Orientational Coherent Effects of High-Energy Particles in a LiNbO3 Crystal.

A bent lithium niobate strip was exposed to a 400-GeV/c proton beam at the external lines of CERN Super Proton Synchrotron to probe its capabilities versus coherent interactions of the particles with the crystal such as channeling and volume reflection. Lithium niobate (LiNbO3) exhibits an interplanar electric field comparable to that of Silicon (Si) and remarkable piezoelectric properties, which could be exploited for the realization of piezo-actuated devices for the control of high-energy particle beams. In contrast to Si and germanium (Ge), LiNbO3 shows an intriguing effect; in spite of a low channeling efficiency (3%), the volume reflection maintains a high deflection efficiency (83%). Such discrepancy was ascribed to the high concentration (10(4) per cm2) of dislocations in our sample, which was obtained from a commercial wafer. Indeed, it has been theoretically shown that a channeling efficiency comparable with that of Si or Ge would be attained with a crystal at low defect concentration (less than ten per cm2). To better understand the role of dislocations on volume reflection, we have worked out computer simulation via dynecharm++ Monte Carlo code to study the effect of dislocations on volume reflection. The results of the simulations agree with experimental records, demonstrating that volume reflection is more robust than channeling in the presence of dislocations.

Cannabinoid CB1 receptors in the paraventricular nucleus and central control of penile erection: immunocytochemistry, autoradiography and behavioral studies.

[N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (SR 141716A), a selective cannabinoid CB1 receptor antagonist, injected into the paraventricular nucleus of the hypothalamus (PVN) of male rats, induces penile erection. This effect is mediated by the release of glutamic acid, which in turn activates central oxytocinergic neurons mediating penile erection. Double immunofluorescence studies with selective antibodies against CB1 receptors, glutamic acid transporters (vesicular glutamate transporters 1 and 2 (VGlut1 and VGlut2), glutamic acid decarboxylase-67 (GAD67) and oxytocin itself, have shown that CB1 receptors in the PVN are located mainly in GABAergic terminals and fibers surrounding oxytocinergic cell bodies. As GABAergic synapses in the PVN impinge directly on oxytocinergic neurons or on excitatory glutamatergic synapses, which also impinge on oxytocinergic neurons, these results suggest that the blockade of CB1 receptors decreases GABA release in the PVN, increasing in turn glutamatergic neurotransmission to activate oxytocinergic neurons mediating penile erection. Autoradiography studies with [(3)H](-)-CP 55,940 show that chronic treatment with SR 141716A for 15 days twice daily (1 mg/kg i.p.) significantly increases the density of CB1 receptors in the PVN. This increase occurs concomitantly with an almost twofold increase in the pro-erectile effect of SR 141716A injected into the PVN as compared with control rats. The present findings confirm that PVN CB1 receptors, localized mainly in GABAergic synapses that control in an inhibitory fashion excitatory synapses, exert an inhibitory control on penile erection, demonstrating for the first time that chronic blockade of CB1 receptors by SR 141716A increases the density of these receptors in the PVN. This increase is related to an enhanced pro-erectile effect of SR 141716A, which is still present 3 days after the end of the chronic treatment.

Neuromodulation of penile erection: an overview of the role of neurotransmitters and neuropeptides.

erection is regulated by several neurotransmitters and neuropeptides at penile tissue and central nervous system levels. At penile level, the key event is the relaxation of corpora cavernosa smooth muscles. Here, three kinds of neural autonomic control have been characterized in detail. one adrenergic stimulatory, that under normal conditions maintains the corpora cavernosa contracted (that is a flaccid penis), a second cholinergic inhibitory that is believed to cooperate with a third, nonadrenergic-noncholinergic control also inhibitory, possibly mediated by nitric oxide (NO), to reduce the adrenergic tone favouring the relaxation of corpora cavernosa, as during a sexual stimulus. However, the complex interactions between these neurotransmitters that determine the final condition of the corpora cavernosa, e.g. the presence or the absence of penile erection, are still a matter of controversy. This is further complicated by the presence of several neuropeptides in nervous penile vascular and smooth muscle tissues such as vasoactive intestinal polypeptide, peptide histidine- isoleucine, peptide histidine-methionine, neuropeptide Y and endothelins,that often exert very potent (relaxant or contractant) effects in penile tissues. Also at the central level, several neurotransmitters and neuropeptides that influence penile erection have been identified. Among neurotransmitters, the most studied are dopamine (DA), serotonin (SHT), acetylcholine (ACh), glutamic acid and NO. DA, ACh. glutamic acid and NO seem to have a facilitatory role, while 5HT may be either facilitatory or inhibitory, depending on the receptor subtype involved. Among neuropeptides, the best known are oxytocin, adrenocorticotropin (ACTH)-cc-melanocyte stimulating hormone (r-MSH)-related peptides and opioid peptides. Interestingly DA, glutamic acid and NO seem to facilitate while opioid peptides inhibit penile erection by increasing and decreasing, respectively, central oxytocinergic transmission by acting in the paraventricular nucleus of the hypothalamus. ACTH-MSH peptides also facilitate penile erection, although with a mechanism(s) different from those recalled above. Despite some recent progress, more has still to be done to clarify the role played by neurotransmitters and neuropeptides at peripheral and central levels in the control of this primary sexual function.

A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance.

The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily. Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 [n = 24] vs. 6.30 +/- 1.39 mg x kg(-1) x min(-1) [n = 49], P = 0.005). Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28-7.0], P < 0.001). Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs. 17.5 +/- 15 ng/mg protein, P = 0.3). These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.

A PC-1 amino acid variant (K121Q) is associated with faster progression of renal disease in patients with type 1 diabetes and albuminuria.

Insulin resistance characterizes type 1 diabetes in patients with albuminuria. A PC-1 glycoprotein amino acid variant, K121Q, is associated with insulin resistance. We examined the impact of the PC-1 K121Q variant on the rate of decline of the glomerular filtration rate (GFR) by creatinine clearance derived from the Cockroft-Gault formula in 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years (range 2.5-15). Patients carrying the Q allele (n = 22; 20 with KQ and 2 with QQ genotypes) had a faster GFR decline than those patients with the KK genotype (n = 55) (median 7.2 vs. 3.7 ml x min(-1) x year(-1); range 0.16 to 16.6 vs. -3.8 to 16.0 ml x min(-1) x year(-1); P < 0.001). Significantly more patients carrying the Q allele belonged to the highest tertile of GFR decline (odds ratio = 5.7, 95% CI 4.1-7.2, P = 0.02). Levels of blood pressure, HbA1c, and albuminuria were comparable in the two genotype groups. Albuminuria (P = 0.001), mean blood pressure (P = 0.046), and PC-1 genotype (P = 0.036) independently correlated with GFR decline. Because all patients were receiving antihypertensive treatment, the faster GFR decline in the patients carrying the Q allele could be the result of reduced sensitivity to the renoprotective effect of antihypertensive therapy. PC-1 genotyping identifies type 1 diabetic patients with a faster progression of diabetic nephropathy.

A cluster of three single nucleotide polymorphisms in the 3'-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities.

Glycoprotein PC-1 inhibits insulin signaling and, when overexpressed, plays a role in human insulin resistance. Mechanisms of PC-1 overexpression are unknown. We have identified a haplotype in the 3'-untranslated region of the PC-1 gene that may modulate PC-1 expression and confer an increased risk for insulin resistance. Individuals from Sicily, Italy, carrying the "P" haplotype (i.e., a cluster of three single nucleotide polymorphisms: G2897A, G2906C, and C2948T) were at higher risk (P < 0.01) for insulin resistance and had higher (P < 0.05) levels of plasma glucose and insulin during an oral glucose tolerance test and higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. They also had higher (P < 0.05-0.01) PC-1 protein content in both skeletal muscle and cultured skin fibroblasts. In CHO cells transfected with either P or wild-type cDNA, specific PC-1 mRNA half-life was increased for those transfected with P (t/2 = 3.73 +/- 1.0 vs. 1.57 +/- 0.2 h; P < 0.01). In a population of different ethnicity (Gargano, East Coast Italy), patients with type 2 diabetes (the most likely clinical outcome of insulin resistance) had a higher P haplotype frequency than healthy control subjects (7.8 vs. 1.5%, P < 0.01), thus replicating the association between the P allele and the insulin resistance-related abnormalities observed among Sicilians. In conclusion, we have identified a possible molecular mechanism for PC-1 overexpression that confers an increased risk for insulin resistance-related abnormalities.

Neuropeptides and sexual behaviour.

Many neuropeptides are involved in the control of sexual behaviour at the central level. Among these, the most studied are adrenocorticotropin, alpha-melanocyte stimulating hormone, oxytocin and opioid peptides. This attempt to review old and new neuropharmacological, biochemical and psychobiological studies in this field, shows that all these neuropeptides apparently facilitate sexual behaviour, except for opioid peptides, which inhibit sexual performance, in most of the species studied so far (rats, mice, monkeys and humans). However, gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin, cholecystokinin, substance P and vasoactive intestinal peptide may be also involved in the control of sexual behaviour. Apparently, corticotropin releasing factor, neuropeptide Y and cholecystokinin inhibit, while substance P and vasoactive intestinal peptide facilitate, sexual behaviour. In contrast, gonadotropin-releasing hormone has been reported to exert a facilitative, inhibitory or no effect at all on sexual behaviour. Galanin was also shown either to facilitate or inhibit sexual behaviour. The above-mentioned putative role of the neuropeptides in sexual behaviour derives mainly from studies done in rats. In these studies, neuropeptides, their antisera or drugs that act as agonists or antagonists of neuropeptide receptors, were tested for their effect on sexual behaviour after systemic, intracerebroventricular, or intracerebral administration. The latter were infused into brain areas relevant for sexual behaviour, such as the medial preoptic area, and the ventromedial and paraventricular nuclei of the hypothalamus. The above studies show that little information is available on the mechanisms by which neuropeptides influence sexual behaviour. Also unclear is whether the above neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behaviour, except for opioid peptides. New information about the role of neuropeptides may come from the application of molecular biology and genetic manipulation techniques to the study of sexual behaviour. Of these, FOS protein determination, antisense oligonucleotides aimed at the neutralisation of neuropeptide and/or neuropeptide receptor mRNAs in specific brain areas, and gene ablation seem the most promising. Although still in the early stages, it is likely that these methodologies will provide new insights into the role of neuropeptides in the control of sexual behaviour.

Dopamine and sexual behavior.

Among central neurotransmitters involved in the control of sexual behavior, dopamine is certainly one of the most extensively studied. Our attempt to review old and recent neuropharmacological, biochemical, electrophysiological, and psychobiological studies performed so far only in rats, monkeys, and humans, provides evidence that dopamine through its different neuronal systems and receptor subtypes plays different roles in the control of several aspects of sexual behavior. In fact, while the nigrostriatal system is necessary for the control of the sensory-motor coordination required for copulation, the mesolimbic-mesocortical system plays a key role in the preparatory phase of the behavior, mainly in sexual arousal, motivation and possibly reward. Conversely, the incertohypothalamic system plays a major role in the consummation of the behavior, mainly in seminal emission and erectile performance, but evidence for its involvement in sexual motivation also exists. The dopaminergic receptors playing the major role in the control of male sexual behavior belong to the D2 receptor subtype. However a D1/D2 receptor interaction is well established and an opposite role for D1 and D2 receptors in the preoptic area suggested. Despite some differences, most studies show that treatments that increase or decrease, respectively, brain dopaminergic activity improve or worsen, respectively, several parameters of copulatory activity, supporting a facilitatory role of dopamine in male sexual behavior. In contrast, no conclusion can be deduced from the available studies on the role of central dopaminergic systems in the control of proceptivity and receptivity, the two main components of female sexual behavior.

Central functions of oxytocin.

Oxytocin, the peptide well-known for its hormonal role in parturition and lactation, is present in several extrahypothalamic brain areas besides the neurohypophyseal system. The peptide is found in neurons which send their projections to brain areas containing specific oxytocin-binding sites. Oxytocin is also released from its synapses in a calcium-dependent fashion and may be the precursor of potent behaviorally active neuropeptides. These findings suggest that this ancient neuropeptide acts as a neurotransmitter in the central nervous system. We have attempted to review the most recent behavioral, morphological, electrophysiological and neurochemical studies providing evidence that oxytocin plays an important role in the expression of central functions, such as maternal behavior, sexual behavior (penile erection, lordosis and copulatory behavior), yawning, memory and learning, tolerance and dependence mechanisms, feeding, grooming, cardiovascular regulation and thermoregulation.

alpha-Melanocyte-stimulating hormone during human perinatal life.

To obtain information on human pituitary intermediate lobe activity throughout the perinatal period, plasma alpha MSH immunoreactivity (IR) was measured in 106 newborns at delivery and during the first week of postnatal life. Subjects were divided into groups according to gestational age at birth, mode of parturition, and antenatal state of health. Plasma alpha MSH IR decreased progressively from severe preterm to fullterm neonates born by vaginal delivery (VD; P < 0.001) or cesarean section (CS) with and without prenatal distress (P < or = 0.001 in both cases). alpha MSH IR was due, in all studied conditions, to three major forms: desacetyl alpha MSH, alpha MSH, and diacetyl alpha MSH. Desacetyl alpha MSH was always the most represented form, but it decreased from 75-80% of the total in severe premature to 40-45% in mature infants. In term neonates, total alpha MSH IR values were higher in subjects born by normal VD than by elective CS (P < or = 0.05), in complicated than in normal VD (P < or = 0.01), and in CS performed because of fetal distress than in elective CS (P < or = 0.01). No significant difference was detectable in mature subjects in the percentages of the three alpha MSH forms in relation to the mode of delivery and fetal state during antenatal life or at parturition. Twelve hours after birth, total alpha MSH IR significantly decreased in all groups of term newborns, reaching a plateau of 0.8-1.4 pmol/L. In premature infants, similar concentrations were detectable by the fourth postnatal day. We conclude that 1) alpha MSH IR intermediate lobe secretion progressively decreases throughout the third trimester of pregnancy; 2) stress, including that pertinent to parturition, stimulates alpha MSH IR release; and 3) pituitary intermediate lobe activity declines shortly after birth independently of the maturity reached by the fetus, the mode of parturition, and the presence of antenatal chronic distress, although the process is slightly retarded in premature newborns.

Brain proteolysis of oxytocin in vitro and in vivo changes during aging in male rats.

Oxytocin proteolysis was studied in vitro with purified synaptic membranes and in vivo after injection into the hippocampus of male Wistar Kyoto rats of different ages. When oxytocin was incubated in vitro with brain synaptic membranes obtained from 2-, 6-, and 12-month-old rats, no difference in the content of C-terminal and N-terminal fragments formed by membrane-bound aminopeptidase-like and endopeptidase-like enzymes, respectively, was found after high performance liquid chromatography separation and quantification by amino acid analysis. In contrast, the content of all fragments decreased by about 20%-25% when membranes obtained from 18- and 24-month-old rats were used. When [3H-Tyr2]oxytocin was injected in vivo in the hippocampus of 2-, 6-, 12-, and 18-month-old rats, no difference in the content of free [3H]-tyrosine and other [3H]-labelled fragments was found in the hippocampal peptidic extract after high performance liquid chromatography fractionation. However, the content of all radioactive fragments was about 50% lower in the extract from 24-month-old rats. The findings suggest that oxytocin proteolysis in brain decreases during aging. Such a decrease might counterbalance the impairment of central oxytocinergic transmission caused by the age-related decrease of oxytocin content in brain.

Oxytocin concentration changes in different rat brain areas but not in plasma during aging.

The concentration of oxytocin was measured by radioimmunoassay in different brain areas, hypophysis, and plasma of male Wistar Kyoto rats during aging. Although no difference in the concentration of oxytocin in any of the above tissues among 2- and 6-month-old rats was found, in 12-month-old rats a 21% decrease was observed in both septum and hippocampus, but not in the hypothalamus, hypophysis, and plasma, when compared to values of 2- and 6-month-old rats. In 18-month-old rats, the decrease of septal and hippocampal oxytocin content was higher than that found in 12-month-old rats, but no change was found in the hypothalamus, neurohypophysis, and plasma. In 24-month-old rats, oxytocin content was similar to that found in 18-month-old rats in all tissues analyzed. The results suggest that aging induces an impairment of oxytocinergic transmission in the central nervous system but not in the neurohypophyseal system.

Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain.

The effect of morphine administered systemically or into the paraventricular nucleus of the hypothalamus (PVN) on penile erection and yawning induced either by oxytocin or by the dopaminergic agonist apomorphine was studied in male rats. Systemic morphine (0.5 to 5 mg/kg intraperitoneally [IP]) prevented in a dose-dependent manner penile erection and yawning induced by the intracerebroventricular injection (ICV) of oxytocin (30 ng) or by the subcutaneous (SC) administration of apomorphine (80 micrograms/kg). Morphine (0.1 to 5 micrograms), but not U-69,593 (5 micrograms), injected into the PVN 10 minutes before oxytocin or apomorphine, was found to be able to prevent penile erection and yawning induced by the unilateral PVN microinjection of oxytocin (10 ng) or apomorphine (50 ng). The morphine-induced prevention of these behavioral responses was abolished by pretreatment with naloxone (3 mg/kg IP) 15 minutes before morphine. The present results suggest that morphine prevents apomorphine- and oxytocin-induced penile erection and yawning by inhibiting the activity of oxytocinergic neurons through mu-type receptors in this hypothalamic nucleus.

Central oxytocinergic neurotransmission: a drug target for the therapy of psychogenic erectile dysfunction.

A group of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to extrahypothalamic brain areas (e.g. hippocampus, medulla oblongata and spinal cord) control penile erection. Activation of these neurons by dopamine and dopamine agonists, excitatory amino acids (N-methyl-D-aspartic acid) or oxytocin itself, or by electrical stimulation leads to penile erection, while their inhibition by GABA and GABA agonists or by opioid peptides and opiate-like drugs inhibits this sexual response. The activation of oxytocinergic neurons in the paraventricular nucleus by dopamine, oxytocin and excitatory amino acids is apparently secondary to the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as yet unidentified, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Several peptide analogues of hexarelin, a growth hormone releasing peptide, also induce penile erection when injected into the paraventricular nucleus and, to a lesser extent, systemically, apparently by acting on a specific receptor to activate oxytocinergic neurons as shown for the above drugs and oxytocin. Paraventricular oxytocinergic neurons and mechanisms similar to those reported above are also involved in the expression of penile erection in physiological contexts, namely when penile erection is induced in the male by the presence of an inaccessible receptive female, which is considered a model for psychogenic impotence in man, as well as during copulation. These findings show that paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and to the spinal cord are a likely target for the treatment of erectile dysfunction of central origin.

Nitric oxide is a central mediator of penile erection.

In order to evaluate a possible role of brain nitric oxide (NO) on the control of penile erection, the effect of nitroglycerin, that is thought to act by producing NO, was studied on spontaneous penile erection in male rats. In addition the effect of drugs that prevent NO formation and/or activity such as NG-nitro-L-arginine methyl ester (NAME) and methylene blue, on N-methyl-D-aspartic acid (NMDA)-, apomorphine- and oxytocin-induced penile erection was also studied. Nitroglycerin induced penile erection in a dose-dependent manner when given intracerebroventricularly (i.c.v.) (33-99 micrograms) or in the paraventricular nucleus of the hypothalamus (0.8-3.3 micrograms). Nitroglycerin-induced penile erection was prevented by the guanylate cyclase inhibitor methylene blue injected i.c.v. (200-400 micrograms) but not in the paraventricular nucleus of the hypothalamus (10-20 micrograms). Conversely, NMDA-, apomorphine- and oxytocin-induced penile erection was prevented by NAME (150 micrograms) or methylene blue (400 micrograms) given i.c.v. NAME (20 micrograms), but not methylene blue (20 micrograms), was effective in preventing the behavioral response also when injected in the paraventricular nucleus. The present results suggest that NO is a common mediator of several neurotransmitters involved in the control of this primary male sexual function.

EP 91073 prevents EP 80661-induced penile erection: new evidence for the existence of specific EP peptide receptors mediating penile erection.

The effect of EP 91073, EP 51389, EP 70555 and EP 51216, peptide analogues of the growth hormone releasing peptide hexarelin, on penile erection induced by EP 80661 or EP 60761 injected into the paraventricular nucleus of the hypothalamus, was studied in male rats. Of the above peptides only EP 91073 (0.2-1 microg) was found capable of reducing penile erection induced by EP 80661 or EP 60761, when given into the paraventricular nucleus. Despite its ability to prevent EP peptide-induced penile erection, EP 91073 (1 microg) was unable to prevent penile erection induced by the dopamine receptor agonist apomorphine (50 ng), oxytocin (30 ng) and N-methyl-D-aspartic acid (50 ng), when given into the paraventricular nucleus 10 min prior to the above substances. The EP 91073-induced prevention of penile erection occurred with a reduction in the increase in nitric oxide production that occurs in the paraventricular nucleus concomitant to penile erection induced by EP 80661 and EP 60761, as measured by intracerebral vertical microdialysis. The present results are in line with the hypothesis that EP 80661 and EP 60761 induce penile erection by activating specific receptors in the paraventricular nucleus, located possibly in oxytocinergic neurons mediating penile erection, and show that EP 91073 acts as an antagonist of these EP peptide receptors mediating penile erection.

Effect of excitatory amino acid, dopamine, and oxytocin receptor antagonists on noncontact penile erections and paraventricular nitric oxide production in male rats.

In male rats, noncontact erections occur concomitantly with an increase in NO2- and NO3- in the paraventricular nucleus of the hypothalamus (PVN). In the present study, both responses were reduced by the blockade of PVN excitatory amino acid receptors by dizocilpine, (+)-MK-801(1 and 5 microg), but not by 6-cyano-7-nitro-quinoxaline-2,3-dione (5 microg) or (+)-2-amino-4-phosphono-butanoic acid (5 microg). Also ineffective when injected into the PVN were the dopamine antagonists SCH 23390 (5 microg), S(+)-raclopride (10 microg), and cis-flupenthixol (10 microg), and the oxytocin antagonist d(CH2)5Tyr(Me)2-Om8-vasotocin (1 microg). However, when the last was given into the lateral ventricles, it reduced noncontact erections without modifying NO2- and NO3- increases. These results suggest that excitatory amino acid transmission increases in the PVN during noncontact erections. This may contribute to increased NO production in the PVN, and it may activate oxytocin neurons mediating this sexual response.

Oxytocin-induced penile erection and yawning in male rats: effect of neonatal monosodium glutamate and hypophysectomy.

Penile erection and yawning induced by the intracerebroventricular (ICV) injection of oxytocin (10-1000 ng) was studied in hypophysectomized rats and in rats neonatally treated with monosodium glutamate (MSG), a treatment that depletes hypothalamic opiomelanocorticotropin-derived peptides without altering their pituitary and circulating concentration. Oxytocin effect was strongly reduced by hypophysectomy, but not by neonatal MSG. Testosterone replacement (50 micrograms/kg/day for 23 days) partially reversed the effect of hypophysectomy on penile erection, but not on yawning. The present results suggest that oxytocin does not induce penile erection and yawning by releasing an ACTH-derived peptide from hypothalamic opiomelanotropinergic neurons, and that the pituitary gland exerts a permissive role on the expression of the above behavioural responses induced by oxytocin.

Repeated electroconvulsive shock prevents the sedative effect of small doses of apomorphine.

Repeated electroconvulsive shock (ECS) (one shock daily for 8 days), but not single ECS, eliminates the sedative response to small doses of apomorphine (25--1000 microgram/kg) and potentiates the stimulant response to high doses (200 microgram/kg) of the drug in rats. This effect is observed 1 and 4 days after the last ECS. However, repeated ECS does not prevent the inhibitory effect of apomorphine on dopamine (DA) synthesis. The results suggest that repeated ECS may lead to the development of subsensitivity in DA receptors that mediate sedation and that these receptors are differentiated from those controlling DA synthesis.

Proteolytic conversion of oxytocin in vivo after microinjection in the rat hippocampus.

Since previous studies in vivo have shown that oxytocin is metabolized by rat synaptic membrane-bound aminopeptidase- and endopeptidase-like enzymes, the proteolytic conversion of oxytocin was studied in vivo after microinjection in the rat hippocampus, a brain area that contains oxytocinergic nerve endings and receptors. Isolation of the formed peptide fragments from the injected brain area after homogenization and adsorption on a Sep-Pak cartridge by high performance liquid chromatography, and their characterization by amino acid analysis, revealed that, when oxytocin (50 nmol in 0.5 microliter) was microinjected in the CA1 field of the rat hippocampus, only the N-terminal fragment oxytocin(1-8) was formed in such amount that could be characterized. The microinjection of [3H-Tyr2]oxytocin (10 pmol) revealed that in addition to oxytocin(1-8), free [3H]tyrosine was formed. Taken together with previous findings showing that C-terminal oxytocin fragments as well oxytocin(1-8) are formed by membrane-bound aminopeptidases and endopeptidases in vitro, respectively, the results suggest that, in addition to aminopeptidases, endopeptidase-like enzymes are involved in the proteolysis of endogenous brain oxytocin.