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T R Insel

Publications and source records attributed to T R Insel.

At least 91 records · Page 5Linked to original sources
PubMed1992

Effects of chlordiazepoxide and beta-carboline 3-carboxylic acid ethyl ester on non-suppressed and minimally-suppressed responding in the squirrel monkey.

Lever-pressing of squirrel monkeys was maintained under a multiple fixed-interval (FI) 5-min schedule of food presentation. In one component, responding was suppressed to various degrees by the presentation of electric shock following each 30th response. When responding was either substantially or minimally suppressed, intermediate doses of chlordiazepoxide (CDAP, 1-30 mg/kg) increased both suppressed and non-suppressed responding. Beta-carboline 3-carboxylic acid ethyl ester (beta-CCE, 0.1-3 mg/kg) had little effect at low to intermediate doses (0.1-0.3 mg/kg) and decreased both minimally-suppressed and non-suppressed responding to a comparable extent at higher doses. Repeated daily dosing with beta-CCE (up to 10 mg/kg) resulted in rapid tolerance to its rate-decreasing effects. As agonists do not typically exhibit rapid tolerance for anxiolytic efficacy, the current results suggest that some behavioral effects of inverse agonists may not be strictly opposite those of benzodiazepines.

Animals↗
PubMed1992

Enhanced social interactions in rats following chronic, centrally infused oxytocin.

Most studies investigating the behavioral effects of centrally administered oxytocin (OT) have been confined to single acute injections followed by brief behavioral observations lasting up to 90 min. The present study examines the behavioral effects of chronic, centrally administered OT in male rats observed continuously for prolonged periods of time. Either artificial cerebrospinal fluid or OT was centrally infused (via osmotic minipump) to gonadally intact male rats. Behavioral observations were made on males paired with either ovariectomized or estrous females during a 6-h time period. Most striking was the observation that durations of physical contact were doubled in pairs containing OT-infused males, even in the absence of sexual interactions. Also, OT-infused males showed significantly higher levels of anogenital sniffing of females and autogrooming; however, sexual interactions were unaffected by chronic OT. Chronic OT had no effect on body temperature, analgesia, or exploratory behavior in an open field. These findings suggest that chronic OT in male rats has behavioral effects that may significantly enhance adult social (nonsexual) interactions, possibly through alterations in olfactory and somatosensory information processing.

Analgesia↗
PubMed1992

Oxytocin--a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies.

Oxytocin (OT) is a nine amino acid peptide synthesized in hypothalamic cells which project either to the neurohypophysis or to sites within the central nervous system. Although neurohypophyseal OT release has long been associated with uterine contraction and milk ejection, the function of intracerebral OT remains unclear. On the basis of behavioral, cellular, and comparative studies, this review suggests that brain OT influences the formation of social bonds. The first part of this review examines evidence linking central OT to several forms of affiliation. Central administration of OT induces maternal and reproductive behaviors in rats primed with gonadal steroids. OT antagonists and hypothalamic lesions block the initiation of maternal and reproductive behaviors but have no effects on these behaviors once established. Our new studies in rat pups demonstrate that central OT selectively decreases the separation response, an effect which mimics social contact. These studies of parental, reproductive, and attachment behaviors suggest that exogenous OT has "prosocial" effects and that endogenous OT may be essential for initiating social interaction. In a second series of experiments, we investigated the cellular mechanisms for OT's effects on social behavior by means of autoradiographic receptor binding. In the rat forebrain, OT receptors are expressed in several limbic regions believed to be involved in the integration of sensory processing. The regulation of these receptors is surprisingly resistant to either ablation of OT cells or repeated central administration of OT. However, receptors in two regions, the bed nucleus of the stria terminalis (BNST) and the ventromedial nucleus of the hypothalamus (VMN), appear selectively induced by exogenous or endogenous increases in gonadal steroids. At parturition, binding to OT receptors increases 84% in the BNST, and at estrus, binding increases 35% in the VMN. These results demonstrate that physiologic changes in gonadal steroids can alter receptor expression in anatomically discrete target fields and thereby direct responsiveness to endogenous neuropeptide release. A model for OT's effects on social behavior is proposed, which relies on the heterologous regulation of the brain OT receptor. A third series of experiments tested the hypothesis that brain OT influences affiliation by comparing prairie and montane voles, two closely related species with dichotomous systems of social organization. Although no differences appear in the presynaptic expression of the neuropeptide, OT receptors are distributed in complementary patterns in the two species. In the highly affiliative prairie vole, receptors are most evident in the BNST and one of its primary afferents, the lateral amygdala, highlighting a circuit previously implicated in maternal behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Homologous regulation of brain oxytocin receptors.

Specific receptors for oxytocin have been identified in rat forebrain. Previous studies have demonstrated that in select regions, these receptors are dependent on heterologous induction by gonadal steroids. To investigate whether brain oxytocin receptors are homologously regulated by oxytocin, we measured oxytocin receptor binding after hypothalamic paraventricular nucleus lesions, repeated central injections of oxytocin, and continuous central infusion of oxytocin via osmotic minipump. Neither lesions of the paraventricular nucleus nor repeated oxytocin injections altered the binding of the selective oxytocin receptor ligand [125I]OTA [125I] d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)] ornithine vasotocin, as measured by in vitro receptor autoradiography. After 10 days of continuous oxytocin infusion by osmotic minipump, oxytocin receptor binding decreased in every target field by at least 50%. This decrease appeared to represent a down-regulation of receptors and not displacement by exogenous peptide, as it persisted for at least 24 h after pump removal, and binding remained reduced in the presence of a saturating concentration of [125I] OTA. Reduction of oxytocin receptors in response to increased oxytocin release may represent an important physiological mechanism for the regulation of central oxytocin neurotransmission.

Animals↗
PubMed1992

Neurobiology of obsessive compulsive disorder.

In this brief review of two of the neurobiologic aspects of OCD, two simplistic models have been suggested. Although these models reflect different perspectives, they may not be independent. For instance, the striatum, which is a focus for the neuroanatomic model, receives a dense serotonergic projection from the dorsal raphé. Similarly, as mentioned previously, combining PET studies and drug treatment demonstrates that the increased metabolic activity seen in the orbital cortex appears to normalize with serotonin uptake inhibitor treatment. Insights into the neurobiology of this syndrome will require combining perspectives as well as developing additional approaches. In addition, the search for neurobiologic abnormalities must be guided by a continuing regard for phenomenology. There is no reason, a priori, to assume that this syndrome subsumes only one disorder. The careful dissection of subgroups--whether based on symptom type, character style, or comorbid diagnoses--will be increasingly vital for understanding the results of neuropharmacologic and functional imaging studies.

Brain↗
PubMed1991

Central administration of oxytocin modulates the infant rat's response to social isolation.

Several lines of evidence suggest that oxytocin modulates the formation and maintenance of social bonds. In the current experiments we investigated the influence of centrally and peripherally administered oxytocin on the behavior of 6-8 day old rat pups during brief periods of social isolation. Ultrasonic vocalizations emitted by isolated pups were decreased following i.c.v. administration of oxytocin, at doses (500, 1000 ng) which did not affect motor activity. S.c. administered oxytocin (1, 10 micrograms) produced a biphasic change in ultrasonic vocalizations, depending on dose. Central administration of the oxytocin antagonist (d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH2(9)]OVT) (OTA, 500 ng) did not measurably affect pup behavior by itself but did block the decrease in calls following central but not peripheral administration of oxytocin. These data demonstrate that oxytocin via its central receptor can regulate the response to social isolation.

Angiotensin Receptor Antagonists↗
PubMed1991

Vasopressin modulates male squirrel monkeys' behavior during social separation.

The central administration of arginine-vasopressin (AVP) in rodents has been associated with the modulation of a number of categories of behavior including social recognition and learning, aggression, grooming, and feeding. Concentrations of AVP in brain have also been functionally related to gonadal steroid hormone manipulations. In the current experiments we investigated the behavioral effects of centrally administered AVP on the behavior of pair-housed male squirrel monkeys during brief social separations. Prior to treatment, pairs of male squirrel monkeys established reliable and persistent dominance relationships measured as different patterns of social behavior and plasma levels of testosterone. Central administration of AVP increased scent-marking and grooming behaviors during the social separation test, however these effects were not influenced by the social status of the treated monkey. The effects of AVP on these measures were not mimicked by doses of oxytocin (OT). Both AVP and OT decreased the frequency of vigilance-checking and 'isolation-peep' calls. The data are consistent with a facilitatory role for AVP in the stress response and also suggest that these particular effects are not influenced by differences in testosterone associated with social dominance.

Analysis of Variance↗
PubMed1991

Comparative neuroanatomy of the sexually dimorphic hypothalamus in monogamous and polygamous voles.

In the present work we evaluated the degree of sexual dimorphism in two cell groups of the medial preoptic-anterior hypothalamus (MPOA-AH) in monogamous and polygamous voles. Quantitative determinations were made of volume, cell number, and cell density for the anteroventral-periventricular nucleus (AVPV) and the sexually dimorphic nucleus of the preoptic area (SDN-POA). Polygamous montane voles (Microtus montanus) had a greater degree of sexual dimorphism in both cell groups than did monogamous prairie voles (M. ochrogaster). Most notable was the complete absence of the AVPV in male montane voles; male montane voles also had a significantly larger SDN-POA volume than did females. The only sexual dimorphism in prairie voles was a greater cell density in the female AVPV. In addition, prairie voles had larger relative brain size than did montane voles. Comparative behavioral studies have revealed a correlation between the degree of sexual dimorphism in external morphology and mating system, i.e., polygamous species display greater levels of dimorphism than do monogamous species. The present results indicate that the effects of sexual selection can also be seen in those brain regions, like the hypothalamus, that underlie social and reproductive behavior. Moreover, these results support the hypothesis that neuroanatomic dimorphisms in the MPOA-AH may be related to sex differences in behavior.

Animals↗
PubMed1991

Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists.

A modulatory role for serotonin has been described for the development and expression of the ultrasonic call of infant rat pups during brief maternal separations. In previous studies, serotonin reuptake inhibitors selectively reduced the rate of calling following acute administration to 9-11-day-old pups and a serotonin neurotoxin (MDMA) systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development. In the current studies, we extended our investigations to include drugs with purported receptor subtype selectivities. Consistent with previous reports, acute administration of 5HT1A agonists buspirone and 8-OH-DPAT [+/-)-8-hydroxy-2-(di-N-propylamino)tetralin) reduced the rate of calling at doses which did not affect motor activity or core body temperature. The rate reducing effects of buspirone persisted up to 1 but not 2 h after injection. Administration of purported 5HT1B receptor agonists, CGS12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline) and TFMPP (1-[3-fluoromethyl)phenyl]-piperazine) increased the rate of calling depending on the specificity of the drug for the 5HT1B receptor. d,l-Propranolol, a 5HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. m-CPP (1-(3-chlorophenyl)piperazine) and DOI [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), drugs with putative actions at 5HT1C and 5HT2 receptor sites both decreased calling but differed according to their effects on motor activity. Ritanserin, a 5HT2 and 5HT1C antagonist, produced a dose-related increase in call rate. A dose of ritanserin with no apparent intrinsic effects effectively antagonized DOI rate reducing effects but potentiated the rate reducing effects of m-CPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Infant rat separation is a sensitive test for novel anxiolytics.

1. Rat pups emit ultrasonic calls during brief episodes of social separation. These calls have been variously described as "distress" calls and may be related to the separation cries expressed by the young of many mammalian species. 2. Ultrasonic call of rat pups are modulated by environmental stimuli such as ambient temperature, olfactory and tactile stimuli associated with the nest. 3. Calls are also sensitive to a variety of purported anxiolytic and anxiogenic drugs, including the benzodiazepines, serotonin agonists, and ligands at the NMDA-glycine receptor complex. 4. In addition to providing a simple test for the anxiolytic properties of drugs, this model may also provide new insights about the development and neurobiology of anxiety.

Animals↗
PubMed1991

The comparative distribution of forebrain receptors for neurohypophyseal peptides in monogamous and polygamous mice.

Several recent studies have suggested that the neurohypophyseal peptide oxytocin may have a role within the brain to mediate various forms of affiliative behavior. As the regulation of oxytocin function may be largely determined by the number and distribution of its membrane bound receptor, we investigated oxytocin receptor distribution in two Peromyscus species selected for differences in affiliative behavior. Using in vitro receptor autoradiography with the selective oxytocin receptor ligand [125I]d(CH2)5[Tyr(Me)2,Tyr-NH9(2)]OVT ([125I]OTA), we compared Peromyscus maniculatus, a polygamous species, to Peromyscus californicus, a monogamous species. Marked species differences in the distribution of [125I]OTA were apparent in several brain areas, including olfactory pathways, bed nucleus of the stria terminalis, amygdala, dorsal lateral septum, and several cortical regions. In addition, gender differences in the binding pattern were evident in several regions, mostly due to sexually dimorphic patterns in the polygamous species, P. maniculatus. To further compare these species, the binding of a [3H]arginine-vasopressin antagonist was assessed in alternate sections from those used for [125I]OTA. Relative to oxytocin receptors, binding to arginine-vasopressin receptors showed fewer species differences, although the monogamous species appeared to have more arginine-vasopressin receptors in the neocortex and lateral septum. The striking differences in oxytocin receptor distribution are consistent with earlier studies in other rodents, suggesting that oxytocin may have an important role for mediating species-typical patterns of social affiliation.

Animals↗
PubMed1991

Endogenous opioids: do they modulate the rat pup's response to social isolation?

Previous studies with several different species have suggested that opioids and their receptors are involved in the mediation of the infant's vocal response to social isolation. In the case of the rat pup, 2 models have been hypothesized to relate opioids and the ultrasonic call emitted during social isolation. One model views the comforting effects of social contact as opioid mediated and the apparent distress of social isolation as analogous to opiate withdrawal. The 2nd model considers social separation as a stressor that recruits endogenous opioids. This article describes 3 experiments that tested both of these models in 7-10-day-old rat pups. In Experiment 1, morphine (0.04-0.40 mg/kg) decreased the rate of isolation calls in a dose-dependent, naloxone-reversible fashion. However, the decrease in calling rate was observed only at doses that decreased locomotor activity. Administration of the reversible opiate antagonist naloxone (0.05-5.0 mg/kg) did not alter the rate of calls during either 2- or 6-min isolation tests at either 24 or 32 degrees C. In Experiment 2, the irreversible mu opioid receptor antagonist beta-funaltrexamine (beta-FNA) was administered into the lateral ventricle of 6-day-old pups. Again, no change in the rate of isolation calls was found, although sensitivity to morphine was markedly decreased, and mu (but not delta or kappa) receptors were decreased in selected brain regions by about 40%. In Experiment 3, in vivo receptor binding was used to directly investigate the availability of mu opioid receptors during social contact and social isolation. Pups injected with 3H-diprenorphine showed relatively high levels of specific in vivo binding that followed the regional pattern of in vitro binding, but no effects of social isolation were apparent in the 5 brain regions assayed. Taken together, the consistent negative results with opiate receptor antagonists, as well as the inability to detect an alteration of in vivo binding, suggest that the mu opioid receptor is not an essential part of the rat pup's vocal response to social separation.

Animals↗
PubMed1991

The regulation of oxytocin receptor binding in the ventromedial hypothalamic nucleus by testosterone and its metabolites.

Oxytocin (OT) receptor binding in the ventromedial hypothalamic nucleus is regulated by testosterone (T) in male rats. However, T is metabolized in the brain, and many of the central effects of T are mediated by its metabolites. The experiments reported here were designed to determine whether T affects OT receptor binding directly or through the action of its metabolites 17 beta-estradiol and 5 alpha-dihydrotestosterone. Adult male rats were either sham operated or castrated and treated 1 week later with T propionate (TP), 17 beta-estradiol benzoate (EB), dihydrotestosterone benzoate (DHTB), DHTB plus EB, or oil. OT receptor binding was assessed autoradiographically using [125I]d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT. In addition, seminal vesicle weights were measured as an index of androgenic activity. These experiments showed that TP and DHTB plus EB increased OT receptor binding in the ventromedial hypothalamic nucleus to the levels in intact males. Treatment with EB alone partially reinstated binding to the levels in intact males, while DHTB treatment was without effect. Castrated males treated with either TP or DHTB had seminal vesicle weights comparable to those of gonadally intact males and greater than those of animals in all other steroid conditions, indicating that sufficient levels of circulating steroids were attained in these groups. These data suggest that the induction of hypothalamic OT receptor binding by T is the result of the combined actions of estradiol and dihydrotestosterone. However, the mechanism underlying this interaction is unknown.

Animals↗