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Clinical results of osanetant and talnetant (selective-NK₃ antagonists) indicate that blocking the NK₃ receptor could be beneficial for the treatment of schizophrenia. The objective of this study was to characterize the in vitro and in vivo properties of a novel dual NK₁/NK₃ antagonist, RO4583298 (2-phenyl-N-(pyridin-3-yl)-N-methylisobutyramide derivative).RO4583298 in vitro pharmacology was investigated using radioligand binding ([³H]-SP, [³H]-osanetant, [³H]-senktide), [³H]-inositol-phosphate accumulation Schild analysis (SP- or [MePhe⁷]-NKB-induced) and electrophysiological studies in guinea-pig substantia nigra pars compacta (SNpc). The in vivo activity of RO4583298 was assessed using reversal of GR73632-induced foot tapping in gerbils (GFT; NK₁) and senktide-induced tail whips in mice (MTW; NK₃).RO4583298 has a high-affinity for NK₁ (human and gerbil) and NK₃ (human, cynomolgus monkey, gerbil and guinea-pig) receptors and behaves as a pseudo-irreversible antagonist. Unusually it binds with high-affinity to mouse and rat NK₃, yet with a partial non-competitive mode of antagonism. In guinea-pig SNpc, RO4583298 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurones with an apparent non-competitive mechanism of action. RO4583298 (p.o.) robustly blocked the GFT response, and inhibited the MTW.RO4583298 is a high-affinity, non-competitive, long-acting in vivo NK₁/NK₃ antagonist; hence providing a useful in vitro and in vivo pharmacological tool to investigate the roles of NK₁ and NK₃ receptors in psychiatric disorders.

Infant-mother bodily contact is believed to be the species-typical pattern of immediate postpartum child care. Mothers and newborns engage in mutually beneficial interactions. Maternal odours stimulate breastfeeding activity and are implicated in individual recognition.Skin-to-skin contact and exposure to maternal odours facilitate infants' adaptation to the early postnatal environment.

An attempt was made to elicit maternal behavior in non-parturient Welsh pony mares through a combination of hormonal treatment and vaginal-cervical stimulation (VCS). Lactation was induced in 16 nonpregnant, non-parturient mares via a combination of estradiol, progesterone and a dopamine antagonist (sulpiride). During the adoption trials, each lactating mare was confined behind a padded bar and a newborn foal was held near her head. Eight of the mares received two 3-min periods of VCS when the foster foal was introduced. Following VCS, the foal was released and its interactions with the adoptive mare observed until the acceptance criterion was met (i.e. the mare accepted the foal at the udder with no signs of aggression). The remaining eight adoptive mares were treated in the same manner but did not receive VCS. All 16 non-parturient mares eventually accepted and nursed their adopted foal. However, acceptance latencies were significantly shorter for mares in the VCS condition than for those without VCS, and did not differ between the VCS condition and a group of control mares with their biological offspring. In subsequent choice tests, both groups of foster mares (with/without VCS), like the control mares, displayed a preference for their 'own' foal. Once the non-parturient mares accepted their foster foal, their maternal behavior resembled that of control mothers. The positive effect of VCS on maternal acceptance may reflect a release of oxytocin triggered by this treatment.

The desensitization characteristics of recombinant human 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors (VSV and INI isoforms) stably expressed in CHO-K1 (Chinese hamster ovary) cells was investigated by calcium fluorimetry. Comparative desensitization characteristics of the agonists 5-HT, m-chlorophenylpiperazine (mCPP), and 2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI) were performed. Human 5-HT(2C (INI)) receptors exhibited a greater degree of desensitization to all agonists tested than edited 5-HT(2C (VSV)) receptors. A 2-hr exposure to 5-HT resulted in a significantly larger reduction in response upon re-exposure to 5-HT at 5-HT(2C (INI)) receptors, as compared to 5-HT(2C (VSV)) receptors (72% and 47% respectively, P0.01). Both receptor isoforms were expressed at similar densities. Human 5-HT(2B) receptors exhibited the most dramatic degree of desensitization, with prior exposure to 5-HT reducing subsequent response to 5-HT by 80%, with an extremely rapid time-course (t(1/2)5 min). The response at 5-HT(2A) receptors was reduced by 54%. The partial agonists mCPP and DOI also elicited desensitization, generally in line with their relative efficacies at each receptor, but exhibited more rapid kinetic profiles than 5-HT. Heterologous desensitization of an endogenously expressed G(q/11)-coupled purinergic receptor was also examined following preincubation of the cell lines with 10 microM 5-HT. Only stimulation of 5-HT(2C (VSV)) receptors resulted in a profound attenuation of subsequent ATP mediated responses. These results demonstrate differing degrees of both homologous and heterologous desensitization of 5-HT(2) receptors. Additionally, the different desensitization profiles of 5-HT(2C (INI)) and 5-HT(2C (VSV)) receptor may be due to signal transduction differences caused by RNA editing.

1. The goal of this study was to characterize the agonist pharmacology of human 5-HT2A, 5-HT2B and 5-HT2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2. We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 3. Stimulation of all three receptors by 5-HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non-transfected control CHO-K1 cells. 4. The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW-723C86, d-norfenfluramine, Ro 60-0175 and LSD exhibited the following rank order of potency; 5-HT2B5-HT2C5-HT2A. Piperazines such as m-Chlorophenylpiperazine (mCPP), ORG-12962, MK-212 and also ORG-37684 exhibited a rank order of potency of 5-HT2C5-HT2B5-HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5-HT2A5-HT2B5-HT2C. 5. Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5-HT2C receptors but25% at either 5-HT2A or 5-HT2B receptors. 6. Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.

Humans, like other mammals, are capable of discriminating between kin and non-kin by olfactory cues alone. Shortly after birth, breastfed infants become familiar with, and respond preferentially to, their mother's unique odor signature. Mothers likewise recognize the characteristic scent of their newborn infant. Close biological relatives share somewhat similar odor signatures (presumably resulting from genetically mediated similarities in bodily biochemistry and metabolism) that could facilitate kin recognition.

About 1-2% of the human genome is allocated to production of receptors for the olfactory epithelium--a hint as to the possible importance of this chemical sense, which includes two anatomically distinct systems: the main olfactory system with sensory cells located in the upper part of the nasal cavity, and the vomero-nasal organ with sensory cells on the nasal septum. In adults, individual odours may influence mate preferences and a growing body of evidence indicates that naturally occurring odours play an important role in the mediation of the infant's behaviour. Even foetal olfactory learning seems to occur and breast odours from the mother exert a pheromone-like effect at the newborn's first attempt to locate the nipple. Newborns are generally responsive to breast odours produced by lactating women. Olfactory recognition may be implicated in the early stages of the mother-infant attachment process, when the newborns learn to recognize the own mother's unique odour signature--a process possibly facilitated by the high norepinephrine release and the arousal of the locus coeruleus at birth. New knowledge about human odour physiology may have diagnostic and therapeutic implications--the initiation and stabilization of breastfeeding and termination of apnoeic spells are mentioned as examples.

Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. The neurotransmitter pool of glutamate is stored in synaptic vesicles and, upon depolarization, is released into the synaptic cleft in a Ca(2+)-dependent fashion. Glutamate is cleared from the synaptic cleft by high-affinity, Na(+)-dependent uptake carriers located in both neurons and glia. Glutamate acts on several distinct families of receptors, each of which has multiple subtypes with distinct pharmacologic and physiologic properties. Under some conditions, glutamate and related compounds act as excitotoxins and might participate in the events leading to neuronal damage and death in a variety of acute and chronic neurologic disorders. The potential for glutamate to become an excitotoxin is highly dependent upon neuronal metabolic status. A great deal of interest in developing selective, well-tolerated glutamate receptor antagonists for the treatment of a variety of neurologic disorders exists.

The competitive N-methyl-D-aspartate (NMDA) receptor antagonist [3H]3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) interacts with two discrete binding sites, one of high- and the other of low-affinity, on rat forebrain synaptic plasma membranes. The high affinity site exhibited a Kd of 101.5 nM and a Bmax of 2.01 pmol/mg, while for the low affinity site the Kd was 4.11 microM with a Bmax of 19.7 pmol/mg. The glycine site antagonists 3-amino-1-hydroxy-2-pyrrolidone (HA-966), 1-aminocyclobutanecarboxylic acid (ACBC), the glycine site agonist 1-aminocyclopropanecarboxylic acid (ACC) and glycine itself (as well as the polyamines spermine and spermidine), enhanced [3H]CPP binding. When subjected to saturation analysis, this enhancement was found primarily to involve an increase in the affinity of the high affinity component of [3H]CPP binding. Neither of the parameters of the low affinity component of binding were affected. Although a similar enhancement was observed with the polyamines, the effects of these two classes of ligands were additive, consistent with their having actions at different recognition sites on the NMDA receptor complex.

The binding of [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) was studied in rat and human brain synaptic membranes. Specific binding was saturable, reversible and inhibited by a range of compounds active at N-methyl-D-aspartate (NMDA) receptors such as 2-amino-5-phosphonopentanoate (AP5), 2-amino-7-phosphonoheptanoate (AP7), NMDA and cis-2,4-methanoglutamate. Binding was heterogeneous as evidenced by non-linear Scatchard plots and Hill coefficients for binding inhibitors significantly different from unity. LIGAND analysis of the binding data indicated the likely presence of two distinct binding components for CPP, one of high (Kd values approx. = 70 nM) and the other of low (Kd values approx. 5 microM) affinity. Possible alterations in the binding of [3H]CPP to either site were investigated in medial frontal and medial temporal cortex from Alzheimer's disease brains and compared with control tissues, carefully matched for age and postmortem delay. While there were considerable inter-individual variations in binding, no significant differences were detected either between brain regions in either Alzheimer or control subjects, or between Alzheimer's disease and control brains. These data suggest the presence of at least two components of [3H]CPP binding in both rat and human brain tissue. The integrity of neither of these components is altered in Alzheimer's disease, consistent with a lack of gross alterations of NMDA receptors in this disorder.

Responses of recently parturient ewes to their familiar versus separated (i.e., unfamiliar) twin lambs were observed in an attempt to elucidate further the characteristics of the phenotypic traits (signatures) mediating maternal recognition and bonding. Ewes responded more positively to their familiar lamb than to its twin that had been isolated at birth. Nonetheless, those same mothers also discriminated between their separated twin and unfamiliar alien lambs. Alien lambs elicited similar rejection behavior regardless of whether they had been housed with their own mother or in isolation prior to testing. Lambs appear to have individually distinct (olfactory) signatures; however, the signatures of twin siblings may be sufficiently similar to enable the mother to detect a resemblance. No evidence suggests that acquired maternal labels play a role in either the acceptance of the ewe's own lamb(s) or rejection of aliens.

Both sorghum and soybeans are relatively new to most Iowa farmers. These crops have usually been late summer or supplementary crops. They may, in normal seasons, be planted from May to August; and since early-, medium-, ’and late-maturing varieties have been available, considerable variation in maturity has occurred at the time of the first killing frost. The result of the .indiscriminate planting of varieties at different periods of the summer and attempts to save seed irrespective of its condition in the fall has been low viability in many seed lots. Because of this condition a study was made of the effect of freezing temperatures on the subsequent viability of sorghum

A series of experiments investigated the salience of newborn infants' facial-visual features for recognition and sex identification. Within 33 hours post-partum, mothers recognized photographs of their own offspring when presented with those of unrelated neonates. Furthermore, adult subjects were able to match photographs of unfamiliar mothers and their infants, and determine the sex of neonates, at a greater than chance level of accuracy. Although recognizable facial features are presumably genetically determined, maternal recognition of offspring probably results from brief exposure and familiarization as well as physical resemblance between the infant and other familiar family members, including the mother herself.

A series of experiments investigated the responses of human infants to olfactory cues produced by lactating females. 2-week-old bottle-feeding girls oriented preferentially to the breast odor (odorized pad) of a nursing woman when paired with such odors from either a nonparturient female or axillary odors from the same lactating female. Responses to axillary odor from a lactating female did not differ from those to a clean (nonodorized) pad. These data indicate that breast odors from lactating females are especially attractive to female infants who are unfamiliar with the stimulus woman and who have had no prior breast-feeding experience.

A series of 5 experiments was conducted to determine whether neonates, at approximately 2 weeks of age, can recognize their parents through axillary odors alone. Breast-feeding infants discriminated between their mother's axillary odor and odors produced by either nonparturient or unfamiliar lactating females. In contrast, breast-feeding infants displayed no evidence of recognizing the axillary odors of their father. Likewise, bottle-feeding infants appeared unable to recognize the odor of their mother when presented along with odors from a nonparturient female or an unfamiliar bottle-feeding female. Several hypotheses were presented in an attempt to account for the differential reactions to maternal odors by breast-feeding versus bottle-feeding infants. It was tentatively concluded that, while breast-feeding, infants are exposed to salient maternal odors and thereby rapidly become familiarized with their mother's unique olfactory signature.

Kin recognition, which can be inferred from differential interactions amongst close relatives as compared to unrelated conspecifics, has been documented in a wide range of vertebrates and invertebrates. Kin may be discriminated by phenotypic traits (signatures) that are genetically mediated, acquired from the environment, or arise from an interaction between these two sources. The developmental mechanisms underlying recognition of relatives (or their signatures) include direct contact and familiarization, indirect familiarity (whereby previously unencountered individuals are recognized by their resemblance to familiar kin) and hypothetical recognition alleles. The biological significance and mediating mechanisms of kin recognition vary across species according to their ecology and natural history. To illustrate this point, the results of laboratory and field studies of larvae of several species of toads and frogs are reviewed.