Age-dependent differences in the rat's conditioned defensive burying behavior: effect of 5-HT1A compounds.

The ontogeny of conditioned defensive-burying behavior was studied in rats from 2 to 21 weeks of age. At early ages this parameter shows low values that gradually increase until the 11th week, decreasing steadily thereafter. Reactivity, measured by the burying-behavior latency, appeared increased in 2-week-old rats. The effect of the serotonergic1A compounds: 8-OH-DPAT (0.25 and 0.5 mg/kg), ipsapirone, buspirone, and indorenate (at 2.5 and 5.0 mg/kg) was studied at 3, 7, 11, and 21 weeks of age. All compounds produced a dose-dependent decrease in burying behavior in rats of 7 and 11 weeks, while at the Week 21, only 8-OH-DPAT and indorenate reduced it. At 3 weeks of age, burying-behavior latency was increased by all compounds, but burying behavior was not altered. Motor coordination was affected by buspirone at all ages and by 8-OH-DPAT at the Week 21. Data are discussed on the bases of the development of defensive behaviors.

Pharmacological analysis of acute morphine dependence in infant rats: close molecular relationship of head-shaking precipitated by opiate antagonists and cholinergic neurotransmission.

The influence of drugs affecting different neurotransmitter systems on an acute abstinence head-shaking (AHS) model induced by nalorphine or naloxone was studied in 9-day-old rat pups pretreated (3 h before) with morphine (10 mg/kg, i.p.). One hour after the injection of nalorphine (10 mg/ kg, i.p.) AHS was stopped by a second dose of morphine (10 mg/kg, i.p.) and reinitiated 1 h later by a higher dose of nalorphine (20 mg/kg, i.p.). In other groups AHS was blocked by spiroperidol (0.1 mg/kg, i.p.), clonidine (0.01 mg/kg, i.p.) or scopolamine (50 mg/kg, i.p.). In these groups a second injection of nalorphine did not reinitiate AHS. In dose-effect curve experiments the AHS induced by naloxone or nalorphine was significantly reduced by previous injections of scopolamine, spiroperidol, metergoline or phentolamine in the corresponding groups. Scopolamine was the only antagonist which displaced the AHS dose-effect curves to the right without affecting the maximal response. Since no common receptors exist for a direct competitive interaction between opiate antagonists and scopolamine, these experiments suggest that a direct molecular relationship exists between the tissue concentration of nalorphine (or naloxone) and the endogenous ACh release during abstinence. Thus, the AHS model in 9-day-old rats clearly differentiates specific from non-specific blockade of the abstinence syndrome, and confirms a distinct or primary role of cholinergic neurotransmission in morphine abstinence.

Two inbred rat sublines that differ in spontaneous yawning behavior also differ in their responses to cholinergic and dopaminergic drugs.

This work compares the sensitivities of high-yawning (HY) and low-yawning (LY) sublines of Sprague-Dawley rats to dopaminergic and cholinergic yawning-inducing drugs. HY animals are significantly more sensitive to apomorphine and (-)3PPP than LY animals. Physostigmine is a less effective yawning-inducer in HY than in LY rats. With pilocarpine no differences were detected between both sublines in regard to its yawning-inducing activity. Since yawning behavior is subject to dopaminergic (inhibitory) and cholinergic (excitatory) influences, it is suggested that the genetic differences between these sublines affect the dopaminergic pathways that normally regulate yawning frequency.

The taiep rat: a myelin mutant with an associated oligodendrocyte microtubular defect.

This report describes a new inherited disorder of myelination in the rat, named taiep, in which failure of normal myelination of the CNS and subsequent demyelination result in a progressive neurological disturbance. At two months of age, myelin is present throughout the spinal cord, but is immature in the fasciculus gracilis and corticospinal tracts despite the presence of abundant oligodendrocytes. By 12 months, myelin has largely been lost in these spinal cord tracts and also in more rostral parts of the CNS, such as the cerebellum and optic nerves. Other funiculi of the spinal cord show a more diffuse lack of myelin. Oligodendrocytes develop a unique cellular abnormality, most obviously in older rats, which is characterized by the accumulation of microtubules throughout their cytoplasm. As the mutant rats age, there is a continued protracted breakdown of myelin throughout the CNS, with evidence suggesting either persistent hypomyelination or attempts at remyelination of affected axons. It is proposed that the microtubular defect in oligodendrocytes results in a disruption of the normal myelination process in certain areas of the CNS of this mutant, and eventually leads to failure of maintenance of the myelin sheath.

Age-dependent changes in serotonergic modulation of yawning in the rat.

Serotonin (5-HT) effects on physostigmine (PHY)-induced yawning were studied in LY Sprague-Dawley rats by injecting Lu 10 171 (citalopram), a specific 5-HT uptake blocker, and two antagonists--methiothepine and ritanserin--which differ slightly in the selectivity of their actions on different 5-HT receptor subtypes. Infant and young rats show significant increases in PHY-induced yawning when preinjected with citalopram (5-10 mg/kg). Two-month-old animals show this effect only with 10 mg/kg. With adult animals (3-5 months old), the effect is the opposite: Yawning decreases. The facilitory effect in infant and young rats was counteracted by methiothepine but not by ritanserin, suggesting that it is mediated through 5-HT1A or 5-HT1B receptor subtypes. The inhibitory effect of citalopram in adult rats was unmodified by the two antagonists used, leaving open the possibility that it is mediated by 5-HT3 receptors.

Sleep and EEG disturbances in a rat neurological mutant (taiep) with immobility episodes: a model of narcolepsy-cataplexy.

The electroencephalographic sleep patterns recorded during short periods of time (3 h) of a neurological mutant rat (taiep) were studied. This rat exhibits, among other signs, immobility episodes that are similar to those observed in narcolepsy-cataplexy. We describe findings of long term (6 months) electroencephalographic studies done in 9 mutant and 5 control rats. The mutant rats present electroencephalographic and behavioral disorders consisting of: (a) bursts of cortical waxing and waning waves occurring during the drowsy state; in some animals this activity represents up to 25% of the total drowsiness time; (b) shortened sleep time; (c) fragmented paradoxical sleep; (d) immobility episodes when the animals are subjected to an emotional excitement; and (e) electrographic activity of paradoxical sleep without atonia during the immobility episodes. These findings show that the taiep mutant shows several aspects of narcolepsy-cataplexy and it may represent an experimental model for the study of this pathology.

Food anticipatory yawning rhythm in the rat.

The effect of feeding schedules on the daily rhythm in spontaneous yawning activity was studied in high yawning (HY) Sprague-Dawley rats. If the animals are fed ad libitum and changed from a standard 12-12 light-dark (LD) illumination regime to constant light (LL), the normal predark circadian peak in yawning disappears, to be replaced, after 3 weeks, by two or more ultradian smaller peaks in yawning frequency. Restriction of food availability to 2-2:30 regular hours of the day, in rats under LL conditions, leads to the appearance of a significant preprandial (food anticipatory) peak in yawning. A similar eating-fasting daily cycle of 2-22 h in rats under LD conditions determines the disappearance of the pre-dark peak in yawning activity, and a significant shift in higher yawning frequency towards the couple of hours preceding food availability. This result suggests that restricted feeding is more potent than the LD transition in the entrainment of the daily rhythm in yawning activity.

Genotypic dependency of spontaneous yawning frequency in the rat.

By inbreeding we have obtained two sublines of Sprague-Dawley rats which differ significantly in spontaneous mean yawning frequency (MYF). In generation F21 of the high-yawning (HY) subline MYF was 21.5 yawns/h (y/h) in males and 1.95 y/h in females, at the age of 2 months. In the low-yawning (LY) subline, in generation F16 the MYF was 0.9 y/h in males and only 0.5 y/h in females. During the first 15 days there are no differences in yawning frequency between HY and LY rats. Thereafter yawning increases with age, more steeply in the HY subline. The results of reciprocal crosses between both sublines indicate that the LY character is partially dominant over the HY one.

GABAergic modulation of yawning behavior.

The hypothetical modulation by GABAergic neurons of yawning behavior in the rat was explored with GABA-active drugs. Gamma-acetylenic-GABA, a specific inhibitor of GABA-T, increases yawning frequency when injected at a dose of 7 mg/kg. Baclofen, a GABAB agonist (3 mg/kg), inhibits yawning completely; GABA antagonists, bicuculline and picrotoxin, at subconvulsant doses, also decrease yawning. All drugs were injected intraperitoneally with the exception of apomorphine, which was injected subcutaneously. It is suggested that GABAB receptors play a role in yawning behavior by modulating ACh release, and that GABAA receptors may modify yawning frequency by modulating inhibitory influences on ACh neurons.

Sprague Dawley rat mutant with tremor, ataxia, tonic immobility episodes, epilepsy and paralysis.

A spontaneous neurological mutation was detected in a colony of Sprague Dawley rats. The animals developed a progressive neurological syndrome characterized by tremor (which appeared at the age of 1 month), ataxia (at 4 months), immobility episodes (after 5-6 months), audiogenic seizures and hindlimb paralysis (after 10 months). Cross breeding experiments indicate that this is an autosomal recessive mutation, which we have named taiep subline.

Association of spontaneous and dopaminergic-induced yawning and penile erections in the rat.

In a Sprague-Dawley-derived line of rats, selectively bred to establish a high incidence of spontaneous yawning behavior, the simultaneous and systematic monitoring of yawning and penile erections, during observation periods of one hour, demonstrates a linear correlation between these two behavioral patterns. Dose-effect curves of yawning and penile erections elicited by apomorphine and bromocriptine, and their inhibition by metoclopramide are quite similar. These results strongly suggest that yawning and penile erection are subject to some common regulating and modulating mechanisms, one of which seems to involve dopaminergic pathways.

Circadian variation of yawning behavior.

Circadian variation of spontaneous yawning is demonstrated in a line of Sprague-Dawley rats, genetically selected for high frequency of this motor pattern. Yawning is highest in late light and early dark hours, both under natural and artificial illumination. The hypothetical neurotransmitters underlying this physiological rhythm in yawning are discussed.

Pre- and post-synaptic dopaminergic receptors involved in apomorphine-induced yawning.

The temporal course of yawning behavior elicited by increasing doses of apomorphine (APO), from 0.01 to 10 mg/kg, was studied experimentally in adult albino rats. In the higher dose range a great prolongation of drug induced yawning latency is observed. This result is explainable by postulating differences in sensitivity of two sets of dopaminergic (DA) receptors: low threshold presynaptic DA receptors which, when activated, disinhibit yawning, and high threshold postsynaptic DA receptors inhibiting yawning. Apomorphine in high doses can entirely suppress physostigmine-elicited yawning.

Rol de la serotonina en la génesis del bostezo / Serotonin role in the production of yawning behavior

El bostezo inducido por inyección intraperitoneal de eserina (0,15 mg kg-1) en ratas de 7 a 8 días de edad es potenciado por quipacina (5 mg kg-1), agonista serotoninérgico, y por fluoxetina (5 a 20 mg kg-1) y pirandamina (2,5 a 5 mg kg-1), bloqueadores de la recaptura neuronal de la serotonina. Estas drogas, en ausencia de serina, no inducen bostezo. Por otra parte, la metergolina (5 a 10 mg kg-1), antagonista serotoninérgico, inhibe, tanto el bostezo inducido por eserina, como su facilitación por la quipacina. Se discuten estos resultados como nuevas evidencias experimentales en apoyo de la hipótesis que propone a la serotonina como un agente modulador positivo de los mecanismos neurohumorales responsables de la conducta del bostezo (AU)

Sex hormone influences on yawning behavior.

Young male albino rats yawn significantly more than females or castrated males when injected with physostigmine (0.10 mg/kg). Treatment with testosterone (100 micrograms daily) during seven days restores cholinomimetically induced yawning in castrated males, and increases yawning in normal and androgenized females. Treatment with estradiol (200 micrograms daily) during one week does not modify physostigmine induced yawning behavior in castrated males nor in androgenized females.

Interaction of cholinergic and dopaminergic influences on yawning behavior.

The possible interaction between cholinergic and dopaminergic influences in the induction of yawning behavior in the rat is explored resorting to several experimental approaches: comparison of the ontogeny of yawning behavior induced by physostigmine (0.15 mg/kg) and apomorphine (0.05 mg/kg); simultaneous injection of both drugs; "crossed blocking" experiments, in which the action of the cholinomimetic agent is examined after injection of spiroperidol (0.05 mg/kg) and that of apomorphine after scopolamine (0.25 mg/kg). While physostigmine-elicited yawning is highest in early postnatal days and tends to decline from the 7th day onwards, reaching its lowest level around 3 wk, yawning induced by apomorphine begins around the 9th day and increases thereafter to a plateau that is reached in the third week. No synergism on yawning behavior is observed by simultaneous injection of optimal or suboptimal doses of physostigmine and apomorphine. Scopolamine blocks apomorphine-induced yawning; spiroperidol blocks apomorphine- but potentiates physostigmine-induced yawning, both in 15-day-old and young adult rats. Two 5-HT uptake blockers, citalopram (10-20 mg/kg) and fluoxetin (10-20 mg/kg) potentiate physostigmine - but not apomorphine-elicited yawning. On the basis of these results a tentative model of "in series" organization of dopaminergic and cholinergic influences on yawning behavior is proposed.

Serotonergic modulation of yawning.

Yawning induced by intraperitoneal (IP) injection of physostigmine (0.15 mgKg-1), in infant or adult rats is potentiated by Lu 10-171 (0.5-10 mgKg-1), a selective serotonin uptake inhibiting drug, which, by itself does not induce yawning. This effect is counteracted by metergoline (5-10 mgKg-1, IP) which blocks serotonin postsynaptic receptors. It is suggested that serotonin may exert a positivie modulating effect on yawning.

Blockade of both pilocarpine and amphetamine-induced head-shaking with dopamine receptor antagonists.

The range of central dopaminergic mechanisms involved in both d-amphetamine- and pilocarpine-induced head-shaking was studied in 7--9 days old rats by means of two DA antagonists: pimozide and spiroperidol. Both blocking agents exert their effects on H--S following dose-response curves which are similar, whatever the drug used to evoke head-shaking. A complete blocking effect on H--S is reached with pimozide at a dose of 2 mg kg-1; with spiroperidol at 0.1 mg kg-1 (for pilocarpine-induced H--S) and at 0.2 mg kg-1 (for H--S evoked by d-amphetamine). These results, together with those previously reported, suggest that dopaminergic and cholinergic facilitatory influences on H--S seem to be organized in series.