Inhibition of glycolytic metabolism and sleep-waking states in cats.
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Biomedical subjects
Publications and source records attributed to J Panksepp.
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Intraventricular injections of beta-endorphin, gamma-endorphin and alpha-endorphin were demonstrated to reduce isolation-induced distress vocalization on 2-4 day old chicks in a dose response manner at doses as small as 12.5 picomoles (pmol). beta-Endorphin was more potent than the other peptides and morphine, while Met-enkephalin was without effect. However, the D-Ala2 substituted form of Met-enkephalin was as potent as morphine. None of the opioid peptides was effective when injected peripherally in doses of 400 pmol/g body weight. Extension of the interval between injection and behavioral observation from 4 minutes eliminated the ability of alpha- and gamma-endorphin to reduce the peeps. Specificity of the opioid effect was determined by testing intraventricular injections (200 pmol) of 9 other endogenously found peptides. Somatostatin, vasoactive intestinal peptide, and human pancreatic peptide reduced the vocalizations modestly, while alpha-MSH reliably increased them.
Intraventricular administration of various chain length casomorphins (CM) reliably reduced separation induced distress vocalizations (DVs) in young domestic chicks. At a dose of 50 nanomoles, CM-5 was more potent than either CM-4 or CM-7, but for each the duration of action was approximately half an hour, with CM-7 having a somewhat longer effect. This suppression of DVs was partially antagonized by naloxone (1 mg/kg).
The effects of centrally administered ACTH(1-24) and ACTH(4-10) on isolation-induced distress vocalizations (DVs) were assessed in the presence or absence of social cues (mirrored and plain environments). A dose-response analysis indicated that ACTH(1-24) at doses of 0.5 nM and above increased DVs relative to controls when the animals were tested in mirrored or social environments which reduce baseline levels of calling. This effect, however, was short-lived (approx. 15 min). When tested again 1 hr after injection, the treated animals did not differ from controls. ACTH/MSH(4-10) had no effect on vocalization when the animals were tested immediately after injection, but marginally increased calling when animals were tested an hour later. In addition to vocalization changes, ACTH(1-24) induced squatting when animals were isolated in the test boxes, and yawning, head shaking, wing flapping and preening when animals were reunited after testing. ACTH(1-24)-treated chicks also exhibited longer latencies to close their eyes when they were held in the cupped hands of the experimenter. Taken together, the results suggest that ACTH(1-24) induces a central state of arousal in chicks that resembles fear/anxiety.
The effects of centrally administered alpha-MSH on separation-induced distress vocalizations (DVs) and squatting were evaluated in domestic chicks for dose-response, time course, and interactions with peripheral naloxone and both peripheral and central morphine. Some of the tests were conducted in both the presence and absence of social stimuli (mirrors or a conspecific). Doses of 0.04 microgram of alpha-MSH or greater eliminated the usual suppression of DVs produced by mirrors or conspecifics. This effect lasted 10-15 minutes and was followed by inhibition of DVs, accompanied by a dose-dependent vigilant squatting posture, that lasted about one hour. These effects showed no development of tolerance to repeated alpha-MSH injections over a six-day period, and no apparent interaction with the effects of peripherally injected naloxone or either peripherally or centrally injected morphine. It is suggested that, in keeping with its role in defensive camouflage in amphibians, alpha-MSH in chicks may activate a central state akin to fear to adaptively modulate DVs and defensive hiding.
All the opiate-like peptides we tested (Met-enkephalin, (D-Ala2)-Met-enkephalin-NH2, beta-endorphin, (D-Ala2)-beta-endorphin, (D-Ala2)-alpha-endorphin, (D-Ala2)-gamma-endorphin) were capable of reducing distress vocalizations (DV's) in socially-isolated chicks when injected into the vicinity of the fourth ventricle in doses as low as 100 picomoles. All of these substances were at least as potent as equimolar doses of morphine sulfate. In general, DV's were a more sensitive measure of opiate-like peptide effects than reductions in body temperature. In a more limited study using peripheral injections, it was determined that (D-Ala2)-Met-enkephalin at doses of 400 nanomoles/kg, like morphine sulfate, was more effective in reducing DV's, than an equimolar dose of beta-endorphin. beta-endorphin was not as effective via a peripheral route as it was via central administration.
A potent convulsant, trimethylolpropane phosphate (TMPP), was evaluated for long-term effects on measures of social behaviors and anxiety in Long-Evans rats. Animals received three to four daily treatments of TMPP (0.1 mg/kg/ml) beginning at age 23 days in Experiment 1 and 73 days in Experiment 2. Gregariousness was measured in juvenile play and adult social investigation. Anxiousness was measured in the open field and elevated plus-maze. Long-lasting changes in social behaviors were found: play and social investigation were elevated, especially in female rats. Also, an aversive environmental experience associated with TMPP treatment influenced the drug effect on social investigation for males, but not females. In males, TMPP- vs. VEH-treated animals displayed greater social investigation when the treatment was in a positive environment than in an aversive one. In contrast, TMPP- vs. VEH-treated females showed greater social investigation regardless of environmental experience. There were no treatment group differences for measures of anxiety. These results suggest short-term exposure to TMPP may lead to long-lasting changes in specific social behaviors and neural substrates related to them, but not to changes in anxiousness.
The proconvulsant compound trimethylolpropane phosphate (TMPP) was evaluated for its effects on motor, social, and emotional behaviors. Long Evans rats were treated prenatally for 13 days and/or neonatally for 10 days. Behavioral tests were performed during treatment and several days after treatment. Beginning on gestation day 9, and continuing for 13 days, 20 dams received once daily i.p. injections. Half were treated with distilled water, the other 10 received 0.2 mg TMPP/kg body weight. No external malformations were observed in the live-born offspring of TMPP- or vehicle-exposed dams. On postnatal day 3 one-half the pups were cross-fostered to dams that had the opposite treatment as their biological mothers. Also on postnatal day 3, pups were divided into two groups, one receiving injections of distilled water, the other receiving injections of 0.2 mg TMPP/kg body weight. Ten daily injections were administered i.p., beginning postnatal day 3. Motor behaviors were evaluated in step-down and paw lift tasks and no group differences were found. At 18 days of age, one half the pups were separated from the dam and their littermates. The other half of the pups continued to be housed with the dam and remaining littermates until postnatal day 50. Social interaction was measured in juvenile play and adult social investigation. Emotional responsivity was assessed in open field activity, elevated plus-maze exploration, and ultrasonic distress vocalizations. Complex interactions were found for measures of social interaction and emotional responsivity related to drug treatment, housing condition, and sex. Due to the observed sex differences. it is hypothesized that the action of TMPP may involve a change in the hormonal systems that control the differentiation of related sex-typical behaviors.
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