James B. Lucot

Physiological basis and pharmacology of motion sickness: an update

Motion sickness can occur when sensory inputs regarding body position in space are contradictory or are different from those predicted from experience. Signals from the vestibular system are essential for triggering motion sickness. The evolutionary significance of this malady is unclear, although it may simply represent the aberrant activation of vestibuloautonomic pathways that typically subserve homeostasis. The neural pathways that produce nausea and vomiting during motion sickness are presumed to be similar to those that generate illness after ingestion of toxins. The neural substrate of nausea is unknown but may include neurons in the hypothalamus and inferior frontal gyrus of the cerebral cortex. The principal motor act of vomiting is accomplished through the simultaneous contractions of inspiratory and expiratory respiratory muscles and is mediated by neurons in the lateral medullary reticular formation and perhaps by cells near the medullary midline. Cocontraction of the diaphragm and abdominal muscles increases pressure on the stomach, which causes gastric contents to be ejected through the mouth. Effective drugs for combating motion sickness include antihistamines, antimuscarinics, 5-HT1A (serotonergic) receptor agonists and neurokinin type 1 receptor antagonists. However, considerable information concerning the physiological basis and pharmacology of motion sickness is unknown; future research using animal models will be required to understand this condition.

Neurobehavioral deficits in db/db diabetic mice

Recent clinical studies indicate neurobehavioral disturbances in type-2 diabetics. However, there is paucity of preclinical research to support this concept. The validity of db/db mouse as an animal model to study type-2 diabetes and related complications is known. The present study was designed to investigate comprehensively the db/db mouse behavior as preclinical evidence of type-2 diabetes related major neurobehavioral complications. We tested juvenile (5-6weeks) and adult (10-11weeks) db/db mice for behavioral depression in forced swim test (FST), psychosis-like symptoms using pre-pulse inhibition (PPI) test, anxiety behavior employing elevated plus maze (EPM) test, locomotor behavior and thigmotaxis using open field test and working memory deficits in Y-maze test. Both juvenile and adult group db/db mice displayed behavioral despair with increased immobility time in FST. There was an age-dependent progression of psychosis-like symptoms with disrupted PPI in adult db/db mice. In the EPM test, db/db mice were less anxious as observed by increased percent open arms time and entries. They were also hypo-locomotive as evident by a decrease in their basic and fine movements. There was no impairment of working memory in the Y-maze test in db/db mice. This is the first report of depression, psychosis-like symptoms and anxiolytic behavior of db/db mouse strain. It is tempting to speculate that this mouse strain can serve as useful preclinical model to study type-2 diabetes related neurobehavioral complications.

8-OH-DPAT suppresses vomiting in the cat elicited by motion, cisplatin or xylazine

Vomiting was suppressed in cats pretreated with 8-OH-DPAT and then challenged with an emetic stimulus; motion, xylazine or cisplatin. The antiemetic effect is likely due to stimulation of postsynaptic serotonin-1A receptors. The most parsimonious explanation is that it acts at a convergent structure, presumably at or near the vomiting center. If so, 8-OH-DPAT may block emesis elicited by virtually any other stimulus. A supplementary experiment revealed that lorazepam suppressed motion sickness at a dose that produced ataxia, but did not suppress xylazine-induced emesis. These results do not support the possibility that the antiemetic effects of 8-OH-DPAT were the result of anxiolytic activity.

Blockade of 5-hydroxytryptamine3 receptors prevents cisplatin-induced but not motion- or xylazine-induced emesis in the cat

5-Hydroxytryptamine3 antagonists have been reported to prevent emesis elicited by cisplatin and radiation. This study investigated the possibility that drugs with this mechanism of action may be useful in preventing emesis elicited by other stimuli. The drugs ICS 205-930 (0.1 and 1.0 mg/kg) and MDL 72222 (0.1 and 1.0 mg/kg) were administered SC to cats before challenging them with either provocative motion or an emetic dose of xylazine. In no instance was a significant reduction in emesis evident. Zacopride was also administered before motion testing (0.01 to 10.0 mg/kg) and found to not have efficacy. To test the possibility that species or route of administration were factors in the negative results, 1.0 mg/kg of ICS 205-930 was administered SC before IV infusion of 7.5 mg/kg of cisplatin. There was a total suppression of emesis for the duration of the six-hour observation periods. This result verifies other work which found 5-hydroxytryptamine3 antagonists to be effective in preventing emesis elicited by cancer chemotherapeutic treatments. However, there is no evidence that they are effective in other syndromes, such as motion sickness and xylazine-induced emesis.

The Influence of Maternal Separation on Plasma Concentrations of ACTH, Epinephrine, and Norepinephrine in Guinea Pig Pups

Preweaning guinea pigs were placed into a test cage either alone or with their mother for 10, 30, or 90 min, or were placed into the cage alone for 24 hr. At 30 and 90 min, pups exhibited higher plasma levels of ACTH if alone than if with the mother. This effect was not apparent at 10 min, and ACTH levels of pups tested alone were no longer greater than baseline levels at 24 hr. These results provide further evidence that brief maternal separation can serve as a potent stimulus for activation of the hypothalamo-pituitary-adrenal system in this species. Plasma epinephrine and norepinephrine concentrations of pups tested alone were not significantly greater than those of pups tested with their mothers. But, pups tested alone for 10 and 30 min did show an elevation of epinephrine and norepinephrine over baseline levels. That is, the combined influence of separation and other aspects of the manipulation (e.g., exposure to novelty) evoked sympathetic responses. In addition, the number of vocalizations emitted by pups during the first 30 min of isolation in the test cage was positively correlated with concentrations of ACTH, epinephrine, and norepinephrine following 24 hr of this procedure, but not following 90 min or at baseline. Thus, the initial behavioral response appears to be predictive of the levels of both hypothalamo-pituitary-adrenal and sympathetic activity 24 hr after separation is initiated.

Circadian Differences in Stress-Induced Pressor Reactivity in Mice

Abstract—The objective of this study was to determine the effect of chronic stress exposure on the circadian pattern of cardiovascular responses in mice. Using male C57BL6 mice with carotid arterial catheters, we tested the effect of 7 days of intermittent shaker stress on body weight, food intake, drinking activity, plasma corticosterone, mean arterial pressure (MAP), and heart rate. The stress was delivered automatically for 2-minute periods (150 cycles/min), 45 times/d for 7 days. Plasma corticosterone was significantly increased in acutely and chronically stressed mice, with a partial attenuation in the chronic condition. Stress increased water intake, produced no change in food intake, and significantly decreased body weight (5% change). MAP and heart rate were measured continuously on stress days 1, 3, and 7 and during the basal and recovery periods. Chronic stress did not produce a sustained increase in MAP; however, there was an increase in MAP during the first stress day and a decrease during the recovery period. There was a circadian pattern in the pressor responses, with greater increases seen during the light period (nonactive phase) than in the dark period (+24% versus +11% on stress day 3, light versus dark). The results suggest that a stress delivered during the nonactive phase represents a higher cardiovascular risk.

Decreased sensitivity of rat pups to long-lasting dopamine and serotonin depletions produced by methylamphetamine

Abstract Neonatal rats were administered 6-hydroxydopamine or high doses of methylamphetamine and the long-lasting effect on monoamine levels were examined. The neonatal rats were very sensitive to dopamine depletions produced by 6-hydroxydopamine. In contrast, the neonatal rats demonstrated little sensitivity to dopamine and serotonin depletions produced by methylamphetamine. Comparison of the depletions produced by these neonatal treatments with the depletions reported for adult treatments revealed that the neonatal rats were more sensitive to the 6-hydroxydopamine-induced depletions and less sensitive to the methylamphetamine-induced depletions.

Monoamine Activity in Anterior Hypothalamus of Guinea Pig Pups Separated from Their Mothers

Brief isolation in a novel environment increased the ratios of 3-methoxy-4-hydroxyphenylethylene glycol to norepinephrine (MHPG:NE) and dihydroxyphenylacetic acid to dopamine (DOPAC:DA) in the anterior hypothalamus of guinea pig pups. Ratios were significantly elevated after 90 min of isolation and for MHPG:NE, after 30 min of isolation; changes were due to increases in MHPG and DOPAC. Home cage isolation produced no change in any measure of catecholamine activity. No changes in levels of serotonin or its metabolite were observed. In 1 experiment, resting levels of NE and DOPAC:DA were predictive of the rate of separation-induced vocalization. Maternal separation in the context of novelty increases hypothalamic NE and DA activity; however, both isolation and novelty are required because neither maternal separation in the home cage nor exposure to a novel cage together with the mother had any discernible effect.

Rosiglitazone treatment reversed depression- but not psychosis-like behavior of db/db diabetic mice:

The objective of the present study was to examine the effect of long-term management of insulin resistance and hyperglycemia on neurobehavioral deficits in db/db mice. In this study, 5-week-old db/db and lean control mice were fed with rosiglitazone (20 mg/kg/day) mixed or standard chow for a duration of 5 weeks. Mice were monitored weekly for blood glucose concentration. Five weeks after the onset of treatment, they were subjected to the forced swim test (FST), pre-pulse inhibition (PPI), open field test (OFT) and fear-potentiated startle (FPS) test to examine for depression, psychosis-like behavior, locomotor activity and emotional learning, respectively. Rosiglitazone normalized hyperglycemia and improved glucose tolerance. Rosiglitazone significantly reduced immobility time in the FST in db/db mice, suggesting an antidepressant-like effect. However, rosiglitazone failed to reverse disruption of PPI in db/db mice, indicating its ineffectiveness against psychosis-like behavior. In the OFT, rosiglitazone did not affect the activity of db/db mice, suggesting its antidepressant-like effect was independent of changes in locomotor activity. In the FPS test, db/db mice showed impaired emotional learning and rosiglitazone failed to correct it. In conclusion, long-term blood glucose management in type-2 diabetics may help to limit the co-occurrence of depression but not the psychotic symptoms and ability to cope with stress.

Antiemetic effects of flesinoxan in cats: comparisons with 8-hydroxy-2-(di-n-propylamino)tetralin

The antiemetic effects of flesinoxan were evaluated following s.c. administration in cats. Flesinoxan produced a dose-dependent suppression of motion sickness and also reduced xylazine-induced emesis at higher doses. Flesinoxan had a short latency to onset and may have a brief duration of action. It was slightly more potent that 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in contrast to their relative potencies on most other in vivo measures. High doses of both agonists produced defensive behavior as a result of 5-HT1A receptor stimulation. (-)-Propranolol, which previously reduced 8-OH-DPAT suppression of feline motion sickness, failed to reduce the antiemetic effect of flesinoxan. The dose of 3 mg/kg of NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine) produced a slight decrease in motion sickness and added to the suppression of motion sickness by low doses of flesinoxan via an uncertain mechanism. It also reduced the antiemetic effect of higher doses of flesinoxan. In contrast, NAN-190 produced additive antiemetic effects when combined with 8-OH-DPAT and little if any reduction. NAN-190 reduced the defensiveness produced by both flesinoxan and 8-OH-DPAT. Phentolamine and sulpiride reduced neither the antiemetic effect nor the defensive behavior produced by flesinoxan, thus ruling out a role for alpha-adrenoceptors and dopamine D2 receptors. Flesinoxan exerted a broad spectrum antiemetic effect by an action at 5-HT1A receptors as does 8-OH-DPAT, but differed in its response to putative 5-HT1A receptor antagonists.