Behavioral alterations induced in rats by a pre- and postnatal exposure to 2,4-dichlorophenoxyacetic acid.

The purpose of this study was to determine whether the behavioral development pattern was altered by a pre- and postnatal exposure to 2,4-Dichlorophenoxyacetic acid (2,4-D). Pregnant rats were daily orally exposed to 70 mg/kg/day of 2,4-D from gestation day (GD) 16 to postnatal day (PND) 23. After weaning, the pups were assigned to one of the two subgroups: T1 (fed with untreated diet until PND 90) and T2 (maintained with 2,4-D diet until PND 90). Effects on offsprings were evaluated with a neurotoxicological test battery. Neuromotor reflexes, spontaneous motor activity, serotonin syndrome, circling, and catalepsy were analyzed during various postnatal ages. 2,4-D neonatal exposure induced delay of the ontogeny of righting reflex and negative geotaxis accompanied by motor abnormalities, stereotypic behaviors (excessive grooming and vertical head movements), and hyperactivity in the open field. Adult rats of both sexes (T2 group) showed a diminution of ambulation and rearing, while excessive grooming responses were only observed in T2 males. Besides, these animals manifested serotonin syndrome behaviors, catalepsy, and right-turning preference. Some behaviors were reversible, but others were permanent, and some were only expressed after pharmacological challenges.     

Prenatal exposure to methylmercury changes dopamine-modulated motor activity during early ontogeny: age and gender-dependent effects

We have shown previously that prenatal exposure of rats to 0.5 mg/kg/day of methylmercury (MeHg) produces gender-dependent changes in motor activity in adulthood. In the present study we have investigated whether changes in motor activity could also be found during early ontogeny of the offspring. Pregnant rats were treated with MeHg from day 7 of pregnancy to day 7 of lactation. The habituation to a novel environment (spontaneous activity) and the response to stimulation of the dopaminergic system were studied on postnatal day 14 and 21. Measures of spontaneous activity showed a slight increase in MeHg-prenatal exposed male and female rats at 14 days, but not at 21 days. Following administration of U91356A, a selective dopamine D(2) receptor agonist, a significantly lower dopamine-mediated locomotor activity was observed in the 21 day old MeHg-treated males, but not in females. These results show that prenatal exposure to MeHg alters postjunctional dopaminergic activity during the period of maturation of the dopamine system in the brain. Moreover, the gender-dependent susceptibility previously found in adulthood is already evident at the prepubertal stage.     

Perinatal methadone exposure and its influence on the behavioral ontogeny of rats

The ontogeny of spontaneous motor and sensorimotor behaviors were evaluated daily from postnatal days 2 to 19 in rats maternally exposed to methadone (5 mg/kg) throughout gestation and/or lactation. In the methadone-treated groups, the age at which a specific behavior initially appeared for any group member and the ages at which 50% and a maximal (usually 100%) number of animals demonstrated a particular behavior was often delayed several days in comparison to controls. In addition, the time interval between the age of initial appearance and maximal achievement of a positive response was protracted. Rats subjected to methadone during either gestation or lactation exhibited the most retarded behavioral development. This study demonstrates that the timetable of behavioral maturation is altered in preweaning rats perinatally exposed to methadone, with the degree of response dependent on the timing and duration of opioid treatment. In addition, these results provide a functional correlate to our earlier observations of macroscopic and neurochemical changes in the brains of methadone-treated offspring.     

Pharmacologic profile of NPC 168 (naltrexone phenyl oxime), a novel compound with activity at opioid receptors

NPC 168 (naltrexone phenyl oxime) was synthesized as a novel opioid antagonist and evaluated in several in vitro and in vivo assays. NPC 168 inhibited binding to the mu, delta and kappa subtypes of the opioid receptor with nanomolar potencies. The potency of NPC 168 to antagonize morphine-induced analgesia was slightly less than that of naltrexone and nalmefene following either intraperitoneal (ED50 = 0.07 mg/kg) or oral (ED50 = 0.82 mg/kg) administration. The duration of action of NPC 168 was approximately 8 hr following subcutaneous administration, compared to 4 hr for nalmefene, to antagonize oxymorphonazine-induced analgesia. The long duration of action of NPC 168 was substantiated by pharmacokinetic data that demonstrated rapid uptake and slow clearance of NPC 168 from brain. NPC 168 (5, 10 and 20 mg/kg) also inhibited cumulative 6-hr food intake in rats that were deprived of food for 24 hr, but chronic administration of this compound to rats over a three-week period resulted in a marginal reduction in cumulative body weight gain. NPC 168 at doses of up to 10 mg/kg did not produce a conditioned taste aversion. However, NPC 168 was slightly more toxic than either naltrexone or nalmefene when administered parenterally, and as toxic as nalmefene when administered by the oral route. These data demonstrate that NPC 168 is a novel opioid antagonist with a longer duration of action than either naltrexone or nalmefene.     

Resistance of cholestatic rats against epinephrine-induced arrhythmia: the role of nitric oxide and endogenous opioids

Short-term ligation of bile duct has been used as a model to study acute cholestasis and is associated with various cardiovascular abnormalities. We examined the role of nitric oxide (NO) and endogenous opioids on epinephrine-induced arrhythmia in 7-day bile duct-ligated (BDL) rats. Six groups of rats, each of which was subdivided into two subgroups (sham-operated and BDL), were examined. First group of animals were chronically treated with normal saline. In the second and third groups, single intraperitoneal administration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or naltrexone (20 mg/kg) was performed 30 min before evaluation of epinephrine-induced arrhythmia. Two groups received chronic administration of low dose (3 mg/kg/day) or high dose (10 mg/kg/day) L-NAME; and the last group was treated chronically with naltrexone (20 mg/kg/day). Chronic drug administration was performed subcutaneously for 6 consecutive days following BDL or sham operation. After induction of arrhythmia by intravenous injection of 10 microg/kg epinephrine, mean arterial pressure and electrocardiogram were recorded for 1 min. Heart rate and mean arterial pressure were significantly lower in BDL rats (P<0.01). Chronic injection of naltrexone increased heart rate and mean arterial pressure in BDL (P<0.05). Chronic low dose L-NAME administration had no effect on baseline hemodynamic parameters. High dose L-NAME injection corrected hypotension in BDL rats, but not bradycardia (P<0.05). Epinephrine induced less arrhythmia in BDL rats (P<0.05). Acute and chronic injection of naltrexone had no effect on the resistance of BDL rats against epinephrine-induced arrhythmia. Although acute L-NAME administration enhanced arrhythmias in sham-operated rats (P<0.001), it had no effect on BDL animals. Chronic injection of low dose or high dose L-NAME, without having any effect on sham-operated animals, increased arrhythmias in BDL rats (P<0.01). This study showed that BDL animals are resistant against epinephrine-induced arrhythmia and this resistance depends on long-term NO overproduction.     

The neurochemical and behavioral effects of the novel cholinesterase-monoamine oxidase inhibitor, ladostigil, in response to L-dopa and L-tryptophan, in rats

The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in na?ve and in L-dopa- or L-tryptophan-induced rats. Chronic treatment of rats with ladostigil (52 mg kg(-1) for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by approximately 50%. Chronic TV3279 (26 mg kg(-1) for 21 days) similarly inhibited approximately 50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg(-1)) or L-tryptophan (100 mg kg(-1)), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg(-1)) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg(-1)) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors.Finally, while chronic ladostigil administration to na?ve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB).     

Social behavior of juvenile rats after in utero exposure to morphine: dose-time-effect relationship.

In the present study, the effects of morphine exposure in utero on social behavior in juvenile male rats was investigated. Pinning, a measure for play behavior, and social grooming of the offspring were measured at postnatal day 21. The subjects were offspring of Wistar rat dams given sc. injections of 1 or 10 mg/kg body weight morphine HCl daily from gestational days 8 (GD8)-GD 21 and control dams injected daily with saline. Pinning and social grooming of the morphine-treated offspring were significantly elevated compared to saline controls. The doses of morphine used neither affected the gestation of pregnant mother rats nor sensorimotor development of the juvenile rats. Prenatal exposure to morphine of 10 mg/kg daily increased both pinning and social grooming, prenatal exposure to a lower dose of 1 mg/kg increased pinning behavior but not social grooming in the offspring. To study the importance of the gestational period, offspring of dams given 10 mg/kg body weight morphine HCl from GD8-GD15 and saline from GD16-parturition or morphine from GD16-parturition and saline from GD8-GD15 was tested. Pinning was only increased when morphine exposure occurred during the third week of gestation, social grooming was increased when morphine exposure had been in the second week of gestation. Subcutaneous administration of 1 mg/kg naltrexone 1 h before the test significantly decreased play behavior in control rats, but not in animals prenatally exposed to morphine. From these experiments we conclude that the long term effect of in utero exposure to morphine on play behavior is established by affecting the endogenous opioid system.     

Behavioral effects of acute and chronic administration of caffeine in the rat

This study investigated the effects of acute and chronic caffeine treatment on behavior in the social interaction, holeboard and home-cage aggression tests and on proconvulsant actions with pentylenetetrazol. Acutely-treated rats received an IP injection of caffeine (20 or 40 mg/kg). Chronically-treated rats received caffeine in their drinking water for 21 days (50 or 100 mg/kg/day) followed by an injection of caffeine on the test day (20 or 40 mg/kg respectively). Acutely, the higher dose of caffeine (40 mg/kg) decreased levels of social interaction. In the holeboard test, 20 mg/kg of acute caffeine increased motor activity whilst 40 mg/kg reduced head-dipping behavior. In the home-cage aggression test, acute caffeine (40 mg/kg) reduced offensive aggressive behaviors. After chronic treatment with caffeine none of these behaviors differed significantly from controls. After both acute and chronic treatment, caffeine (20 and 40 mg/kg) was proconvulsant with pentylenetetrazol.     

The effects of acrylamide given acutely or in repeated doses on fore- and hindlimb function of rats.

Male, albino rats of the Fischer strain were given 50 to 250 mg/kg acrylamide orally. The LD50 (and 95% confidence intervals) was estimated to be 251 mg/kg (203–300) at 24 hr postdosing and 175 mg/kg (159–191) at 168 hr postdosing. Rats given 50, 100, and 200 mg/kg acrylamide orally were tested for muscular dysfunction at 12 and 168 hr post-dosing. At 12 hr after dosing, acrylamide produced marked deficits in hindlimb motor functioning, as measured by the hindlimb extensor test and performance on the inclined screen. Recovery of hindlimb function was complete at 168 hr after dosing. Forelimb grip strength was not affected at either test period. In a 4-week repeated dosing experiment, rats given 10 or 20 mg/kg/day, 5 days per week, showed hindlimb dysfunction at a cumulative dose of 50 to 100 mg/kg while rats receiving up to 400 mg/kg over a period of 4 weeks showed no signs of diminished forelimb grip strength. Recovery of hindlimb motor function was evident, but not complete, 2 weeks after cessation of dosing. The tests of motor function used in this study were sensitive to and capable of detecting specific motor deficits in rats treated with relatively low doses of acrylamide. The rapidity and ease with which the tests can be used in experiments involving repeated measures suggest their use in assessing other chemicals for potential neurotoxicity.     

Opioid receptor blockade promotes weight loss and improves the display of sexual behaviors in obese Zucker female rats.

Obese Zucker female rats are hyperphagic, overweight, infertile, and hyporesponsive to the inductive effects of ovarian steroid hormones on sexual behaviors. It has been postulated that endogenous opioid activity may contribute to their obesity and reproductive dysfunction. To test this hypothesis, ovariectomized, adult obese Zucker rats were treated with the opioid receptor antagonist, naltrexone, or saline prior to measurement of steroid-induced sexual behaviors, food intake, and body weight. In estradiol benzoate (EB)-treated rats, naltrexone injection increased the display of sexual receptivity (lordosis quotient, LQ: saline, 11+/-10%; 5 mg/kg naltrexone, 54+/-15%, p < 0.05) and also elicited proceptivity (PRO), which was never observed after saline injection. In EB plus progesterone-treated animals, naltrexone administration enhanced both sexual receptivity and proceptivity (LQ: saline, 17+/-10%; 5 mg/kg naltrexone, 96+/-3%; p < 0.05; PRO: saline, 3.0+/-2.4 bouts/min; 5 mg/kg naltrexone, 45.3+/-12 bouts/min; p < 0.01). Naltrexone injection also decreased 24-h food intake (saline, 24.2+/-0.7 g; 5 mg/kg naltrexone, 17.6+/-1.2 g; p < 0.05) and weight change (saline, +7.3+/-0.8 g; 5 mg/kg naltrexone, -4.5+/-1.4 g, p < 0.01). Morphine treatment blocked these effects of naltrexone on sexual behaviors, food intake, and body weight. These data suggest that endogenous opioids contribute to hyperphagia, obesity, and behavioral hyporesponsiveness to ovarian steroid hormones in obese Zucker rats.     

Gender, estrous cycle, ovariectomy, and ovarian hormones influence the effects of diazepam on avoidance conditioning in rats

This study examines whether the hormonal condition of the rat modifies the effects of diazepam (0.25 and 1.0 mg/kg) on avoidance conditioning and other behavioral responses. Acquisition of a conditioning avoidance response (CAR) and spontaneous motor behaviors were assessed in intact male, in intact diestrous and estrous females, and in ovariectomized (OVX) rats injected with estradiol (2 microg/rat, SC) or progesterone (5 mg/rat, SC). A higher dose (1.0 mg/kg) of diazepam significantly impaired the acquisition of CARs in diestrous, OVX, OVX + progesterone, and male rats. Conversely, both doses of diazepam significantly improved the acquisition of CAR in estrous rats and in OVX rats injected with estradiol. These effects on conditioning avoidance were not accompanied with equivalent changes in spontaneous motor behaviors. Motor activity and grooming behavior decreased in all experimental groups after administration of 1.0 mg/kg of diazepam. On the contrary, diazepam 0.25 mg/kg increased motor activity in estrous, OVX + estradiol, and OVX + progesterone rats after, whereas grooming behavior was not affected in any group. These findings suggest a physiological influence of ovarian steroid hormones in modifying the benzodiazepine effects on conditioning avoidance and motor activity. The results are discussed considering that ovarian steroids may interact with diazepam on the GABA(A)/benzodiazapine/chloride ionophore complex, modifying the coupling between benzodiazepine sites and GABA(A) receptors.     

Functional and structural alterations of the rat kidney induced by the naturally occurring organonitrile 2S-1-cyano-2-hydroxy-3,4-epithiobutane

The organonitriles, 2S-1-Cyano-2-hydroxy-3,4-epithiobutane (erythro and threo) (CHEB), isolated from the seed of Crambe abyssinica were administered by gavage to male Fischer-344 rats. Rats given 50 mg/kg/day were killed at 24, 48, and 72 hr. The rats given 100 mg/kg/day were killed at 48 and 72 hr. Serum urea nitrogen and creatinine were increased by 48 hr and further elevated by 72 hr. Glomerular filtration rate (GFR) of the 50 mg/kg CHEB rats was elevated at 24 hr but fell to subnormal values by 72 hr. The GFR of the 100-mg/kg group was decreased at 48 and 72 hr. Urine output of the 50-mg/kg group increased continuously through 72 hr, while urine output of the 100-mg/kg group was increased to a lesser degree. Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity (nmol/hr/mg creatinine) was significantly elevated in both groups by 48 hr, and further increased by 72 hr. Twenty-four hours after administration of 50 mg/kg, renal proximal tubular epithelial cells of some rats had fine cytoplasmic vacuolation. At 48 and 72 hr, necrosis and coarse vacuolation of proximal tubular epithelial cells occurred in both dose groups. The necrosis was most severe at the apexes of the medullary rays and the coarse vacuolation extended deeply toward the outer stripe of the outer zone of the medulla. Higher doses and/or longer times of CHEB administration resulted in a more extensive lesion distribution. It is concluded that CHEB induces nephrotoxicity in rats characterized by nonoliguric, acute renal failure, and morphological lesions preferentially involving the pars recta of the proximal tubules.     

Reproductive and developmental toxicity studies on cefepime dihydrochloride administered subcutaneously to rats during the premating, gestation and lactation periods]

Cefepime dihydrochloride (CFPM) was administered subcutaneously daily at doses of 0, 150, 500 and 1,000 mg/kg for 63 days prior to mating and during mating to male Crj: CD (SD) rats and for 14 days prior to mating and during mating, as well as periods of gestation and lactation to female SD rats. Saline and L-arginine hydrochloride (L-arginine) were used as control articles. Daily doses of test and control articles were equally divided and administered twice a day (b.i.d.). The results obtained are summarized as follows: 1. Soft stool was observed for both male and female F0 rats at CFPM 1,000 mg/kg at the first week of administration period. Further, depilation of injection sites was found in 7 males and 12 females at the same dose level. 2. Body weight gains were suppressed in male F0 rats from Day 28 to 63 of administration period at CFPM 1,000 mg/kg. Moreover, food consumption was reduced in F0 female rats during the first week of administration period at all dose levels of CFPM. 3. CFPM failed to affect the reproductive performance in both male and female F0 rats. 4. Kidney weights were increased in both male and female F0 rats and adrenal weights were augmented in male F0 rats at CFPM 1,000 mg/kg. On the other hand, cecal enlargement were observed for F0 dams treated with CFPM. However, these changes were not considered to be unique to this drug, because they have been described with most antibiotics in this species and appears to be results of modifications in gut flora. 5. Prenatal developments in F1 fetuses were not affected by CFPM. 6. CFPM failed to affect delivery status of F0 dams or survival and lactation indices in F1 pups. 7. CFPM did not affect postnatal differentiations, developmental behaviors, learning ability and memory, spontaneous motor activity or emotionality in F1 rats. 8. Body weight gains and food consumption in both male and female F1 rats were not affected by CFPM. 9. CFPM did not alter the organ weights in both male and female F1 rats. 10. There were no significant differences between drug treated animals and controls regarding the reproductive performance and delivery status of F1 rats. 11. Influences on survival indices, body weights and organ weights were not apparently observed for F2 pups even at CFPM 1,000 mg/kg. Based on the reproductive and developmental indices, the no-effect dose level of CFPM under the present experimental condition was estimated to be 1,000 mg/kg/day against dams (F0) and their offspring (F1).     

Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats

The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.     

Opiate modification of amygdaloid-kindled seizures in rats

Male Long-Evans rats were stereotaxically implanted bilaterally with bipolar electrodes in the central amygdala. Rats were then kindled once daily for 1 sec until 3 consecutive Stage V [25] kindled seizures were elicited. On the following day, animals were injected (IP) with either saline, naloxone (10 mg/kg), naltrexone (10 mg/kg) or morphine sulfate (10 mg/kg) and again stimulated parameters the kindling stimulation parameters. Saline injected animals continued to show long bilateral AD's and behaviors (i.e., forelimb clonus, rearing, falling) typical of Stage V kindled animals. In contrast, rats injected with naloxone or naltrexone showed reduced behavioral seizures. Potentiation of post-ictal spiking by morphine in amygdaloid-kindled rats was also observed supporting previous reports [7,21]. In a second experiment, the reduction of kindled seizure severity by naloxone was systematically replicated. It is concluded that opiates can significantly modify amygaloid-kindled seizures, and that brain endorphins may play a role in the development of maintenance of an amygdaloid-kindled seizure focus.     

Effect of muscimol on ethanol-induced central nervous system depression

In male Sprague-Dawley rats acute ethanol (1.0 and 2.0 g/kg) produced impairment of motor coordination and induced hypnosis (4.0 g/kg). Muscimol (1.25 mg/kg, IP) prior to ethanol administration enhanced motor impairment as measured by the aerial righting reflex. The rate of ethanol disappearance from the blood was unaltered by muscimol. Functional tolerance to the effect of ethanol on sleep time was produced by a 24 hr ethanol inhalation procedure. Animals tested 48 hr after ethanol inhalation exhibited a reduced sleep time from ethanol (4.0 g/kg). Muscimol (1.75 mg/kg) was administered along with ethanol 48 hr following 1 day of ethanol inhalation. Although the animals exhibited tolerance to ethanol-induced hypnosis, they did not manifest tolerance to the effect of muscimol.     

Role of endogenous opioids on ventilation and chemical control of breathing in pentobarbitone-anesthetized rats

To investigate the role of endogenous opioids on ventilatory control in pentobarbitone-anesthetized rats, the opioid antagonists naloxone and naltrexone were studied for their effects on ventilation, arterial blood gases and on ventilatory responses to hypoxia and carbon dioxide. In animals breathing room air, intravenous administration of naloxone and naltrexone (4 and 10 mg/kg) caused a dose-related increase in tidal volume, respiratory rate and minute volume. These ventilatory responses were rapid in onset and were associated with a decrease in arterial PaCO2, an increase in arterial pH and an increase in arterial PaO2. Intravenous naloxone (4 mg/kg) antagonized the increase in PaCO2 and decrease in arterial pH induced by the administration of morphine (3 mg/kg, i.v.). In animals breathing 100% O2, intravenous administration of naloxone and naltrexone (4 and 10 mg/kg) did not stimulate ventilation. Furthermore, intracerebroventricular administration of naloxone (15 and 150 micrograms) had no measurable effect on ventilation. Ventilatory responses to both hypoxia and carbon dioxide were not augmented by intravenous naloxone (4 mg/kg) and naltrexone (4 and 10 mg/kg). In fact, the increase in respiratory rate due to hypoxia was significantly (p less than 0.05) reduced by naltrexone (10 mg/kg, i.v.). In conclusion, our results demonstrate that naloxone and naltrexone caused hyperventilation in pentobarbitone-anesthetized rats. This effect was probably triggered by stimulation of the peripheral arterial chemoreceptors and did not involve mechanisms directly associated with the central nervous system. However, endogenous opioids were not involved in the chemical control of breathing in pentobarbitone-anesthetized rats since ventilatory responses to hypoxia and carbon dioxide were not changed by administration of these opioid antagonists.     

Ontogeny of behavioral sensitization to cocaine

The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56–60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21–25 or 28–32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later.     

Repeated lindane exposure in the rat results in changes in spontaneous motor activity at 2 weeks post-exposure.

Male Wistar rats were given 25 doses of lindane, 10 mg/kg per day, 1 ml/kg p.o. in olive oil, or control vehicle. Two weeks after the last dose, the animals were assessed for modifications in spontaneous motor activity, plus-maze behavior, shuttle-box active avoidance acquisition, brain regional concentrations of biogenic amines and metabolites, and regional [35S]TBPS binding. Rats treated with lindane showed an increase in spontaneous motor activity. Although no additional behavioral or neurochemical modifications were found, the changes in activity observed at 2 weeks post-exposure further demonstrate the need to assess for long lasting neurobehavioral sequelae of repeated lindane exposure.     

Assessing the Neurotoxic Potential of Methyl Ethyl Ketoxime in Rats

Assessing the Neurotoxic Potential of Methyl Ethyl Ketoximein Rats. SCHULZE, G. E., AND DERELANKO, M. J. (1993). Fundam.Appl. Toxicol. 21, 476–485. The potential of methyl ethyl ketoxime (MEKO) to produce neurotoxicityfollowing acute and subchronic exposure was studed in rats.A Functional Observational Battery, assessment of motor activity,and neuropathology evaluations were conducted in the contextof acute and subchronic toxicity studies. Three independentstudies are reported: a pilot time-effect study designed todetermine the time course and time to peak effect followinga single high dose of MEKO, a single-dose neurotoxicity study,and a subchronic (13-week) repeated-dose neurotoxicity studyin rats. An acrylamide-positive control group was included inthe acute and subchronic studies for comparison with MEKO. Followingan acute oral exposure of MEKO at a dose level of 900 mg/kg,locomotor activity was decreased compared to control with maximumdecreases occurring between 30 and 60 min following oral administration.In the acute study, transient treatment-related changes in easeof cage removal, ease of handling, and in posture and gait wereobserved 1 hr after dosing with 900 mg/kg MEKO, as were significantdepressions in motor activity. Following a single 300 mg/kgdose, transient MEKO-related changes in gait and aerial rightingreflex were noted 1 hr after dosing. All effects were reversiblewithin 24 hr of dosing. The single 100 mg/kg dose of MEKO waswithout observable effects. No acrylamide-related behavioraleffects were noted following a single 50 mg/kg dose. In thesubchronic study, transient treatment-related changes in easeof cage removal, ease of handling, and in posture, gait, andaerial righting were observed at the 400 mg/kg/day dose levelwhen assessments were conducted immediately after dose administration.No consistent behavioral effects were observed prior to dailydose administration even after 13 weeks of exposure, indicatinga lack of cumulative behavioral effect. No consistent behavioralchanges were noted at doses of 125 mg/kg/day and below. Significantdose-related decreases in red cell mass, and increases in methemoglobinlevels, reticulocyte, leukocyte, Heinz body counts, and spleenweights occurred at subchronic MEKO doses of 40 mg/kg/day andhigher. No MEKO-related neuropathological changes occurred.Animals receiving acrylamide at 20 mg/kg/day showed expectedbehavioral and neuropathological changes consistent with peripheralneuropathy. In conclusion, high doses of MEKO can produce transientand reversible changes in neurobehavioral function consistentwith central nervous system (CNS) depression. No evidence ofcumulative neurotoxicity was detected. The hematopoietic systemwas effected at doses which did not produce detectable changesin CNS function.