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J N Hingtgen

Publications and source records attributed to J N Hingtgen.

At least 19 recordsLinked to original sources
PubMed1999

Stress-induced changes of norepinephrine uptake sites in the locus coeruleus of C57BL/6J and DBA/2J mice: a quantitative autoradiographic study using [3H]-tomoxetine.

Inbred C57BL/6J (C57) and DBA/2J (DBA) mice were subjected to open-field evaluation and Porsolt swim test after restraint stress. Norepinephrine (NE) uptake sites in the locus coeruleus (LC) of these inbred mice were studied by using [3H]-tomoxetine. Results showed that naive C57 mice were more active in the open field and possessed more NE uptake sites in the LC than naive DBA mice. Previous work has shown that restraint decreases open field activity in C57 mice, but not DBA mice, whereas the present study has demonstrated that, after restraint stress, C57 mice spent more time immobile than DBA mice did in the forced swim test. Furthermore, in these stressed animals, NE uptake sites in the LC were greatly increased with consistently more uptake sites in C57 mice. Collectively, results of this study and the literature suggest that enhanced NE function in the LC of C57 mice is associated with their susceptibility to stress-induced behavioral depression.

Animals↗
PubMed1995

Identification of a locus on mouse chromosome 17 associated with high-affinity choline uptake using BXD recombinant inbred mice and quantitative trait loci analysis.

Using the quantitative trait loci (QTL) approach, preliminary identification has been made of a region on mouse chromosome 17 that influences high-affinity choline uptake (HACU) in the mouse brain. The rate of HACU was measured in synaptosomes prepared from the frontal cortex, hippocampus, and striatum of C57BL/6J (B6), DBA/2J (D2), and 25 BXD recombinant inbred (RI) strains of mice, using a final concentration of 0.5 microM [3H]choline. The strain means of HACU in each area were then correlated with the strain distribution pattern of each of 1300 known genetic markers using a point biserial correlation and 0 (B6 allele) and 1 (D2 allele). Correlations of P < 0.00001 were found between striatal HACU and chromosome 17 markers D17Tu50 and Tcp1. Correlations of P < 0.0001 were found between striatal HACU and chromosome 17 markers D17Leh66e, D17Leh119, D17Rp17e, Plg, D17Leh66d, Ckb-rs2, and Trp53-ps. QTL analyses of HACU in the frontal cortex and hippocampus also revealed correlations with these markers at the level of P < 0.05 and P < 0.01. These data suggest that at least one locus located on mouse chromosome 17 near or between 6 and 13 cM from the centromere influences HACU in the striatum and possibly the frontal cortex and hippocampus of the mouse.

Animals↗
PubMed1995

Amelioration of the behavioral phenotype in weaver mutant mice through bilateral intrastriatal grafting of fetal dopamine cells.

Weaver mutant mice lose more than two-thirds of their nigral dopamine neurons. Behaviorally, weaver homozygotes display tremor, gait instability, and toppling over to the sides after a few steps. The recovery of functional responses was determined in a battery of behavioral tests in weaver mutants after bilateral transplantation of mesencephalic cell suspensions (prepared from wild-type mice) to the striatum. Equilibrium was tested by the time mice were able to stay on a suspended balance rod before falling off. Locomotor coordination was measured by the number of times mice toppled over to the sides as they moved about in an open-field matrix. Locomotor activity was quantified by the number of square crossings in an open-field matrix. Grafted weaver mutants performed significantly better than non-grafted mutant mice in all of these three tasks. The findings clearly demonstrate that bilateral transplants of foetal DA cells enhance motor performance in the weaver model of chronic nigrostriatal DA deficiency.

Animals↗
PubMed1995

Quantitative trait loci associated with the behavioral response of B x D recombinant inbred mice to restraint stress: a preliminary communication.

Quantitative trait loci (QTL) analysis was used to make provisional identification of loci containing genes influencing vulnerability to stress. The effect of restraint stress on open-field activity was measured in C57BL/6J and DBA/2J inbred strains of mice and in 22 B x D recombinant inbred strains of mice. QTL analyses were performed by correlating the behavioral delta scores for each group with the strain distribution pattern of 1300 markers for the B x D mice. A significant association was found between postrestraint rearings during min 5 through 8 in the open field and the Lamb2 marker on chromosome 1 (r = .718, p < .0001). Significant associations at the p < .0001 level were also found between baseline open-field rearings of control mice during min 0 through 5 and the Zp3, Ache, and Mr66-1 markers on chromosome 5, baseline open-field rearings of control mice during min 5 through 8 and the Pmv42 marker on chromosome 15, and open-field rearings of experimental mice during min 0 through 5 and the D11Ncvs61 marker on chromosome 11.

Animals↗
PubMed1995

Operant response suppression induced with systemic administration of 5-hydroxytryptophan is centrally mediated.

Intracerebroventricular (ICV) administration of selective serotonergic agents was used to examine the extent of central mediation of 5-HTP-induced operant response suppression in rats. ICV administration of LY53857 (1.0, 3.75, or 7.5 micrograms/5 microliters/5 min) dose dependently blocked response suppression induced with systemically administered 5-HTP (25 mg/kg, IP), whereas ICV 0.9% saline (5 microliters over 5 min) had no significant effect on 5-HTP-induced response suppression. ICV ketanserin (7.5 micrograms/5 microliters/5 min) also blocked response suppression induced with systemically administered 5-HTP. ICV administration of the 5-HT2A/2C receptor agonist DOI (80 micrograms/5 microliters/5 min) induced significant periods of response suppression in this model, which was blocked with LY53857 (1.0 mg/kg, IP) pretreatment. These data demonstrate that central administration of 5-HT2A/2C antagonists potently attenuate operant response suppression induced with systemically administered 5-HTP or DOI and are in agreement with previous findings suggesting central mediation of 5-HTP-induced operant response suppression.

5-Hydroxytryptophan↗
PubMed1992

Response suppression induced with selective 5-HT agonists can be differentially blocked with LY53857 in an animal model of depression.

Studies from this laboratory have demonstrated that administration of the selective 5-HT2/1C antagonist LY53857 can block 5-HTP-induced response suppression. To further investigate the serotonergic mechanisms involved in this effect, we decided to test the capacity of LY53857 to block response suppression induced with two selective 5-HT agonists. After a 15 minute baseline period, rats trained to press a lever for milk reinforcement on a VI 1' schedule were given IP injections of 1.0 mg/kg DOI, or 1.0 mg/kg 8-OH-DPAT to induce response suppression. Subsequently, rats were injected with 1.0 mg/kg LY53857 1 hour prior to DOI- or 8-OH-DPAT-induced response suppression. Preinjections with LY53857 resulted in a 100% blockade of DOI-induced response suppression whereas the same dose did not block response suppression induced with 8-OH-DPAT. These results indicate that the 5-HTP-induced response suppression shows some pharmacological similarity to DOI-induced response suppression and may be mediated through 5-HT2 and/or 5-HT1C receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Differential effect of 5-hydroxytryptophan on approach and avoidance behavior in rats.

The current hypersensitive postsynaptic serotonin receptor theory of depression developed and expanded by Aprison and Hingtgen was based on an animal model of behavior in which food-reinforced approach behavior was suppressed following 5-hydroxytryptophan (5-HTP) administration. In this paper, data are presented to show that when the same animal is taught to emit, alternatingly, approach and avoidance behavior, and the serotonin precursor, 5-HTP, is administered, only the approach behavior is affected. Adult, male Wistar rats were trained on Sidman avoidance (RS20:SS10) and food-reinforced approach (VI 1) schedules. During the first part of this study, rats received separately 50-min sessions for approach and avoidance responding. For the second part, both schedules were given in the same experimental chamber. In the third part, 10-min alternating approach and avoidance components were combined in the same 50-min sessions. Significant behavioral suppression of approach responding was observed following administration of L-5-HTP (50 mg/kg IP), as well as after D,L-5-HTP (25 and 50 mg/kg IP) in a dose-dependent relationship, whereas no significant effect was seen for Sidman avoidance responding during this type of session. These results support the role of serotonin in food-reinforced approach behavior and suggest that suppression of Sidman avoidance behavior may be mediated by other neurotransmitter systems.

5-Hydroxytryptophan↗
PubMed1990

GABA receptors in the posterior hypothalamus regulate experimental anxiety in rats.

Blockade of gamma-aminobutyric acid (GABA) function in the posterior hypothalamus of rats elicits a pattern of physiological and behavioral arousal consisting of increases in heart rate, respiration and blood pressure as well as intense locomotor stimulation and a selective enhancement of avoidance responding. The present study was conducted to assess the possibility that GABA-mediated neurotransmission in the posterior hypothalamus of the rat may regulate anxiety. Male rats were trained in a 'conflict' schedule consisting of a high and a low intensity of punishment ('high' and 'low' conflict) capable of measuring decreases and increases in the level of 'anxiety', respectively. Guide cannulae were stereotaxically implanted bilaterally in the posterior hypothalamus of these rats at sites where microinjection of bicuculline methiodide (BMI) 25 ng caused increases in heart rate under anesthesia. After recovery, they were tested: (1) in the high conflict schedule after microinjection of saline and two doses of the GABAA receptor agonist muscimol; and (2) in the low conflict schedule after injecting saline, the GABAA receptor antagonists, BMI and picrotoxin, and the glycine antagonist, strychnine. Injection of muscimol caused a significant and selective anti-conflict effect while both BMI and, at appropriate doses, picrotoxin produced pro-conflict effects. Microinjection of strychnine into the posterior hypothalamus or muscimol and picrotoxin into the lateral hypothalamus did not influence conflict responding. These results suggest that endogenous GABA acts on GABAA receptors in a discrete area of the posterior hypothalamus to regulate the level of experimental anxiety in rats.

Animals↗
PubMed1989

Anxiogenic effects of noreleagnine, a water soluble beta-carboline in rats.

We tested noreleagnine, a beta-carboline which unlike other beta-carbolines remains in aqueous solution at physiological pH, as well as chlordiazepoxide, a traditional benzodiazepine, and their interaction with the benzodiazepine receptor antagonist R0 15-1788 in a modified approach schedule with two levels of conflict. Noreleagnine displayed pro-conflict activity characteristic of beta-carbolines and chlordiazepoxide elicited an anti-conflict effect, both of which were blocked by pretreatment with R0 15-1788. We believe this to be the first clear demonstration that noreleagnine has an anxiogenic effect and that this effect is mediated by its action on benzodiazepine receptors.

Animals↗
PubMed1989

Activity-wheel stress and serotonergic hypersensitivity in rats.

Adult male Wistar rats were subjected to activity wheel stress: unlimited access to an activity wheel for up to twelve days and food for 30 to 60 min each day. Each treated rat was paired with a control, the latter being housed in home cages and given sufficient food to maintain a weight similar to the stressed partner. All rats were previously trained on a variable interval schedule for milk reinforcement. When the activity of the stressed rat increased rapidly then decreased suddenly, the pair was decapitated for biochemical analysis. Levels of the serotonin metabolite, 5-hydroxyindoleacetic acid, decreased by 50%, and the Bmax for ketanserin binding increased by 19% in frontal cortical homogenates from the stressed rats when compared to controls. These data support the concept that stress increases the sensitivity of central serotonin receptors.

Animals↗
PubMed1988

Response suppression in rats after bilateral microinjection of 5-hydroxytryptophan in lateral hypothalamus.

Studies using the 5-hydroxytryptophan (5-HTP) animal model of depression have led to the development of the hypersensitive postsynaptic serotonin receptor theory of depression. To demonstrate more clearly that the 5-HTP-induced suppression is a centrally mediated phenomenon, rats were implanted with bilateral cannulae in the lateral hypothalamus and received microinjections of D,L-5-HTP (100-500 ng) 15 min after the start of a VI operant session (milk reinforcement). Significant decreases in responding were observed that were comparable to those obtained after a systemic injection of 50 mg/kg D,L-5-HTP. Rats receiving a microinjection of 5-HTP in the posterior hypothalamus did not exhibit a behavioral effect. Rats working on shock-avoidance schedules did not demonstrate response suppression following microinjection of 5-HTP into the lateral hypothalamus, which is the same result as that following systemic 5-HTP administration. These data support the important role previously assigned to central 5-HT mechanisms in the 5-HTP animal model of depression.

5-Hydroxytryptophan↗
PubMed1987

Selective enhancement of shock avoidance responding elicited by GABA blockade in the posterior hypothalamus of rats.

Recent studies have shown that blockade of gamma-aminobutyric acid (GABA) in the posterior hypothalamus in anesthetized rats elicits cardio-respiratory stimulation similar to that seen in emotional defense reactions and, in conscious rats, locomotor arousal suggesting a flight response. The present study was conducted in order to test the hypothesis that the behavioral effects elicited by GABA blockade in the posterior hypothalamus were the results of disinhibiting a mechanism whose activation selectively enhances reactivity to aversive stimuli. Male rats were trained on a Sidman shock avoidance schedule (RS20:SS10) as well as a food-reinforced approach schedule (VI 1). Under anesthesia, guide cannulae were stereotaxically implanted bilaterally in the posterior hypothalamus at sites where microinjection of the GABA antagonist, bicuculline methiodide (BMI) 25 ng, increased heart rate. After recovery, rats were tested in both the avoidance and VI 1 schedules after hypothalamic microinjection of saline, BMI 25 ng, and the GABA agonist, muscimol 25 ng. Microinjection of BMI significantly increased the avoidance responses but had no effect on the approach responses. Muscimol decreased both the avoidance and approach responses. When microinjected into the lateral hypothalamic area, BMI had no effect on the response rates in either schedule while muscimol decreased the approach responding only. Therefore, GABA blockade at the discrete area of the posterior hypothalamic nucleus appears to elicit a selective enhancement of avoidance responses. These results suggest that an endogenous GABAergic system in the posterior hypothalamus may tonically inhibit a constellation of autonomic, locomotor and motivational responses that are necessary for some types of defense reaction.

Animals↗
PubMed1987

Potentiated 5-hydroxytryptophan induced response suppression in rats following chronic reserpine.

Since reserpine precipitates depression in some hypertensive patients, we tested this drug on our animal model of depression. The present experiment was designed to measure the effects of chronic reserpine treatment on 5-hydroxytryptophan (5-HTP) induced behavioral depression in rats trained on a food reinforcement operant schedule. Based on the Aprison et al. model of depression involving the serotonergic system, we predicted the development of receptor supersensitivity of postsynaptic serotonin (5-HT) receptors due to the decreased release of this neurotransmitter as a consequence of chronic reserpine treatment. Rats were trained on a VI 1 reinforcement schedule and then divided into 3 chronic treatment groups. One received daily injections of a placebo, another 0.025 mg/kg reserpine and the third 0.05 mg/kg reserpine. We found that 5-HTP induced behavioral depression was potentiated in rats chronically treated with reserpine, thus suggesting the development of supersensitive 5-HT receptors. These results support the hypothesis that in some types of human depression a decreased release of 5-HT occurs of sufficient duration to permit the subsequent development of supersensitive 5-HT receptors.

5-Hydroxytryptophan↗
PubMed1985

Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857).

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).

5-Hydroxytryptophan↗
PubMed1984

Postsynaptic serotonergic blockade following chronic antidepressive treatment with trazodone in an animal model of depression.

Acute pretreatment with clinically equivalent doses of antidepressive drugs has been observed to block D,L-5-hydroxytryptophan (5-HTP) induced behavioral depression in rats working on a food-reinforced operant schedule. Data from studies designed to distinguish presynaptic from postsynaptic events, indicated that the antidepressants were acting in part as blockers of postsynaptic serotonergic receptors. Using the same 5-HTP model of depression, we studied both the chronic and acute effects of a recently introduced antidepressant, triazolopyridine compound. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 50 mg/kg 5-HTP were pretreated (one hr before 5-HTP) with 1, 2, or 4 mg/kg trazodone with resulting blockade of 5-HTP induced depression of 35, 62 and 70% respectively. Chronic administration of trazodone (2 mg/kg trazodone/day) also resulted in a significant blockade of the 5-HTP effect (75%). Neither 2 mg/kg or 4 mg/kg trazodone was found to potentiate the shorter period of depression following 25 mg/kg 5-HTP. Chronic treatment with the antidepressant drugs, amitriptyline or mianserin also blocked 5-HTP depression. Thus, as in our earlier studies, these data suggest an important postsynaptic mechanism associated with chronic administration of trazodone, amitriptyline and mianserin which could be implicated in the therapeutic effectiveness of these drugs. The potency of trazodone in relation to other antidepressant drugs in our behavioral model of depression paralleled their potency in displacing radioligand binding to 5-HT receptors, and gives additional support for the new hypersensitive postsynaptic serotonin receptor theory of depression.

5-Hydroxytryptophan↗
PubMed1983

Serotonergic changes in specific areas of rat brain associated with activity--stress gastric lesions.

To study serotonergic involvement in the development of gastric lesions following activity wheel stress, three groups of rats (gastric lesions, no gastric lesions, and home--cage controls) were killed following exposure to the experimental procedures. The brains were dissected into eight specific areas and subjected to analyses for serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) using high performance liquid chromatography with EC detection. Lower levels of 5-HT were found in the midbrain, cortex, and hippocampus of rats with gastric lesions compared to either the no lesion group, subjected to shorter periods of activity--stress, or the home--cage control group. Levels of 5-HT and 5-HIAA were elevated in the pons/medulla oblongata of both the lesion and the no lesion groups compared to the home--cage controls. Corticosterone levels in blood were also significantly elevated in the lesion group. These data on serotonin changes in the CNS suggest a possible role for this neurotransmitter in stress-induced gastric pathology.

Animals↗