Decrease In Spontaneous Activity Research Articles

Behavioural effects of crude and semi-purified extracts ofSyzygium cuminii linn. skeels

In this study, different extracts, fractions and subfractions from the seeds of Syzygium cuminii Linn. Skeels, have been evaluated for behavioural effects in mice, particularly in relation to their sedative and anticonvulsant actions. Oral treatment with the hydroalcoholic extract showed an anticonvulsant activity in pentylenetetrazol- and maximal electroshock-induced convulsions, besides a hypothermic effect. The infusion, the aqueous and ethyl acetate fractions of the hydroalcoholic extract, as well as the subfractions of the latter subfraction, promoted a decrease in spontaneous activity of mice after i.p. but not after p.o. treatment. The ethyl acetate fraction and its subfractions enhanced latency and duration of the first convulsion induced by pentylenetetrazol. One of the subfractions of the ethyl acetate fraction, a mixture of about five polyphenolic compounds, whose main constituent is gallic acid, also presented a depressant profile without an anticonvulsant activity. Our results suggest that S. cuminii has some active principles with central depressant properties, and some of them also present an anticonvulsant action, although the polyphenolic compounds do not seem be the main constitutents responsible for this effect.

Mesolimbic dopaminergic decline after cannabinoid withdrawal.

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, Delta9-tetrahydrocannabinol (Delta9-THC). Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt Delta9-THC suspension failed to produce overt signs of abstinence. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified meso-accumbens dopamine neurons. The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs; these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction.

The alpha 2-adrenergic antagonist idazoxan enhances the frequency selectivity and increases the threshold of auditory cortex neurons.

Idazoxan (IDA), an alpha 2 antagonist of adrenoceptors, has been shown to increase cortical release of norepinephrine (NE) by an action mediated primarily by the alpha 2 autoreceptors located on the NE terminals. In the present experiment, IDA application was used to increase the cortial concentration of NE. Single unit activity (n = 107) was recorded in the rat auditory cortex, and the neurons' frequency receptive fields (FRF) were determined before and after systemic (intraperitoneal or intravenous) or local application of IDA. In the whole population (n = 107) there was a decrease in spontaneous activity and/or evoked activity for 84% of the recordings (90/107 cells). Decreased tone-evoked responses were obtained after systemic injections (n = 39), as well as after local applications (n = 68) of IDA. These effects were not observed after either systemic injections (n = 13) or local applications (n = 9) of saline. The signal-to-noise ratio (the mean evoked responses divided by the spontaneous activity) was slightly decreased after systemic injections and slightly increased after local applications. However, after both systemic and local injections the frequency selectivity of the neuronal responses was increased. For a group of neurons (n = 27), testing the FRF at three intensities indicated that this increased selectivity can be expressed at high or middle range intensity but not at low intensity. For 37 cells, the intensity function was tested at the best frequency before and after IDA application, and the threshold for excitatory responses was determined in 28 cases. An increased threshold was observed in 16 of 28 cases after IDA application. Thus, using a pharmacological procedure to increase the extracellular concentration of NE, the dominant inhibitory effect on the auditory cortex neurons led to an enhancement of the frequency selectivity, but also an increase in the threshold of these neurons.

Apically administered cytochalasin B and D decreases sensitivity of electroreceptor organs in the North-American catfish, Ictalurus nebulosus

The receptor cells of the ampullary electroreceptor organs of Ictalurus nebulosus bear microvilli on the apical membrane. Whereas microvilli in mechanoreceptive hair cells and in chemoreceptor cells have a transduction function, the function of these membrane specializations in electroreceptor cells is not fully understood. To study the role of the microvilli of the electroreceptor cells, the ampullary electroreceptor organs were apically exposed to the microfilament-disrupting agents cytochalasin B and D. Electrophysiological measurements showed that cytochalasin caused a high decrease in sensitivity and a slight decrease in spontaneous activity. Exposure to cytochalasin B resulted in a striking disorganization of the microvilli on the apical membrane of the electroreceptor cells. The most plausible explanation for the results is that treatment with cytochalasin mainly affects the actin filaments of the microvilli causing an increase of the resistance of the apical membrane. A high apical resistance results in a decrease of the voltage over the basal membrane, which in turn reduces the sensitivity. The conclusion is that intact apical microvilli are necessary for proper functioning of ampullary electroreceptor organs. Alterations in microvillar properties, like surface area and ion channel conductancy might play a considerable role in the regulation of the sensitivity.

Effect of longitudinal muscle-myenteric plexus removal and indomethacin on the response to tachykinin NK-2 and NK-3 receptor agonists in the circular muscle of the guinea-pig ileum.

1. The effect of removal of the longitudinal muscle-myenteric plexus (LM-MP) and/or indomethacin (10 microM) on the response to the tachykinin NK-2 receptor selective agonist, [beta Ala8]NKA(4-10), or to the NK-3 receptor selective agonist, senktide, was investigated by measuring mechanical activity (isotonic recording) of circular muscle (ring preparation) of the guinea-pig ileum. 2. Indomethacin (10 microM) increased the percentage of ileal rings displaying spontaneous activity, either intact or LM-MP-free. The response to senktide (10 nM and 1 microM) was lower in LM-MP-free than in intact ileal rings, either in the absence or presence of indomethacin. The response to a low concentration (10 nM) of [beta Ala8] NKA (4-10) was enhanced in LM-MP-free rings and by indomethacin. 3. In intact ileal rings, the response to senktide was unaffected by atropine (3 microM) alone or by the tachykinin NK-2 receptor antagonist MEN 10,376 (10 microM) alone while it was reduced by the combined administration of the two antagonists. The response to senktide was greatly reduced by tetrodotoxin (TTX, 1 microM). Senktide-induced contractions (10 nM) were also reduced by the blocker of N-type voltage-sensitive calcium channels, omega-contoxin (CTX, 0.1 microM). 4. In about 30% of preparations tested, an inhibitory response (decrease in spontaneous activity) to 10 nM senktide, was disclosed in CTX-treated intact ileal rings. This inhibitory effect was TTX-sensitive. 5. In LM-MP-free ileal rings, the response to senktide was abolished or reduced by atropine and MEN 10,376, alone or in combination, and was also reduced or abolished by TTX and CTX. 6. The response to [beta Ala8]NKA (4-10) was inhibited by MEN 10,376, in both intact and LM-MP-free ileal rings while it was unaffected by atropine, TTX or CTX. 7. These results indicate that indomethacin pretreatment induces a regular background activity for studying the motor response to tachykinins in the circular muscle of the ileum, probably by blocking the formation of relaxant prostanoids. A further increase in sensitivity to direct smooth muscle stimulation (NK-2 receptor agonist) can be obtained by removal of the LM-MP. The response to NK-3 receptor stimulation is diminished but not abolished by removal of the LM-MP, suggesting that NK-3 receptors are located on neuronal bodies of myenteric neurons, but possibly also at other sites (possibly, nerve terminals).(ABSTRACT TRUNCATED AT 400 WORDS)

Reticular thalamic inhibitory input to lateral hypothalamic neurons: a functional and histochemical determination

Both the lateral hypothalamus (LH) and reticular thalamus (RT) have been implicated in the integration of a variety of vital functions. To determine relevant connections more specifically between cells of these two regions in the rat, functional neurophysiological and horseradish peroxidase (HRP) histochemical techniques were utilized. Single pulse electrical stimulation of the RT modified the discharge frequency of the majority of LH neurons tested. LH neuronal responses to RT stimulation included; inhibition (66.32%), excitation followed by inhibition (6.12%), and excitation (7.14%). Because RT stimulation resulted primarily in the inhibition of LH neuronal activity with a relative short mean latency of 1.87 ± 0.23 ms, the existence of a possible direct inhibitory pathway from the RT to LH also was evaluated using HRP histochemistry. Retrogradely HRP labeled soma were identified in the RT after HRP was ejected extracellularly onto LH neurons, which exhibited a decrease in spontaneous activity in response to RT stimulation. These data demonstrate direct projections from the RT to the LH. In addition, HRP labeling of neurons and axons in the zona incerta-LH area following LH HRP ejections suggest this route as a synaptic pathway from RT to LH.

Physiologic effects of nucleus basalis magnocellularis stimulation on rat barrel cortex neurons.

Cholinergic neurons in the nucleus basalis magnocellularis (NBM) project to the cerebral cortex and are thought to play an important role in learning and memory, and other cognitive functions. In the present study, we examined the effects of NBM stimulation on the response properties of individual cortical neurons in layer V of the rat somatosensory cortex. Seventy-three neurons were studied before and after a brief electrical stimulation of NBM. Transient changes in spontaneous activity were observed in 60% of the cells, and in most cases this background activity decreased. Recordings lasting more than 1 h stimulation were obtained from 56 cells. Because some NBM stimulation-induced effects lasted several hours, neurons were evaluated in two groups, NBM1 and NBM2. NBM1 neurons were those exposed to either the first NBM stimulation of the day or an NBM restimulation following a more than 5 h stimulation-free period. Neurons exposed to NBM restimulation following a stimulation free interval of less than 5 h were classified as NBM2. Sixty-nine percent of the 32 NBM1 neurons displayed marked decreases in spontaneous activity and/or increases in the response evoked by deflecting a contralateral facial vibrissa. NBM1 stimulation caused some units to respond to previously minimally effective whisker stimuli. Stimulation effects often lasted several hours. By contrast, long-lasting changes were observed in only 25% of the 24 NBM2 neurons, and the only consistent effect was on spontaneous, not stimulus-evoked, activity. Systemic injection of atropine blocked NBM stimulation-induced changes in spontaneous and stimulus-evoked activities. Control neurons, studied without NBM stimulation, failed to display consistent alterations in their response properties during the course of 1 h or more. Results demonstrate that NBM activation produces long-lasting, cholinergically mediated alterations in the response properties of somatosensory cortical neurons. Effects were complex, being influenced by factors such as the time interval between successive stimulations during an experiment. The complexity of these NBM mediated effects should be considered when designing therapies for neurodegenerative disorders characterized by loss of NBM neurons.

Effects of river red gum, Eucalyptus camaldulensis, litter on golden perch, Macquaria ambigua

Aquaria with added river red gum, Eucalyptus camaldulensis, litter became hypoxic, with decreased pH and contained up to 30 mg 1−1 tannin and lignin. Survival of golden perch, Macquaria ambigua, larvae in aquaria treated with a simulated annual litter density of 450 g m−2 for 72 h was 14·9% for 15‐day‐old larvae and 0% for 8‐day‐old larvae. A litter density of 1223 g m−2 resulted in total mortality for both age groups of larvae. Aeration increased survival of larvae to a minimum of 68·8% in 1223 g m−2 litter treatments compared to 89·8% in aerated controls and 86·8% in non‐aerated controls. A kinetic behavioural assay was used to detect alarm responses in golden perch larvae and juveniles exposed to leachates from river red gum bark, leaves and wood. Eight‐day‐old larvae exposed to bark and wood leachates (0·001–10 g 1−1) exhibited an initial period of hyperactivity, followed by a concentration‐dependent decrease in spontaneous activity. Larvae exposed to leaf leachates displayed only a decrease in spontaneous activity. Four‐month‐old juveniles exposed to wood leachates were also initially hyperactive, then progressively developed mild hypoactivity at increasing leachate concentrations. Juveniles exposed to wood leachates at 20g 1−1 for 30min suffered 97·5% mortality in 96 h. Wood leachates induced dose‐dependent lamellar fusion, epithelial dissociation and necrosis in the gills. The presence of toxic leachates and low oxygen availability in flooded river red gum forests may make these habitats unsuitable as nursery areas for native fish.

Hyperpolarization-activated inward current in embryonic chick cardiac myocytes: developmental changes and modulation by isoproterenol and carbachol

Modulation of the hyperpolarization-activated inward current (I f) in embryonic chick ventricular myocytes was examined using whole-cell voltage-clamp. Long (3 s) hyperpolarizing pulses were applied from a holding potential of −30 mV to steps of −40 to − 120 mV. I f was marked in 3-day-old cells, diminished at 10 days, and was almost completely gone at 17 days. I f current density (at −120 mV) was −6.7 ± 1.3 (3 days), −3.3 ± 1.0 (10 days), and −2.0 ± 0.5 pA/pF (17 days). I f reduction paralleled the decrease in spontaneous activity. In 3-day cells, the threshold potential was −50 to −60 mV, and the reversal potential was −13.4 ± 1.3 mV. The time course of activation was fitted by a single exponential and was temperature dependent: τ was 1.3 ± 0.4 s at 20°C(and 0.7 ± 0.4 s at 30°C (at−120 mV). I f amplitude was enhanced by 12.1 ± 1.8% at 30 °C compared with 20°C. Cs + (3 mM) blocked I f and had a negative chronotropic effect (rate decreased by 61%). Isoproterenol (1 μM) caused a positive chronotropic effect (17.1 ± 2.9%) and increased I f by 65.2 ± 5.6%. Carbachol (0.1 μM) had a negative chronotropic effect (26.3 ± 3.4%), and decreased I f by 41.2 ± 1.3%; it also reversed the enhancement produced by isoproterenol. Intracellular application of 100 μM GTP-γS decreased basal I f by 35.2 ± 5.0%, but potentiated the stimulant effect of isoproterenol (by 37.8 ± 4.7%) and the inhibitory effect of carbachol (21.2 ± 4.3%). These results indicate that the I f current may contribute to the pacemaker potential of young embryonic chick heart cells and decreases during development. β-Adrenoceptor agonists stimulate I f, whereas muscarinic cholinergic agonists inhibit I f and reverse β-adrenoceptor stimulation. G proteins may directly and indirectly couple autonomic receptors to I f channels.

Energy expenditure by indirect calorimetry in premenopausal women: variation within one menstrual cycle

Energy expenditure in relation to the menstrual cycle was determined by indirect calorimetry in premenopausal women. For each subject, three measurements were made within a single menstrual cycle. Energy expenditure measurements coincided with the subject's expected hormonal fluxes of estradiol and progesterone: menstrual phase-both hormones at basal levels; follicular phase-elevated estradiol; and luteal phase-elevated progesterone. In experiment I, resting energy expenditure of 14 women was determined for 1 hour using a canopy system for calorimetry; in experiment 2, 24-hour energy expenditures of 12 subjects were measured in a room-size calorimeter. Blood from fasted (12 hours) subjects was collected following measurements of energy expenditure and analyzed for serum estradiol-17B and progesterone by radioimmunoassay. In experiment 1, resting energy expenditure did not differ within one menstrual cycle; neither estradiol nor progesterone affected resting energy expenditure. In experiment 2, 24-hour energy expenditure was significantly lower ( P < 0.013) during the follicular phase when compared with the menstrual (−3.8%) and luteal (−4.9%) phases. Lowered 24-hour energy expenditure during the follicular phase may in part be due to a decrease in spontaneous activity and exercise. Energy expenditure during sleep, an indicator of metabolic energy expenditure, was significantly greater ( P < 0.0001) during the luteal phase than during the menstrual (+6.7%) and follicular (+5.4%) phases; this was a reflection of increased progesterone ( P < 0.0001). Twenty-four hour energy expenditure (mean ± SEM) during the menstrual, follicular, and luteal phases was 8.86 ± 0.26, 8.52 ± 0.22, and 8.96 ± 0.21 MJ/d, respectively. Corresponding values for energy expenditure during sleep were 5.49 ± 0.09, 5.56 ± 0.10, and 5.86 ± 0.11 MJ/d. The menstrual cycle is a significant contributor to variation in energy expenditure through progesterone-mediated increases in metabolic rate. Variation in metabolic energy expenditure was detectable when the contributory components of 24-hour energy expenditure were measured.

Neuropsychopharmacological study of 2,4-dihydro[1,2,4] triazolo[3,4-C][1,4]benzothiazine-1-one (IDPH-791)

The neuropsychopharmacological profile of a new centrally acting skeletal muscle relaxant, 2,4-dihydro[1,2,4]triazolo[3,4-c][1,4]benzothiazine-1-one (IDPH-791), an analogue of triazolobenzothiazine, has been described and compared to mephenesin, a well known centrally-acting muscle relaxant. IDPH-791 was found to be safer and of longer duration of action than mephenesin in all the tests conducted in this study. Both IDPH-791 and mephenesin caused ataxia, decrease in spontaneous activity and inhibition of pinnal reflex. IDPH-791 was 1.5 to 2.0 times more potent in exhibiting motor inco-ordination and anticonvulsant activity than mephenesin in mice and rats. IDPH-791 was twice as active in inhibiting various spinal polysynaptic reflexes, crossed extensor, flexor, and linguomandibular reflexes; however, both did not affect the typical monosynaptic reflex, patellar reflex. IDPH-791 and mephenesin did not have sedative activity. Although mephenesin exhibited haemolytic activity, IDPH-791 was devoid of this activity. It is concluded that IDPH-791 is a safe and effective centrally-acting muscle relaxant having a longer duration of action than mephenesin. IDPH-791 is also devoid of sedative and haemolytic activity.

Mammalian toxicity of empenthrin (Vaporthrin, S-2852F)

1. Acute toxicity: Empenthrin ((RS)-(EZ)-1-ethynyl-2-methyl-2-pentenyl (1R)-cis/trans-chrysanthemate) caused some toxic signs such as muscular fibrillation, tremor, hypersensitivity, decrease of spontaneous activity, ataxic gait, lymb paralysis, irregular respiration, excretion of oily substance, loose stool and urinary incontinence in oral acute toxicity studies at 1000 mg/kg and above in rats, and at 2000 mg/kg and above in mice. The oral LD50 value was estimated greater than 5000 mg/kg (male) and greater than 3500 mg/kg (female) in rats and greater than 3500 mg/kg (both sexes) in mice. In both rats and mice, the toxic signs were not found at 2000 mg/kg by dermal administration. The dermal LD50 value was estimated greater than 2000 mg/kg (both sexes) in both rats and mice. The LC50 value in rats for the acute inhalation toxicity of empenthrin was estimated to be greater than 4610 mg/m3 for both sexes. The LC50 value in mice was determined to be 2700 mg/m3 for male and 2300 mg/m3 for female. Mice showed higher sensitivity to empenthrin than rats. 2. Reproductive and developmental toxicity: Empenthrin was orally administered to fetal organogenesis periods of rats at the dose levels of 50, 150 and 500 mg/kg, and of rabbits at 100, 300 and 1000mg/kg. Maternal toxicity was found at 500 mg/kg in rats and at 300 mg/kg or more in rabbits. There were no teratogenicity, no embryotoxicity and no fetal retardation in rats or rabbits. In addition, there were no adverse effects on F1 pups growth, development or reproductive performance. 3. Subchronic toxicity: Empenthrin was orally administered to male and female SD rats at dose levels of 0 (corn oil), 10, 100 and 300 mg/kg for 26 weeks. Clinical signs, body weight, food and water consumption were monitered, and hematological, blood biochemical, ophthalmological and histopathological examination were carried out. As a result, changes related to administration of empenthrin were observed mainly in the liver and kidneys in rats receiving 100 mg/kg or more. Therefore, the no-effect-level of empenthrin is determined to be 10 mg/kg in both sexes of rats in this study.

Involvement of supraspinal and spinal segmental alpha-2-adrenergic mechanisms in the medetomidine-induced antinociception

The effect of systemically administered medetomidine, a selective alpha-2-adrenoceptor agonist, was studied by electrophysiological recordings of the peripherally evoked responses of three different types of sensory neuronal populations in the rat: medial thalamic neurons exclusively responding to mechanical cutaneous stimuli at noxious intensities, spinothalamic tract neurons of the spinal cord responding exclusively or differentially to mechanical cutaneous stimuli at noxious intensities, and low-threshold mechanoreceptive spinal dorsal horn neurons with ascending projections. The neuronal effects were compared with the behavioral data obtained in mechanically and thermally induced nociceptive tail reflex tests in intact and spinal rats. A reversal of the antinociceptive effects was attempted by systemically (1.5mg/kg, i.p.) or intrathecally (25 μ g) administered atipamezole, a selective alpha-2-adrenoceptor antagonist. Systemically administered medetomidine produced an atipamezole-reversible, dose-dependent suppressive effect on the evoked responses of nociceptive medial thalamic and spinothalamic tract neurons. A lower dose of medetomidine was needed to suppress significantly (half-maximally) evoked responses of the nociceptive medial thalamic neurons (100/μg/kg) than those of the nociceptive spinothalamic tract neurons (300 μg/kg). The decrease of evoked responses of the nociceptive spinothalamic tract neurons was accompanied by a decrease in spontaneous activity. The responses of the low-threshold mechanoreceptive projection neurons of the spinal cord were not influenced by medetomidine (30–300 μg/kg). The reflex studies with a (anesthetic) medetomidine dose of 300 μg/kg indicated that in intact and otherwise drug-free rats, medetomidine produced a significant prolongation of the nociceptive reflex response latency to a tail-pinch and heat; these antinociceptive effects of systemic medetomidine were reversed by systemically and intrathecally applied atipamezole. In spinal rats systemically applied medetomidine (300 μg/kg) also produced a significant prolongation of the tail-flick latency, which was reversed by systemically applied atipamezole. The results suggest that a high anesthetic dose of systemically applied medetomidine (300/μg/kg) can suppress nociceptive sensory neuronal and reflex responses due to spinal segmental mechanisms through an action on alpha-2-adrenoceptors. This spinal effect is selective to responses of nociceptive neurons, and at least partly postsynaptic as indicated by the concomitant decrease in spontaneous activity. At a lower, subanesthetic (but sedative) dose (100 μg/kg) the antinociceptive effect of systemically applied medetomidine can be explained by supraspinal alpha-2-adrenergic mechanisms.

The physiology of somatostatin in the rabbit retina

The neuropeptide somatostatin (SS) has been localized to neurons of the rabbit retina by immunochemical and biochemical methods (Sagar et al., 1982, 1986; Marshak and Yamada 1984). We examined the effects of bath-applied SS on neurons of the rabbit retina, using intra- and extracellular electrophysiological techniques in an in vitro retina eyecup preparation. All commonly encountered ganglion cell receptive field types were affected by SS, and the effects were of 3 kinds: The first was a general excitation, occurring with a threshold concentration of about 100 nM; the onset of the excitation was too slow (seconds) for SS to participate in any rapid light-evoked responses. The second SS effect was an increase in the "signal-to-noise ratio," defined here as the ratio of light-evoked to spontaneous spiking, which resulted from a decrease in spontaneous activity and, usually, a concomitant increase in light-evoked spiking. The third effect was a shift in center-surround balance towards a more dominant center. The signal-to-noise and center-surround effects were evident at concentrations as low as 0.5 nM; both were slow onset (tens of seconds) and long lasting (tens of minutes). SS acted at multiple levels within the retinal circuitry to produce the observed changes in ganglion cell output. These effects included direct actions on ganglion and amacrine cells, and a decrease in the efficiency with which horizontal cells could drive the retinal network. At least part of these SS actions on third-order neurons resulted from a decrease in conductance to ions with an equilibrium potential more positive than dark membrane potential. The degradation-resistant SS agonist SMS201-995 had effects qualitatively and quantitatively similar to those of SS, suggesting that SS may be degraded slowly enough to act at a distance from its sites of release. While no adequate SS antagonist is available, the greater sensitivity to exogenous SS, in retinas depleted of their SS content (with cysteamine), suggests a role for endogenous SS. The potency of SS also reinforces this view. The results of this study suggest that SS may be a neuromodulator in the rabbit retina, producing long-lasting changes in the "signal-to-noise" discharge pattern and center-surround balance of ganglion cells.

TERATOLOGICAL STUDY OF CEFPIROME SULFATE IN RATS

A teratogenicity study was performed in rats by intraperitoneal or intravenous administration of cefpirome sulfate (CPR) at dose level of 0 (control), 200, 400 and 800 mg/kg/day to dams from day 7 to day 17 of pregnancy. Twenty one to twenty eight female rats in each intraperitoneal and intravenous administrated group were sacrificed on day 21 of pregnancy for examination of their fetuses, and ten to thirteen female rats in each intraperitoneal administrated group were allowed to deliver for the postnatal examination of their offsprings. In the 800 mg/kg/day intravenous administrated group, two dams out of twenty four died during administration period, however no animal died in any intraperitoneal administrated group. The doses of 400 and 800 mg/kg/day caused piloerection, diarrhea or loose feces in the both administration routes, and accelerated breathing, a decrease in spontaneous activity, systemic spasms, cataleptic symptoms and wild running in the intravenous route. The suppression of body weight gain was detected in the 800 mg/kg/day intraperitoneal administrated group and 200, 400 and 800 mg/kg/day intravenous administrated groups, however there were no significant differences in food and water intakes between treated and control groups. At autopsy, enlargement of caecum and an increase in adrenal weight were detected in the 800 mg/kg/day groups of both administration routes. Body weight of the fetuses was decreased in both sexes in the 800 mg/kg/day group and in male fetuses in the 400 mg/kg/day group, and placental weight was decreased in the 800 mg/kg/day group, in the both administration routes respectively. However, embryonal or fetal mortality and incidences of external or visceral anomalies were not increased. In offspring, the dose of 800 mg/kg/day caused very slight suppression of body weight gain, however CPR had no adverse effects on the postnatal development such as viability, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of CPR is 200 mg/kg/day in maternal animals and fetuses, 400 mg/kg/day in offsprings in intraperitoneal route, lower than 200 mg/kg/day in maternal animals and 200 mg/kg/day in fetuses in intravenous route respectively.

Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT 2antagonists

As previously reported, systematic administration of the hallucinogens d-lysergic acid diethylamide (LSD) (5–10μg/kg) and mescaline (2 mg/kg) in the anesthetized rat produced a decrease in spontaneous activity but, paradoxically, facilitated activation of locus coeruleus (LC) neurons by sciatic nerve stimulation. In the present study, the hallucinogens 2,5-dimethoxy-4-methylamphetamine (DOM) (20–80 μg/kg) was found to have similar effects. Systematic administration of the selective 5-HT 2 antagonists LY 53857 (0.02–0.8 mg/kg) and ritanserin (0.1–0.3 mg/kg) completely reversed both actions of the hallucinogens on the LC. In contrast, LY 53857 did not reverse the effects of (+)-amphetamine (0.5 mg/kg) on the spontaneous or sensory-evoked activity of the LC. These results suggest that the common actions of indoleamine and phenethylamine hallucinogens displayed in the LC are mediated via 5-HT 2 receptors; however, these receptors appear to be located outside the LC itself.

Morphine microinjected into the periaqueductal gray has differential effects on 3 classes of medullary neurons

The effects of microinjection of 5–10 μg of morphine into the midbrain periaqueductal gray (PAG) on the activity of neurons in the rostral ventral medulla (RVM) were studied in lightly anesthetized rats. Based on the relationship between changes in neuronal activity and the occurrence of the tail-flick reflex (TF), RVM neurons were divided into 3 groups: off-cells, on-cells and neutral cells. The off-cells exhibited an abrupt pause and the on-cells an acceleration beginning just prior to the occurrence of the TF. Neutral cell firing did not change at the time of the TF. Microinjections of morphine into the PAG which inhibited the TF had differential effects on the spontaneous activity of the 3 groups of neurons in RVM. Off-cells showed an increase and on-cells a decrease in spontaneous activity which preceded the inhibition of the TF. These microinjections also reduced the TF-related responses of off- and on-cells. The effects on cell activity were reversed by systemically administered naloxone and were not seen following microinjections which failed to block the TF. Neutral cell activity was unchanged following microinjection of morphine into the PAG. These results support the hypothesis that off- and on-cells in the RVM mediate the effects of microinjection of morphine into the PAG on spinal nociceptive reflexes.

Pharmacological evidence for the involvement of alpha-2 adrenoceptors in the sedative effect of detomidine, a novel sedative-analgesic.

The sedative effect and mechanism of action of a novel imidazole derivative, detomidine, were studied in laboratory animals. Three methods were used to quantify drug-induced sedation: (i) decrease in spontaneous activity of mice; (ii) increase in barbiturate induced anaesthesia time in mice; (iii) loss of righting reflex in chicks. Clonidine and xylazine were included in the studies for comparison. The sedative potency of detomidine was shown to be approximately equal to that of clonidine and much higher than that of xylazine. In all tests, the sedative effect of detomidine was inhibited by antagonists of alpha-2 adrenoceptors (yohimbine, rauwolscine and idazoxan) but not by alpha-1 antagonists (prazosin, corynanthine). Furthermore, an ex vivo receptor binding study in the rat showed that detomidine-induced decrease in spontaneous activity was significantly correlated to [3H]clonidine but not to [3H]prazosin displacement in brain membranes. These results show that detomidine has potent sedative effects in mice, rats and chicks, and suggest that this action is mediated through stimulation of alpha-2 adrenoceptors.

Responses of midbrain raphe neurons to ethanol

The effects of ethanol on single midbrain raphe neurons were studied in the rat. For dorsal raphe neurons, only the units with rhythmic slow firing were consistently inhibited by ethanol. Those units often exhibited periodic cessation of spontaneous discharges in the initial responses, but later showed a dose-related slowing of discharge rates. Although median raphe neurons were also inhibited by ethanol, their responses consisted of an early tendency to fire more regularly, and then a decrease in spontaneous activity with bursting discharges. The data indicate thatn ethanol exerts different modes of inhibition on these two functionally different cell groups in the midbrain raphe complex.

Low threshold mechanical stimulation of the vagina depresses dorsal horn unit activity in the spinal cat

Low threshold (0.5–15 g) mechanical punctate stimulation of the labia and vagina depressed dorsal horn neurons in the cat with spinal transection at L1. Similar stimulation 2 mm or more from the outer margin of the labia was without effect. The depression was observable within 1–2 sec, and usually required 4–6 min for full recovery, although a smaller more prolonged depression may also have occurred. Stronger stimuli evoked greater inhibition, requiring longer times for recovery. Vaginal stimulation depressed 9 of 10 sensory dorsal horn neurones (including non-nociceptive, wide dynamic range and nociceptive specific). Depression included a decrease in spontaneous activity and a decrease of naturally elicited responses to noxious and innocuous cutaneous stimuli: therefore the effect is not modality related. One unit without sensory input was unaffected by vaginal stimulation. In the one case tested, vaginal stimulation depressed glutamate-evoked excitation, suggesting that the depression of naturally, elicited responses was via a postsynaptic mechanism.