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Functions of the caudal periaqueductal gray in lactating rats: kyphosis, lordosis, maternal aggression, and fearfulness.

Severe impairment of the kyphotic nursing posture in lactating rats found previously after prepartum lesions of the caudal intercollicular periaqueductal gray (cPAG-x) was confirmed and was extended to a continuous 24-hr period. Litters of cPAG-x dams gained approximately 10% less weight postnatally than controls, which was in part related to their dams' compensatory prone nursing posture that was ineffective for milk letdown. Sexual proceptivity and receptivity (lordosis) during the postpartum estrus were virtually eliminated in subjects with relatively large bilateral cPAG lesions. The doubling of maternal attacks toward a male intruder after lesioning was also confirmed and was related to reduced fearfulness in an elevated plus-maze. Thus, the cPAG plays a multifaceted role in parturient rats; it is involved in the mediation of nursing, sexual, aggressive, and fear behaviors.

Aggression↗

The prevalence of teachers who bully students in schools with differing levels of behavioral problems.

OBJECTIVE: This study looked for a relationship between the prevalence of teachers who bully students and school behavioral problems reflected in suspensions from school. METHOD: A convenience sample of 214 teachers answered an anonymous questionnaire about their perceptions of teachers who bully students and their own practices. Teachers were grouped into whether they taught at schools with low, medium, or high rates of suspensions. Analyses of variance were used to analyze continuous variables, and chi-square statistics were used to study categorical variables. RESULTS: Teachers from schools with high rates of suspensions reported that they themselves bullied more students, had experienced more bullying when they were students, had worked with more bullying teachers over the past 3 years, and had seen more bullying teachers over the past year. CONCLUSIONS: These findings suggest that teachers who bully students may have some role in the etiology of behavioral problems in schoolchildren.

Adult↗

Species-specific danger signals, endogenous opioid analgesia, and defensive behavior.

The effects of handling stimuli and stress odors on species-specific defensive behavior and pain sensitivity were examined in rats. Animals not adapted to handling had longer jump latencies on the hot plate test of pain sensitivity than those with extensive handling experience. In a postshock freezing test, naltrexone enhanced defensive freezing relative to saline controls in nonadapted animals. However, naltrexone produced no such effect in rats that were adapted to handling. These two studies indicate that the handling procedure triggered an endogenous opioid analgesic response in rats not adapted to handling. Experiment 3 showed that a similar naltrexone-reversible opioid analgesia can be triggered by stress odors. Naltrexone, when compared to saline, enhanced postshock freezing in the presence of conspecific stress odors, but not in their absence. In Experiment 4, stress odors and nonadapted handling were able to activate defensive freezing directly, when tested in compound but not in isolation. The studies are consistent with the view that stress odors and handling stimuli are danger signals that activate endogenous opioid analgesia as well as defensive behavior, suggesting that analgesia is a component of the rat's defensive behavior system.

Adaptation, Psychological↗

The participation of serotoninergic system in the regulation of emotional-defensive behavior evoked by intrahypothalamic carbachol injections in the cat.

The influence of bilateral injections of serotonin (5-HT) and methysergide (MET) to antero-medial hypothalamus (HA) on carbachol-induced emotional-defensive behavior was investigated. Earlier (15 min) stimulation of 5-HT receptors in HA region by 5-HT injections evoked a decrease in the level of vocal response (number and time of growling), while previous blocking of these receptors by means of MET brought about a considerable increase of vocalization level evoked by carbachol (Cch) injections (10 pg) to the same loci of HA. Intrahypothalamic injections of 5-HT alone or MET did not evoke any observable changes in the animals behavior. The alterations of the level of Cch-induced vocal response 3 to 35 days after chemical damage of 5-HT neurons in HA or in the middle forebrain bundle (MFB) in posterolateral hypothalamus caused by 5,7-dihydroxytryptamine were examined. Local neurotoxin injections both to MFB and to HA evoked a long lasting increase in the level of Cch-induced vocalization, which began on the 5th-7th day after lesioning and lasted till the completion of the experiment (35 days). Results data indicate that the 5-HT system exerts an inhibiting influence on the emotional-defensive behavior induced by the cholinergic system.

Aggression↗

Dopamine agonist induced self-mutilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: possible pharmacological model for Lesch-Nyhan syndrome.

We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10-14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2-4 years old. The administration of mixed DA agonists, such as L-DOPA, apomorphine (Apo) and abeorphine 201-678, elicit a self-mutilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D1, but not D2 DA receptors, and was prevented or abolished by the D1 DA antagonist SCH 23390 or by the D1 and D2 DA antagonist fluphenazine (Flu), but not by the D2 antagonist (+/-)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D1 and/or by both D1 and D2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.

Animals↗

Analgesia produced by centrally administered DAGO, DPDPE and U50488H in the formalin test.

Three opioid agonists ([D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAGO), [D-Pen2,D-Pen5]enkephalin (DPDPE) and U50488H) were tested independently for their ability to produce analgesia in the formalin test. These agonists were chosen based upon their ability to act selectively at mu, delta and kappa opioid receptor types respectively. Rats received one intracerebroventricular (i.c.v.) injection of an agonist 20 min after subcutaneous injection of 15% formalin into a rear paw. Formalin injection produces continuous pain that results in two stereotypic behaviors, paw licking and paw lifting. Ten minutes after i.c.v. injection rats were observed for an 8 min period and scored for formalin-induced behavior. All agonists produced analgesia as indicated by a dose-dependent attenuation of formalin-induced behavior. At the doses tested, the rank order of analgesic efficacy was DAGO greater than DPDPE greater than U50488H. We suggest that centrally located mu, delta and kappa opioid receptors can each modulate the perception of this clinically relevant form of continuous pain. Additionally, the highest dose of DPDPE tested significantly increased rearing whereas DAGO and U50488H failed to affect rearing.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

Pre-exposure to the cannabinoid receptor agonist CP 55940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats.

Three experiments examined the influence of pre-exposure to the cannabinoid receptor agonist CP 55940 ((-)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55940 (0.1 mg/kg) or the cannabinoid CB(1) receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive ('dummy') lever presses were increased by cannabinoid pre-treatment. Overall, these results suggest that cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for 'gateway' theories of cannabinoid effects in humans are discussed.

Analgesics↗

Dopamine receptor occupancy in vivo: behavioral correlates using NNC-112, NNC-687 and NNC-756, new selective dopamine D1 receptor antagonists.

The ability of dopamine D2, mixed D1/D2 and selective D1 receptor antagonists, including NNC-112, NNC-687, NNC-756, to inhibit the in vivo binding of [3H]SCH 23390 or [3H]raclopride to dopamine receptors was studied in mice and rats. Furthermore, the dopamine-antagonistic effects of these drugs were also studied in various behavioral models. Significant levels of in vivo receptor blockade were required for antagonism of typical dopamine agonist-mediated behaviors. However, fewer D1 than D2 receptors had to be blocked to produce similar antagonistic effects. Thus, there may be a greater receptor reserve for D2 receptors than for D1 receptors.

Amphetamine↗

Evidence for a decline with age in behavioral responsivity to the serotonin agonist, m-chlorophenylpiperazine, in healthy human subjects.

The functional significance of alterations in brain serotonin (5HT) associated with normal aging in both animals and humans is largely unknown. Using the effects of the 5HT agonist, m-chlorophenylpiperazine (m-CPP), as a measure of central serotonergic responsivity, we compared the behavioral and neuroendocrine responses of older normal volunteers (mean age +/- SD = 62.4 +/- 4.12) to those of younger normal volunteers (mean age +/- SD = 31.6 +/- 5.52). When m-CPP was administered intravenously, older subjects showed decreased behavioral responses but similar neuroendocrine responses, compared to younger subjects. The decreased behavioral responsivity was unrelated to pharmaco-kinetic differences between the groups, since m-CPP plasma levels were similar in both groups. This report is the first in vivo study in humans to demonstrate decreased behavioral responsivity with age following serotonergic stimulation, and may indicate a functionally less responsive 5HT subsystem in older subjects.

Adult↗

Effects of a novel cholinergic M1 agonist, AF102B, on ambulation and water drinking behavior in rats.

Effects of a novel M1 agonist, AF102B (cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine HCl), on ambulation and water drinking behavior were examined using an Ambulo-Drinkometer. AF64A-treated rats, an animal model for senile dementia of the Alzheimer type (SDAT), and non-treated control rats were used. AF102B was administered orally via tap water at a concentration of 0.01% and 0.1% for an experimental therapeutic dose and a supramaximal dose, respectively. Four-week administration of 0.01% AF102B did not affect either ambulatory activity or water drinking activity in non-treated rats. Successive 0.1% AF102B administration for 4 weeks produced a significant decrease in drinking activity as compared with non-treated control rats. In AF64A-treated rats, AF102B did not change the cholinotoxin AF64A-induced high activity in ambulation. However, a decrease in water drinking activity was observed after 0.1% AF102B administration, as in non-treated rats. These results suggest that therapeutic dose of AF102B do not produce any changes in the spontaneous moter activity and water drinking behavior in normal rats or the animal model for SDAT. Several investigators reported that AF102B (FSK-508; cis-2-methylspiro (1,3-oxathiolane-5,3') quinuclidine HCl) had the property of a relatively specific muscarinic agonist of the M1-type This novel M1 agonist, AF102B, also exerted and ameliorating effect on experimental amnesia; in a T-maze, radial-arm maze task and passive avoidance tasks. AF102B improves the cognitive impairment in various animal models for memory disorders including senile dementia of the Alzheimer type (SDAT). Based on these observations, AF102B has been proposed for the treatment of SDAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Antidepressant-like behavioral effects of serotonin receptor agonists.

The clinical discoveries that drugs that stimulate 5-HT neurotransmission, either by inhibiting 5-HT uptake or by stimulating postsynaptic receptors directly, have antidepressant properties has stimulated interest in defining the role of the 5-HT receptor system in the clinical effects of antidepressant drugs. Two approaches are reviewed in this paper that address the neurochemical mediation of the therapeutic effects of antidepressant drugs from the standpoint of animal behavior. The first approach utilizes a behavioral response in rats, the forced swimming test, that correlates well with predicting antidepressant drugs in humans. Studies are reviewed that examined serotonergic compounds in the forced swimming test, from the standpoint of identifying better serotonergic mechanisms involved in the antidepressant response. Both 5-HT uptake inhibitors and 5-HT1A receptor agonists produce effects in the forced swimming test that are similar to those of other classes of antidepressant drugs. In contrast, agonists at other 5-HT receptors or 5-HT receptor antagonists do not produce antidepressant-like behavioral effects. Evidence for an important role of 5-HT1A receptors in the antidepressant response is supported by findings that antagonists of 5HT1A receptors prevent the ability of 5-HT1A receptor agonists to reduce immobility in the forced swimming test. The results of studies interfering with 5-HT neurotransmission, either by inhibition of 5-HT synthesis or by the destruction of 5-HT neurons, favor the idea that the effects of 5-HT1A receptor agonists are produced by the stimulation of postsynaptic 5-HT1A receptors. The second approach for studying the behavioral effects of antidepressant drugs employs drug discrimination studies, conducted using a discriminated taste aversion procedure, to provide a method for studying the discriminative stimulus effects of the antidepressant 5-HT uptake inhibitor sertraline. Rats were trained to discriminate the effects of sertraline (10 mg/kg) from saline. Other 5-HT uptake inhibitors, such as fluoxetine, fluvoxamine and paroxetine, substituted for the sertraline stimulus. High doses of norepinephrine uptake inhibitors, such as desipramine or maprotiline, were required to produce similar effects. These two behavioral approaches promise to be useful for defining the important pharmacological effects associated with the behavioral effects of antidepressant drugs.

Animals↗

Behavioral effects of chronic exposure to selective D-1 and D-2 dopamine receptor agonists.

Chronic treatment with the selective D-1 agonist SKF 38393 induced behavioral supersensitivity (increased stereotypy and decreased locomotor activity) in response to apomorphine, In contrast, chronic treatment with the selective D-2 agonist LY 171555 resulted in a subsensitive behavioral response to apomorphine challenge. Chronic treatment with the combination of these drugs augmented apomorphine-induced stereotypic behaviors, but these were different in nature from those observed in animals treated with SKF 38393 alone. Chronic SKF 38393 treatment resulted in an enhanced behavioral response to SKF 38393 itself. Behavioral response to LY 171555 was affected only by chronic treatment with the combination of selective agonists. These results suggest that chronic D-1 receptor stimulation may be necessary and sufficient for the development of dopamine agonist-induced behavioral sensitization in the intact rat; the mechanism may involve increased sensitivity of D-1 receptor-associated mechanisms. Chronic D-2 receptor stimulation appears to have the opposite effect. These results also provide evidence that a synergistic interaction between receptor subtypes may underlie certain behavioral effects of chronic agonist exposure.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Intracranial androgenic and estrogenic stimulation of male-typical behaviors in house mice (Mus domesticus).

Two experiments in house mice (Mus domesticus) examined the neural sites at which steroid hormones activate the following male-typical behaviors: 70 kHz ultrasonic mating vocalizations in response to stimulus females or their urine, urinary marking in response to stimulus males or stimulus females, mounting of estrous females, and intermale aggression. In the first experiment, four groups of castrated males received bilateral intracranial implants of testosterone (T) into either the septum (SEPTUM), medial preoptic area (MPO), anterior hypothalamus (AHA), or ventromedial hypothalamus (VMH). Two control groups received subcutaneous silastic capsules of T (TSIL) or empty silastic capsules (BSIL). The TSIL males performed all behaviors at male-typical levels while the BSIL males were unresponsive. MPO males emitted ultrasonic mating vocalizations at high levels while few vocalizations were seen in males of the other brain implant groups. The VMH, AHA, and MPO males urine marked at higher levels than the BSIL males but did not exhibit the high levels of the TSIL males. Mounting was observed only in MPO and TSIL males. Aggression was rare in males from any of the brain implant groups. In the second experiment, the hormone activity of the implants was increased by using testosterone propionate (TP) or a 50% mixture of estradiol (E2) and cholesterol. The six groups were SEPTUMTP, SEPTUME2, MPOTP, MPOE2, TPSIL, and BSIL. The TPSIL males performed all behaviors at male-typical levels while the BSIL males were unresponsive. TP was effective at restoring vocalizations and urine marking only when placed in the MPO; however, E2 was effective at both sites. Again aggression and mounting were less evident in the brain implanted males. In conclusion, implants of T or TP were effective in restoring ultrasonic mating vocalization when placed into the MPO. MPO implants of T and TP were also effective in stimulating urine marking, although VMH and AHA implants also showed some effectiveness. The restorative effects of E2 were not localized which is probably related to the greater hormonal activity of this treatment. Comparisons of the properties of the various brain implants to restore more than one behavior were discussed.

Aggression↗