma insulin in both types of hamsters (N and TB). This latter dose of SRIF decreased plasma glucagon in normal but not in tumor-bearing hamsters. Intravenous infusion of 250 microgram SRIF did not reduce the hyperglucagonemia of TB hamsters either. These results indicate that somatostatin does not reduce the hyperglucagonemia due to the transplantable islet-cell tumor but nevertheless decreases blood glucose and plasma insulin.     

The participation of the neostriatal cholinergic system in the differentiation of acoustic signals in dogs]

In chronic experiments on six dogs the influence was studied of micro-injections of choline agonist carbocholine (0.05-0.2 mkg) and of blocker of choline receptors atropine (40 mkg) in the caudate nucleus head of the left and right hemispheres on realization of instrumental defensive reflexes, connected with the maintenance of definite posture and on differentiation of signals in defensive situation. It has been shown that the cholinergic system of the neostriatum participated in realization of both the motor and sensory mechanisms in connection with the realization of motor responses to defensive and differentiation signals. Analysis of the obtained results also allowed to make a conclusion that the influence of carbocholine micro-injections into the neostriatum on differentiation depended on a number of factors: it did not take place when the signal was poorly distinguished (judging by the values of motor components to defensive and differentiation signals) or, on the other hand, against the background of stable differentiation reaction in other animals, i.e. in case of complete learning.     

Differential effects of ethanol ingestion on somatostatin content, somatostatin receptors and adenylyl cyclase activity in the frontoparietal cortex of virgin and parturient rats

Chronic ethanol ingestion decreases the number of somatostatin (SRIF) receptors in the rat frontoparietal cortex and female sex hormones modulate the effects of ethanol in the brain. Therefore, we investigated the differential effects of ethanol consumption on the SRIFergic system in the frontoparietal cortex of virgin and parturient rats given ethanol in their drinking water before and during gestation. In parturient rats, ethanol consumption decreased the density of SRIF receptors (25%, p<0.01 vs control parturient group) whereas the SRIF-like immunoreactivity (SRIF-LI) content was increased (140%, p<0.01). In virgin rats, ethanol ingestion decreased the density of SRIF receptors (42%, p<0.01) more than in alcoholic parturient rats. SRIF-LI levels were unaffected. The inhibitory effect of SRIF on basal and forskolin-stimulated adenylyl cyclase was significantly lower in alcoholic virgin rats as compared to alcoholic parturient rats. No differences in the levels of the G inhibitory (Gi) alpha1 and Gialpha2 proteins were observed among the experimental groups. These results suggest that gestation may confer partial resistance to the ethanol-induced effect on the SRIFergic system.     

Central somatostatinergic regulation of growth hormone secretion in dwarf chickens.

1. Basal circulating growth hormone (GH) concentrations in sex-linked-dwarf (SLD) chickens were unaffected by the intracerebroventricular (icv) injection of 10, 50 or 100 micrograms somatostatin (SRIF). 2. The GH response to systemic thyrotropin-releasing hormone (TRH; 10 micrograms/kg, iv) was, however, 'paradoxically' enhanced 20 min after icv SRIF administration. 3. A lower dose (1.0 micrograms) of SRIF had no effect on basal or TRH-induced GH release. 4. High-titre SRIF antisera (4 microliters) also had no acute effect on basal plasma GH concentrations, but augmented the GH response to TRH challenge. 5. SRIF would appear to act at central sites to modulate stimulated GH secretion in SLD chickens.     

Administration of a nonpeptidyl growth hormone secretagogue, L-163, 255, changes somatostatin pattern, but has no effect on patterns of growth hormone-releasing factor in the hypophyseal-portal circulation of the conscious pig.

The activity of the growth hormone secretagog, L-163,255, on growth hormone (GH), growth hormone-releasing factor (GRF), and somatostatin (SRIF) levels was evaluated in a porcine model of hypophyseal portal blood (HPB) collection. Young, castrated pigs had HPB and jugular blood collected for approximately 300 min. The blood collection was divided into discrete periods: baseline (BL) approximately 180 min; GH response period (RSP) approximately 90 min; and positive control period following a GRF bolus, 30 min. RSP was divided into a dominant response period (DOM) and a tail (TL). The spontaneous relationship between HPB GRF and SRIF and peripheral GH during BL has been reported (Proc Soc Exp Biol Med 217:188-196, 1998). The apex of the GH pulse resulting from L-163,255 administration was nonrandomly associated (P < 0.05) with descending periods of SRIF troughs. Frequency and amplitude of GRF and SRIF pulses, and frequency and depth of SRIF troughs were not different between BL and the beginning of DOM (the 20-30 min of GH increase). GH AUC was significantly greater (P < 0.05) for DOM compared to BL and TL, and for TL compared to BL. GRF AUC tended to be greater (P < 0.1) for RSP compared to BL, but the majority of the increase was in the TL period. There were no significant differences in the SRIF AUCs between the sampling periods. Furthermore, in a separate experiment, fos activity (a marker of neuronal activation) in the hypothalamus of pigs was examined after either L-163,255 (1x or 4x), isotonic saline (control), or hypertonic saline (positive control) administration. There were no differences in fos activity in the GRF, SRIF, or CRH immunopositive neurons between L-163,255 treatment and control. The pituitaries of the L-163,255-treated pigs showed marked fos activation compared to the controls. In conclusion, L-163,255 in pigs has its primary effect at the level of the anterior pituitary.     

Genome sequencing for rightward hemispheric language dominance

Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.     

Motor and cognitive functions of the neostriatum during bilateral blocking of its dopamine receptors

In experiments on 60 Sprague-Dawley rats, effects of systemic and intrastriatal injections of se-lective blocker of D1 receptors SCH23390 on elaboration of discriminational conditioned reflex of active avoidance (CRAA) were studied in T-maze and on behavior in test of the "open field". Systemic administration of this inhibitor at doses of 0.025 mg/kg produced a several fold decrease of percentage of correct realizations of the discriminational CRAA and of motor activity in the "open field" test. Bilateral microinjections of SCH23390 into the rat neostriatum at a dose of 0.004-1.0 mkg did not deteriorate learning of the discriminational CRAA as compared with intact control, although a marked inhibition of motor activity was observed in the open field, test. Analysis of the data has also shown a statistically significant decrease of percentage of errors in the starting maze compartment in experiments with intrastriatal injection of SCH23390 to rats. At the same time, the intrastriatal injection to rats of raclopride, a blocker of D2 dopamine receptors, at a dose of 0.004 mkg produced a sharp and prolonged deterioration of learning of the discriminational CRAA. The data obtained have allowed the following conclusions to be made: 1. Difference of effects of the systemic and intrastriatal SCH23390 injections seems to be due to that the behavioral changes observed at the systemic administration can be provided predominanantly by structures differing from neostriatal D1 receptors; 2. Effect of nigrostriatal dopaminergic system on the neostriatum through D1 receptors is complex: activation of motor activity (efferent spine cells of the direct pathway) and a poor modulation of the learning process (large aspine cholinergic interneurons); 3. The modulation of the learning process seems to occur through neostriatal D2 receptors (large aspine cholinergic interneurons).     

Neuroanatomical connections between corticotropin-releasing factor (CRF) and somatostatin (SRIF) nerve endings and thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of rat hypothalamus.

In order to investigate the possible involvement of corticotropin-releasing factor (CRF) and somatostatin (SRIF) on thyrotropin-releasing hormone (TRH) neuronal cell activity in the rat hypothalamic paraventricular nucleus, we have proceeded to the simultaneous localization of CRF or SRIF and TRH. For this purpose, we used a dual immunostaining procedure that employed antibodies to CRF and SRIF and peroxidase-labeled goat anti-rabbit IgG as a first sequence, and antibodies to a cryptic fragment (Phe178-Glu199) of pro-TRH (to label TRH neurons) and alkaline phosphatase-labeled goat anti-rabbit IgG as the second sequence. A rich innervation of the paraventricular nucleus by immunoreactive CRF and SRIF fibers was observed. A large number of CRF and SRIF nerve endings were seen intimate anatomic proximity and often appeared to surround TRH-containing cell bodies. These results strongly suggest that TRH neurons might be regulated by both CRF and SRIF. These interactions might be the neuroanatomical basis for the already observed inhibitory effects of CRF and SRIF on TRH release.