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Biomedical subjects

T R Insel

Publications and source records attributed to T R Insel.

At least 127 records · Page 7Linked to original sources
PubMed1989

Anxiety and cerebral blood flow during behavioral challenge. Dissociation of central from peripheral and subjective measures.

To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO2 did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during in vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.

Adult↗
PubMed1989

Rat pup isolation distress and the brain benzodiazepine receptor.

Pharmacologic studies have demonstrated that benzodiazepines can modulate the ultrasonic vocalizations (USV) associated with social separation of rat pups. In this study, in vivo receptor autoradiography was used to determine if brain benzodiazepine receptors were functionally less available to bind an exogenous ligand during social separation. The labeled benzodiazepine receptor antagonist. 3H-RO 15-1788, was given to 10-day-old rat pups with varying schedules of social separation. In initial studies with homogenized and solubilized tissue, we found a 30% reduction in binding to cortex when pups were separated for 25 min beginning 5 min prior to tracer injection. In subsequent autoradiographic studies with this same separation schedule, the binding of 3H-RO 15-1788 was examined in 21 brain regions. Again binding was decreased in neocortex (frontal, motor, and somatosensory). In addition, we found significantly decreased binding in hippocampus, dentate gyrus, and superior and inferior colliculi. These same regions showed no alteration of in vitro binding of 3H-RO 15-1788. Therefore, these decreases in in vivo binding do not reflect changes in receptor number. The interpretation of decreased in vivo binding and implications of these results for defining the neural substrates of separation behavior are discussed.

Aging↗
PubMed1989

Ontogeny of oxytocin receptors in rat forebrain: a quantitative study.

The ontogeny of oxytocin receptors in rat forebrain was studied using the selective oxytocin receptor antagonist 125I-d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH29]OVT [( 125I]-OTA). With in vitro receptor autoradiography, binding wa noted on the first postnatal day in dorsal subiculum and thalamus. On postnatal days 5-18, intense labeling was evident in posterior cingulate cortex, dorsal subiculum, lateral septum, and the CA1 subfield of hippocampus. Of these regions only the lateral septum expressed oxytocin receptors in adult brain. Competition studies on coronal sections through posterior cingulate, septum, and dorsal subiculum at P10 demonstrated that transient binding sites in these areas were indeed oxytocin selective (OXY greater than AVP greater tha V1 greater than V2). Result of saturation studies on cingulate membranes from 10-day-old pups agreed favorably with previous reports of the kinetics of [125I]-OTA binding to adult oxytocin receptors (Kd = 0.1 nM in P10 cingulate cortex vs. 0.07 nM for adult ventral subiculum). In contrast to these evanescent developmental sites, oxytocin receptors in the bed nucleus of the stria terminalis and the ventromedial nucleus of the hypothalamus only appeared in adulthood, presumably in response to the surge of gonadal steroids at puberty.

Aging↗
PubMed1989

Decreased in vivo binding to brain benzodiazepine receptors during social isolation.

Pharmacologic studies have demonstrated that benzodiazepines can modulate the ultrasonic vocalizations (USV) associated with social separation of rat pups. In this study, in vivo receptor autoradiography was used to determine if brain benzodiazepine receptors were functionally less available to bind an exogenous ligand during social separation. The labelled benzodiazepine receptor antagonist 3H-RO 15-1788 was given to 10-day-old rat pups during 25 minutes of social separation. In autoradiographic studies of brains from separated pups, the binding of 3H-RO 15-1788 was decreased in neocortex (frontal, motor, and somatosensory), hippocampus, and superior and inferior colliculi. As these same regions showed no alteration of in vitro binding of 3H-RO 15-1788, these in vivo binding decreases do not reflect changes in receptor number. The interpretation of decreased in vivo binding and implications of these results for defining the neural substrates of separation behavior are discussed.

Animals↗
PubMed1989

Lesions of the hypothalamic paraventricular nucleus disrupt the initiation of maternal behavior.

Electrolytic lesions of the paraventricular nucleus (PVN) of the hypothalamus were found to disrupt the initiation but not the maintenance of maternal behavior in primiparous Sprague-Dawley rats. Following lesions performed on Day 15 of gestation, measures of maternal behavior (grouping, crouching, and nest building), pup retrieval, and pup weight gain were all impaired, but only if the lesion included the most rostral and medial aspects of the PVN. Lesions sparing these regions and sham surgery were generally ineffective. In a separate experiment, PVN lesions performed on Day 4 postpartum had relatively little effect on maternal behavior. As females lesioned prepartum showed changes in open-field behavior as well as maternal behavior, the PVN may be important for modulating responses not only to pups but to several kinds of novel stimuli. These results may also further implicate oxytocin, which is synthesized in the PVN, in the initiation of maternal behavior.

Animals↗
PubMed1989

CRH and alpha-helical-CRH modulate behavioral measures of arousal in monkeys.

Several neuropeptides involved in the control of pituitary-adrenal activation have also been shown to have behavioral effects which may be mediated by actions on brain mechanisms independent of pituitary release. The behavioral effects of intraventricular administration of CRH and the synthetic peptide antagonist alpha-helical-CRH were assessed in socially separated squirrel monkeys. Treated monkeys were presented with a sequence of behavioral challenges including undisturbed social separation, presentation of a mirror image, and presentation of a "predator" stimulus. The test sequence was repeated at several time intervals after administration of the peptides. CRH produced dose-related increases in several species-typical measures of arousal including motor activity, vigilance-checking, and marking. Pretreatment with alpha-helical-CRH prevented the increased motor activity but not the marking behavior associated with CRH. When administered alone, alpha-helical-CRH increased vigilance-checking. In addition, alpha-helical-CRH increased aggressive behaviors exhibited at the mirror stimulus. The data provide further support for a central role for CRH in the mediation of both activational and inhibitory behavioral responses to stressful stimuli. These data also suggest both antagonistic and partial agonist effects for alpha-helical-CRH.

Animals↗
PubMed1989

Central administration of corticotropin releasing factor alters rat pup isolation calls.

Rat pups, when socially isolated, emit ultrasonic vocalizations which are believed to indicate distress. This study investigated the effect of intracerebroventricular (ICV) administration of corticotropin releasing factor (CRF) on the production of ultrasonic isolation calls. Following a 2-minute baseline isolation test, rat pups (5-6 days old) were injected ICV with CRF or the CRF antagonist, alpha-helical CRF (9-41). Thirty minutes later, calls were significantly decreased following CRF (0.1 and 0.01 micrograms) and increased following the CRF antagonist (1.0 micrograms). These effects were not explained by changes in locomotor activity, thermoregulation, or plasma glucocorticoid levels following peptide administration. Peripheral administration of CRF (1.0 and 10.0 micrograms) did not alter the number of isolation calls.

Animals↗
PubMed1989

Testosterone modulates oxytocin binding in the hypothalamus of castrated male rats.

Oxytocin (OT) binding sites are modulated by estrogens in several brain regions including the ventromedial hypothalamic nucleus (VMN) in both male and female rats. To further study steroid regulation of OT receptor binding, we examined the effect of androgen replacement in castrated male rats on OT binding with quantitative autoradiographic methods. Castrated adult male rats were treated with either 250 micrograms testosterone propionate (TP) or oil for 2 days and killed 48 h after the last injection. Brain sections through the preoptic area and VMN were labeled with 5.0 nM[3H]-OT +/- 5.0 microM unlabeled OT or 1.0 microM[Thr4,Gly7]OT and apposed to tritium-sensitive film for 7 weeks. Results of this study show that TP increased [3H]-OT binding up to 5-fold in the ventrolateral VMN and 4-fold in the bed nucleus of the stria terminalis. In addition [Thr4,Gly7]OT completely displaced [3H]-OT binding in the VMN indicating that binding in this brain region was specific to OT receptors. Because estrogens also increase OT receptor binding in male rats, it is possible that TP affects OT binding after being converted by aromatase to estradiol.

Animals↗
PubMed1989

Time course of the estradiol-dependent induction of oxytocin receptor binding in the ventromedial hypothalamic nucleus of the rat.

Oxytocin (OT) transmission is involved in the steroid-dependent display of sexual receptivity in rats. One of the biochemical processes stimulated by the ovarian steroid 17 beta-estradiol (E2) that is relevant to reproduction is the induction of OT receptor binding in the ventromedial hypothalamic nucleus (VMN). The purpose of these experiments was to determine if E2-induced changes in OT receptor binding in the VMN occur within a time frame relevant to cyclic changes in ovarian steroid secretion. OT receptor binding was measured in the VMN of ovariectomized rats implanted for 0-96 h with E2-containing Silastic capsules. The rate of decay of OT receptor binding was measured in another group of animals 6-48 h after capsule removal. Receptors were labeled with the specific OT receptor antagonist [125I]d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT, and binding was measured with quantitative autoradiographic methods. In addition, plasma E2 levels and uterine weights were assessed in animals from each treatment condition. Significant increases in E2-dependent OT receptor binding and uterine weight occurred within 24 h of steroid treatment. After E2 withdrawal, OT receptor binding and uterine weight decreased significantly within 24 h. These results are consistent with the hypothesis that steroid modulation of OT receptor binding is necessary for the induction of sexual receptivity.

Animals↗
PubMed1989

3,4-Methylenedioxymethamphetamine ("ecstasy") selectively destroys brain serotonin terminals in rhesus monkeys.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), an amphetamine analog, is a "designer drug" which is being increasingly abused. The potential neurotoxic hazard of MDMA in humans was assessed by examining the effects of repeated systemic administration of MDMA on selected neurochemical and behavioral measures in rhesus monkeys. In the first study, MDMA (2.5 or 10 mg/kg twice daily for 4 days) produced selective and significant neurochemical decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and brain concentrations of serotonin and 5-HIAA. At the high dose of MDMA, a selective decrease in serotonin uptake sites (reflecting destruction of brain serotonin terminals) was observed. To determine if these changes after high dose MDMA were pharmacologic or truly neurotoxic, in a subsequent study monkeys were treated with MDMA (10 mg/kg twice daily for 4 days) and then monitored for 14 weeks. Throughout this period, CSF 5-HIAA was decreased in MDMA-treated animals but not in saline-injected controls. At the end of this period, significant decreases in the concentration of serotonin, 5-HIAA and serotonin uptake sites were observed in cerebral cortex and striatum but not in hypothalamus or spinal cord. In contrast to these widespread alterations in serotonin markers, comparable noradrenergic and dopaminergic measures in CSF and brain appeared generally unaffected. These data demonstrating potent and selective effects of MDMA on various brain serotonin parameters in rhesus monkeys suggest that the drug may produce similar effects in humans.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Obsessive-compulsive disorder as a 5-HT subsystem-related behavioural disorder.

Involvement of the brain serotonin (5-HT) neurotransmitter system in obsessive-compulsive disorder (OCD) was originally suggested on the basis of therapeutic effects found with the semiselective serotonin uptake inhibitor, clomipramine. More recent studies directly comparing clomipramine with non-selective or norepinephrine-selective uptake inhibitors, such as desipramine or nortriptyline, as well as studies with new, more selective serotonin uptake inhibitors, including fluvoxamine and fluoxetine, have supported that hypothesis. Clomipramine's antiobsessional effect has been augmented with the serotonin precursor, L-tryptophan, or with lithium, which has prominent serotonergic effects. Patients whose OCD symptoms improved on clomipramine worsened when the drug was discontinued (regardless of duration of therapy) and improved when clomipramine was reinstituted. OCD symptoms also worsened when metergoline, a 5-HT antagonist, was given to patients who had improved with clomipramine. Metergoline given alone had no effect. Administration of m-chlorophenylpiperazine (m-CPP), a 5-HT receptor agonist, to untreated OCD patients increased their anxiety, depression, and dysphoria, and exacerbated their OC symptoms. After 4 months of clomipramine therapy, m-CPP failed to produce the same behavioural effects, suggesting an alteration of a 5-HT subsystem (possibly downregulation of some 5-HT receptors). The data reviewed suggest an important role for an abnormal brain 5-HT subsystem in patients with OCD.

Brain↗
PubMed1988

Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment.

Clomipramine is a potent serotonin reuptake blocker that decreases the symptoms of obsessive-compulsive disorder (OCD). To investigate whether clomipramine treatment in OCD affects brain serotonergic responsiveness, metachlorophenylpiperazine (mCPP), a selective serotonin agonist, and placebo were given under double-blind conditions to nine patients with OCD before and after treatment with clomipramine. Unlike our previous observations of a marked transient increase in obsessional symptoms and anxiety following 0.5 mg/kg of mCPP, readministration of mCPP after four months of treatment with clomipramine did not significantly increase obsessional symptoms and anxiety. Similarly, the hyperthermic effect of mCPP observed before treatment was eliminated after treatment with clomipramine. These findings are consistent with the development of adaptive subsensitivity to the serotonergic agonist mCPP during clomipramine treatment. A similar alteration in the response to endogenous serotonin may mediate clomipramine's antiobsessional effects.

Adult↗
PubMed1988

Gender differences in caring for infant Cebuella pygmaea: the role of infant age and relatedness.

This paper describes a three-part study of the parenting behaviors of 6 family groups of Cebuella pygmaea (pygmy marmosets). In the first part, the parenting patterns of undisturbed family groups housed under laboratory conditions were scored throughout the first 10 weeks following the birth of their second infant(s). To further investigate the role of infant age in determining parental behavior, caretaking patterns were studied after a brief separation of infants of varying ages from their families. Finally, an unrelated infant, age 1-5 weeks, was placed inside the home cage of each family, and caretaking of this novel infant was scored. The main findings that emerged from the study were: (1) sex differences in carrying the infants were dependent upon the age of the infant, i.e., adult females were the predominant carriers of infants less than or equal to 3 weeks of age and males (either adult or juvenile) the main carriers for infants greater than 3 weeks of age; (2) some caretaking behaviors, e.g., grooming and protective retrieval, were performed predominantly by the adult females throughout infancy; and (3) the relatedness of the infant, i.e., one's own vs. another's, appeared to primarily affect the behavior of adult females. In general, experimental manipulations confirmed results of the observational part of the study and thus may be useful paradigms for testing specific hypotheses about parental behaviors.

Age Factors↗
PubMed1988

Rearing paradigm in a nonhuman primate affects response to beta-CCE challenge.

Two groups of socially housed rhesus monkeys were raised under conditions differing in the degree of control or mastery over appetitive stimuli (food, water, and treats) in the 1st year of life. At age 18-24 months, a benzodiazepine receptor inverse agonist, beta-carboline-3-carboxylic acid ethyl ester (beta-CCE), was administered to both social groups to investigate the effects of differential rearing on the response to a putative anxiogenic drug. In both groups beta-CCE was followed by behavioral activation with a profile suggesting increases in aggression rather than fear or anxiety. A group by drug analysis revealed that the increase in aggression was observed predominantly in the subjects reared with mastery during the 1st year. Plasma cortisol increased in both groups, but its increase was greater in the yoked subjects. These results suggest that early experience with controllability may have long term consequences which can be revealed by challenge with beta-CCE.

Aggression↗
PubMed1988

The ontogeny of brain receptors for corticotropin-releasing factor and the development of their functional association with adenylate cyclase.

This study reports the ontogeny of corticotropin-releasing factor (CRF) receptor binding sites in rat brain, using both membrane binding assays and in vitro receptor autoradiography. CRF binding sites are evident by prenatal day 17, increase to 312% of their adult density by postnatal day 8, then decrease to reach adult values by day 21. Not only the density, but the distribution of CRF binding undergoes major modifications in development. CRF binding sites are most numerous in striatum prenatally, but postnatally, binding is more dense in the cortex, reaching the adult laminar distribution by postnatal day 14. Brain CRF receptors are linked to adenylate cyclase early in postnatal life. This contrasts with the later appearance of most of the guanine nucleotide stimulatory protein and catalytic subunit sites in the rat brain and suggests that CRF receptors may become functional earlier than several other brain receptors that are linked to adenylate cyclase.

Adenylyl Cyclases↗
PubMed1987

Brain adenosine receptors in Maudsley reactive and non-reactive rats.

Previous work in our laboratory has shown that the Maudsley reactive (MR) strain of rats cannot be differentiated from the Maudsley non-reactive (MNR) strain regarding the number or affinity of their brain benzodiazepine binding sites. In the present study we show that the number of cerebellar adenosine receptors (as studied using [3H]cyclohexyladenosine, [3H]CHA, as the ligand) are increased by 15-30% in the MR strain. This alteration was corroborated by quantitative autoradiographic analysis and found to be localized to the molecular layer of the cerebellum where adenosine receptors are believed to reside on parallel fibers of cerebellar granule cells.

Adenosine↗
PubMed1987

Acute and chronic effects of desipramine administration to rhesus monkeys.

Rhesus monkeys were studied for changes in noradrenergic functioning before and after chronic oral administration (28 days) of the tricyclic antidepressant desipramine (DMI). Decreases in cerebrospinal fluid concentration of the norepinephrine metabolite MHPG were evident following the first dose (5.0 mg/kg) of DMI, but not after chronic administration of the drug. The alpha 2-adrenoceptor agonist clonidine reduced plasma norepinephrine prior to DMI treatment, but not after 28 days of treatment with DMI. These adaptive changes in noradrenergic function were evident in spite of very low plasma levels of DMI due to rapid metabolism of the drug in the rhesus monkey. The development of changes compatible with alpha 2-adrenoceptor subsensitivity in the presence of plasma levels of the drug that are well below those considered therapeutic in the treatment of depression suggests that such a receptor change may be dissociated from the drug's antidepressant effect.

Animals↗