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T R Insel

Publications and source records attributed to T R Insel.

At least 109 records · Page 6Linked to original sources
PubMed1991

A selective oxytocin antagonist attenuates progesterone facilitation of female sexual behavior.

Although previous studies have demonstrated that exogenous administration of oxytocin (OT) enhances sexual receptivity in female rats, there is no compelling evidence that endogenous OT has a physiological role in the regulation of female sexual behavior. In the current studies we centrally administered d(CH2)5[Tyr(Me)2Thr4,Tyr-NH2(9)]ornithine vasotocin (or OTA), a selective OT receptor antagonist, to block endogenous OT in ovariectomized females primed with different levels of gonadal steroids. After OTA administration (100-1000 ng), females primed with estradiol benzoate (EB; 1 microgram) and progesterone (P; 250 micrograms) showed reductions in both receptive and proceptive behaviors. These effects of OTA were also evident, though less striking, in females primed with higher doses of EB (10 micrograms) and P (250 micrograms), but significant OTA effects were absent in females primed with EB (10 micrograms) alone. Thus, OTA appeared to attenuate P's facilitation of sexual behavior. Surprisingly, these behavioral effects of OTA administration were not apparent immediately, but emerged only when OTA was given with P 4-6 h before behavioral testing. To determine if these delayed, but lasting, behavioral effects were associated with OTA occupancy of the OT receptor, we measured OT receptor binding ex vivo using receptor autoradiography. Six hours after intracerebroventricular administration of OTA (1000 ng), OT receptor binding was reduced at least 75% in the ventromedial nucleus of the hypothalamus relative to control levels of binding. Thus, those OT receptors previously implicated in the regulation of sexual receptivity appear to be significantly blocked throughout the period of OTA's behavioral effects. Together, these studies lend support to the hypothesis that endogenous OT has a physiological role in the regulation of female sexual behavior.

Animals↗
PubMed1991

Social status in pairs of male squirrel monkeys determines the behavioral response to central oxytocin administration.

Oxytocin, when administered centrally, has been associated with the modulation of various social initiatives including maternal and sexual behaviors. The nature of these effects depends on gonadal hormone status. In the present experiments, we investigated the effects of centrally administered oxytocin on the behavior of pair-housed male squirrel monkeys during interactions with a familiar female monkey. Pairs of male squirrel monkeys established reliable and persistent dominance relationships with dominant males showing increased sexual and aggressive behavior as well as higher plasma concentrations of testosterone. Oxytocin (0.1, 1.0 micrograms) increased the sexual and aggressive behavior of dominant monkeys without affecting these measures in the subordinate monkeys. In contrast to these effects in the dominant monkeys, oxytocin increased associative and marking behaviors only in subordinate monkeys. Central administration of the oxytocin receptor antagonis d(CH2)5 [Tyr(Me)2, Thr4,Tyr-NH2(9)] OVT (OTA; 0.05 microgram) had no intrinsic effect on behavior but blocked the effects of exogenous oxytocin. To investigate further the specificity of oxytocin's effects on social behavior, we administered the structurally related peptide arginine vasopressin under identical conditions. Vasopressin (0.5, 5.0 micrograms) decreased social behaviors and increased motor activity in both dominant and subordinate monkeys. Previous studies in rodents have demonstrated that oxytocin receptors are induced by gonadal steroids in a regionally specific fashion. The status-related behavioral effects of oxytocin in the squirrel monkey may reflect differences in brain oxytocin receptor density associated with the higher concentrations of testosterone in the dominant animal. Alternatively, the status-related effects may depend on the conditioned behavioral differences associated with social organization.

Aggression↗
PubMed1990

Rat pup isolation calls are reduced by functional antagonists of the NMDA receptor complex.

Compounds that reduce ion flux through N-methyl-D-aspartate (NMDA) coupled cation channels were evaluated for their effects on rat pup ultrasonic vocalizations (USV). Previous studies have demonstrated that rat pups emit ultrasonic calls during social isolation and that several classes of anxiolytics decrease, while putative anxiogenics increase, the number of these calls. The competitive NMDA antagonists 2-amino-7-phosphonoheptanoic acid (AP-7) and (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid [+/-)-CPP) as well as a partial agonist at the strychnine-insensitive glycine receptor, 1-aminocyclopropanecarboxylic acid (ACPC), reduced USV at doses that did not affect either motor activity or core temperature. A dose of glycine sufficient to elevate hippocampal glycine concentrations by 85% antagonized the effects of ACPC, but not AP-7. Glycine alone did not alter USV, but NMDA when given by itself increased USV by almost 50% at subconvulsant doses. Moreover, a dose of NMDA that did not affect USV antagonized the effects of AP-7 but not ACPC. Taken together, these findings are consistent with previous studies using conflict procedures which indicate that agents which reduce activity at NMDA receptor coupled cation channels may constitute a new class of anxiolytic agents.

2-Amino-5-phosphonovalerate↗
PubMed1990

Prenatal stress has long-term effects on brain opiate receptors.

Prenatal stress has been associated with a number of behavioral consequences including altered sensitivity to exogenous opiates. In the present study, mu opiate receptors were compared in the 42-day-old offspring from females stressed on days 15-22 of gestation and from females who were unstressed controls. Membrane homogenates from the prenatal stress group showed less binding of the mu opiate receptor ligand, [3H]DAGO in striatum but not in several other brain regions. Saturation studies suggest this difference is due to fewer striatal mu opiate receptors in offspring of prenatally stressed females. Using in vitro receptor autoradiography, the decreased binding in striatum was found mostly in the rostral striatum, extending into the nucleus accumbens with conservation of the normal anatomic distribution of receptor rich patches.

Animals↗
PubMed1990

Infant's response to social separation reflects adult differences in affiliative behavior: a comparative developmental study in prairie and montane voles.

As part of a comparative study of affiliative behavior, pups of two different vole species, Microtus ochrogaster (prairie voles) and M. montanus (montane voles), were compared for their responses to social isolation during the first 2 weeks of postnatal life. Previous studies have demonstrated that under both laboratory and field conditions, adult prairie voles show higher levels of affiliation than adult montane voles, although the species closely resemble each other morphologically. In the current study, prairie vole and montane vole pups showed profound differences in the behavioral and physiologic responses to social isolation. During 5 minutes of isolation, prairie vole pups emitted 314 +/- 60 (days 4-6) and 601 +/- 55 (days 8-10) ultrasonic vocalizations. At these same ages, plasma corticosterone increased 4-6 fold within 30 minutes of separation. The increase in corticosterone was highly correlated with the number of calls (r = .66). In contrast, most montane vole pups emitted no isolation calls under identical conditions. Moreover, montane vole pups had equivalent baseline corticosterone concentrations, but showed only a minor increase in corticosterone following separation at 4-6 days with no increase apparent at 8-10 days. As montane vole pups were capable of producing high levels of ultrasonic vocalizations and increased concentrations of plasma corticosterone in response to known stressors (tail suspension and halothane vapors), these results suggest that social isolation evokes less distress for montane vole pups than for prairie vole pups. The developmental difference in the amount of parent-young contact was not a sufficient explanation for the differences in the response to separation as cross-fostered montane voles failed to show an increase in ultrasonic vocalizations (although a slight increase in corticosterone was observed). Taken together, these studies indicate that species-typical adult patterns of affiliation may be apparent early in development in the response of infants to social separation.

Age Factors↗
PubMed1990

New pharmacologic approaches to obsessive compulsive disorder.

Although obsessive compulsive disorder (OCD) traditionally has been considered a treatment-refractory syndrome, rigorous treatment studies over the past decade have demonstrated that most OCD patients respond to specific behavioral or pharmacologic therapies. In terms of the pharmacologic treatment of OCD, a relatively small group of antidepressant drugs (clomipramine, fluvoxamine, and fluoxetine) have been demonstrated to be antiobsessional. Several related antidepressants (desipramine, nortriptyline) appear to be ineffective for OCD. Clinical response requires prolonged treatment (greater than 6 weeks) with antiobsessional drugs and efficacy is not limited to depressed OCD patients. The few drugs that have been demonstrated to be antiobsessional share a high potency for the blockade of serotonin reuptake, suggesting a serotonergic mechanism for antiobsessional drug action. This suggestion has been further strengthened by studies demonstrating a high correlation between clinical response and changes in serotonergic markers with clomipramine treatment. Moreover, a serotonin antagonist, metergoline, appears to partly reverse the improvement observed following chronic clomipramine treatment. Overall, only about 50% of OCD patients appear to respond in any given pharmacologic treatment trial. Adjunctive treatments, such as lithium or L-tryptophan, have been reported to help in some cases. In addition, the use of neuroleptics either alone or in combination with antiobsessional drugs may be useful for OCD patients with psychotic features or tics. Pharmacologic treatments should be considered only one element of the therapeutic approach to be integrated with behavioral techniques as well as psychosocial interventions for the relief of this very intriguing syndrome.

Behavior Therapy↗
PubMed1990

The ontogeny of excitatory amino acid receptors in rat forebrain--I. N-methyl-D-aspartate and quisqualate receptors.

The ontogeny of radioligand binding to N-methyl-D-aspartate and quisqualate receptors in rat forebrain was studied quantitatively using in vitro receptor autoradiography. Specific binding to both receptors could be detected by postnatal day 1 in hippocampus and striatum. The adult pattern of binding to N-methyl-D-aspartate receptors emerged by postnatal day 14 with high densities of binding in CA1 (stratum oriens and stratum radiatum), dentate gyrus (molecular layer) and striatum (caudate-putamen). Binding to the outer laminae of frontal cortex was as much as 45% above adult levels during development. Binding of [3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid to quisqualate receptors showed a similar overshoot during development, but also manifested a unique distribution with CA3 and medial aspects of the amygdala exhibiting transient, intense labeling. Homogenate binding studies with [3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid demonstrated a 73% increase in quisqualate receptors in whole brain at postnatal day 21 compared with adult levels. The selectivity of excitatory amino acid binding to the quisqualate site in development was similar to the selectivity in adult brain. These data taken with other recent reports, suggest that quisqualate receptors may have a role in development distinct from their function in the adult brain.

Aging↗
PubMed1990

The ontogeny of excitatory amino acid receptors in the rat forebrain--II. Kainic acid receptors.

The ontogeny of [3H]kainic acid binding in rat forebrain was studied quantitatively using in vitro receptor autoradiography. Specific binding was detectable in ventral thalamus, hippocampus, striatum and olfactory bulb by postnatal day 1. In regions with high densities of receptors in adulthood, such as CA3, dentate gyrus and striatum, binding increased progressively across development peaking at postnatal day 21. In ventral thalamus and the inner lamina of the neocortex, [3H]kainic acid binding was high in the first three postnatal weeks and relatively low thereafter. Saturation studies performed on adults and 14-day-old animals suggest differences in both the affinity and the maximal binding capacity contributed to the observed developmental changes in binding of [3H]kainic acid.

Aging↗
PubMed1990

Neurotoxic effect of MDMA on brain serotonin neurons: evidence from neurochemical and radioligand binding studies.

In summary, the data from both neurochemical and neuroanatomical studies demonstrate widespread and long-lasting degeneration of serotonin neurons in brain without any major or consistent effects on catecholamine neurons following in vivo administration of MDMA in both rats and rhesus monkeys. A detailed examination of the parameters involved in the neurotoxic and neurodegenerative effects of MDMA on brain serotonin neurons indicate that the severity of the lesion is dependent on the dose of drug administered with the drug being more potent in rhesus monkeys than in rats. Furthermore, the neurodegenerative effects of the drug are long-lasting (up to one year) with respect to neuronal regeneration (i.e. recovery of serotonin uptake sites) while functional recovery may be permanently impaired since serotonin content remains markedly (40-50%) below levels in age-matched controls for as long as one year after drug administration. The neurochemical and autoradiographic data suggest that there are some regional differences and morphological specificity to the neurodegenerative effects of MDMA as demonstrated by greater reductions in serotonin uptake sites in brain regions containing primarily terminals while regions containing axons of passage and cell bodies are relatively unaffected.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Regional induction of c-fos-like protein in rat brain after estradiol administration.

The protooncogene c-fos is induced in rat brain by various forms of physiological stimulation. In this study immunocytochemical staining for a peptide fragment of the c-fos protein was used to assess estradiol's effects on c-fos in rat brain. After estradiol benzoate (100 micrograms/kg) administration to ovariectomized rats, the number of cells staining for c-fos-like protein increased in the anterior medial preoptic area, the medial preoptic area, the medial amygdala nucleus, and the ventromedial nucleus of hypothalamus, all regions rich in estradiol-concentrating cells. This increase peaked between 12-48 h (depending on the region) after estradiol administration and was not observed in several areas with a lower density of estradiol-concentrating cells. In the most affected region, the anterior medial preoptic area, estradiol effects were dose dependent and not altered by progesterone administration. It is not yet clear whether estradiol induces c-fos expression in brain directly or whether c-fos is part of a cascade of mechanisms by which estradiol regulates gene expression.

Animals↗
PubMed1990

Serotonergic modulation of rat pup ultrasonic vocal development: studies with 3,4-methylenedioxymethamphetamine.

3,4-Methylenedioxymethamphetamine (MDMA) has previously been shown to destroy serotonin terminals in the rat brain. Despite profound and prolonged loss of serotonin innervation, long-term behavioral effects of MDMA have not previously been reported. In this study, we monitored the short- and long-term effects of MDMA administration on the ultrasonic isolation call of the rat pup. At 30 to 60 min after a single dose of MDMA (0.5-10.0 mg/kg), isolation calls decreased as much as 90%, with a rebound increase in calling noted 10 to 25 h following administration of the highest dose. Repeated administration of 10 mg/kg MDMA (once or twice daily on postnatal days 1-4) resulted in a lasting, dose-dependent decrease in ultrasonic vocalization monitored on days 6, 9, 12 and 15. Concurrent measures of locomotor behavior, geotaxis and weight gain were not altered subsequent to repeated MDMA treatment. Both serotonin content and serotonin terminals (assessed by [3H]paroxetine binding) in cortex were reduced by repeated MDMA treatment, whereas concentrations of catecholamines and their metabolites were unaltered. Repeated prenatal MDMA exposure did not affect postnatal rates of calling or the biochemical markers of serotonin in cortex. Pups lesioned with MDMA postnatally showed not only long-term behavioral and biochemical changes but also altered responsiveness to the serotonin 1B agonist 1-[3-(trifluromethyl)phenyl]piperazine. Taken together, these studies indicate that serotonergic lesions in a sensitive phase of development can have long-term selective effects on the rat pup ultrasonic isolation call, a behavior critical for mother-infant affiliation.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Serotonergic and catecholaminergic reuptake inhibitors have opposite effects on the ultrasonic isolation calls of rat pups.

Rat pups emit a highly stereotyped and well-characterized distress call in the ultrasonic range when socially isolated. We compared the modulatory influence of catecholamines and indoleamines on rat pup ultrasonic calls using pharmacologic probes. Administration of low doses of monoamine reuptake inhibitors produced significant, selective changes in the calls emitted by isolated 10-day-old pups. Acute administration of clomipramine (CMI; relatively 5-HT specific) reduced the rate of calling at low doses (1.0 and 5.0 mg/kg [3.2 and 18.0 mmol/kg] SC) but had reduced efficacy at higher doses (10 and 20 mg/kg [32.0 and 63.7 mmol/kg] SC). Motor activity and rectal body temperature were unaffected at these doses. Similarly, low doses of other 5-HT-selective uptake inhibitors, such as paroxetine (1.0 mg/kg [3.1 mmol/kg] SC) and citalopram (1.0 mg/kg [3.09 mmol/kg] SC), virtually eliminated isolation calling. The effects of CMI were not antagonized by either naltrexone (0.1 mg/kg [0.28 mmol/kg] SC) or Ro 15-1788 (5.0 mg/kg [16.5 mmol/kg] SC). Desipramine (DMI; norepinephrine [NE] specific) significantly increased calling rates at all doses tested (1.0 to 10.0 mg/kg [3.8 to 75 mmol/kg] SC). These effects were associated with significant reductions in body temperature, but not motor activity. Similar increases in the rate of isolation calling, reduction in rectal body temperature, and an increase in motor activity were produced by low doses of mazindol (0.5 mg/kg [1.75 mmol/kg] SC) and nortriptyline (1.0 mg/kg [19 mmol/kg] SC). In an additional study, the chronic effects of CMI and desipramine were evaluated with treatment beginning within 24 hours after birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Neurobiology of obsessive compulsive disorder: a possible role for serotonin.

At the current time, it appears that the only medications with consistent antiobsessional effects are the potent serotonin uptake blockers (clomipramine, fluoxetine, and fluvoxamine). Not only is serotonin uptake blockade an apparent prerequisite for clinical improvement, but there is a correlation between the magnitude of clinical response and the reduction in various serotonin markers during treatment with these drugs. Further evidence for the importance of serotonin in pharmacologic mediation of antiobsessional effects comes from a recent study in which administration of a serotonin antagonist (metergoline) to obsessive compulsive disorder (OCD) patients partly reversed the clinical improvement observed with clomipramine treatment. Although these observations have implicated serotonin in the mechanism of antiobsessional drug action, there is still little evidence demonstrating a role for serotonin in the pathophysiology of OCD. This review summarizes various studies of serotonin function in untreated OCD patients and concludes that the most compelling evidence for an abnormality has come from single-dose challenge studies of serotonin receptor agonists in untreated OCD patients. These studies remain controversial, but a preliminary interpretation of the results suggests that OCD patients may be more sensitive than healthy controls to the behavioral effects of one such serotonin agonist, m-CPP. An abnormality in the sensitivity to endogenous serotonin may link OCD research to the broader scientific question of serotonin's role in the modulation of aggression.

Humans↗
PubMed1990

Phenomenology of obsessive compulsive disorder.

A syndrome related to obsessive compulsive disorder (OCD) has been recognized for more than 300 years. Early descriptions focused on different aspects of this syndrome, reflecting the prevailing culture of the observer. English explanations stressed religious aspects and a relationship to melancholy. French phenomenologists emphasized the importance of doubt and loss of will. The German view focused on the irrational nature of the thoughts, finding a link to psychosis. Currently, OCD is considered an anxiety disorder in which either obsessions or compulsions contribute to significant distress or interference with functioning. However, obsessions and compulsions are also part of normal mental life. One current challenge is to understand the relationship between normal obsessions and compulsions and those that lead to interference and distress. The author presents a working model which helps resolve issues relating to our understanding of OCD.

History, 17th Century↗
PubMed1989

Changes in mu opiate receptors following inescapable shock.

Rats exposed to inescapable shock exhibit profound hypoalgesia. Pharmacological evidence has suggested that changes in endogenous opiate activity may be responsible for the hypoalgesic response. We measured the binding of [3H]DAGO, a selective mu-opiate receptor agonist, in brains of rats exposed to no shock, inescapable shock, or escapable shock. Binding of [3H]DAGO in the midbrains of rats in the inescapable shock group was decreased relative to the other two groups. The decrease in binding appeared to result from a decrease in number of mu-receptors and not a change in affinity. These results support the hypothesis that inescapable shock produces long-term changes in endogenous opiate systems.

Animals↗
PubMed1989

Clomipramine in obsessive-compulsive disorder. Further evidence for a serotonergic mechanism of action.

Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.

Adult↗