The anticonvulsant action of 1,5-benzodiazepine clobazam was studied in 12-, 18-, and 25-day-old rats. Cortical epileptic afterdischarges (ADs) elicited by rhythmic electrical stimulation of the sensorimotor cortical area were used as a model in animals with implanted electrodes. As far as the duration of ADs is concerned, clobazam in doses of 1 or 5 mg/kg i.p. blocked the progressive increase with repeated stimulations in all age groups and the higher dose significantly shortened ADs in 25-day-old rats. The intensity of movements accompanying stimulation was decreased only by the 5 mg/kg dose in 25-day-old animals, whereas clonic seizures were less intense after both doses in 12- and 25-day-old rat pups. Clobazam exerted an anticonvulsant action at all the developmental stages studied; the lower efficacy in 18-day-old rats (described also for clonazepam) remains to be analyzed.
Prenatal exposure to opiates can have devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. The present study was aimed at identifying cross-generational effects of prenatal morphine exposure in Sprague-Dawley rats. Pregnant rats were injected subcutaneously with either saline or morphine (10 mg/kg) twice daily during gestational days 11-18. Litter size, percentage of males and females, anogenital distances (AGDs), righting reflex, and body weight were assessed in prenatally morphine-exposed pups (first generation) and their offspring (second generation). Both prenatally morphine-exposed pups and offspring of prenatally morphine-exposed dams exhibited an increased latency to right. Additionally, second generation pups were slower in righting than first generation pups. During the early postnatal period the second generation pups weighed less than the first generation regardless of drug exposure. The AGDs of second generation male pups were decreased relative to the first generation. Our data provide important novel information about the trans-generational effects of maternal opiate abuse that may be useful for understanding/evaluating the teratogenic effects of prenatal opiate exposure.
Psychostimulants, including methamphetamine (MA), haveneurotoxic effect,
especially, if they are targeting CNS during its critical periods of development. The present study was aimed to examine cognitive changes after prenatal and neonatal MAtreatment in combination with chronic MA
exposure in adulthoodof male rats. Eight groups of male rats were tested in adulthood:males whose mothers were exposed to MA (5 mg/kg) or saline(SA, 1 ml/kg) during the first half of gestation period (GD 1-11),the second half of gestation period (GD 12-22) and neonatalperiod (PD 1-11). In addition, we compared indirect neonatalapplication via the breast milk
with the group of rat pups that received MA or SA directly by injection
(PD 1-11). Males weretested in adulthood for cognitive changes in the
Morris WaterMaze (MWM). MWM experiment lasted for 12 days: Learning(Day 1-6), Probe test (Day 8) and Retrieval Memory test
(Day 12). Each day of the MWM animals were injected with MA(1 mg/kg)
or SA (1 ml/kg). Prenatal MA exposure did not inducechanges in learning abilities of male rats, but neonatal exposureto MA leads to an increase search errorsand latencies to find thehidden platform. Prenatal and also
neonatal MA exposureimpaired cognitive ability to remember the position of the platform in Retrieval Memory test in adulthood. Animals exposed to the
prenatal treatment within the second half of gestation(ED 12-22) swam longer, slower and spent more time to find the hidden platform in Retrieval Memory test than animals exposedthroughout other periods. The present
study demonstrated thatstage of development is crucial for determination
the cognitivedeficits induced by prenatal or neonatal MA exposure.
Behavioral sensitization is defined as augmented psychomotor activity, which can be observed after drug re-administration following withdrawal of repeated drug exposure. It has been shown that abuse of one drug can lead to increased sensitivity to certain other drugs. This effect of developed general drug sensitivity is called cross-sensitization and has been reported between drugs with similar as well as different mechanisms of action. There is growing evidence that exposure to drugs in utero not only causes birth defects and delays in infant development, but also impairs the neural reward pathways, in the brains of developing offspring, in such a way that it can increase the tendency for drug addiction later in life. This review summarizes the results of preclinical studies that focused on testing
behavioral cross-sensitization, after prenatal methamphetamine exposure, to drugs administered in adulthood, with both similar and different mechanisms of action. Traditionally, behavioral sensitization has been examined using the Open field or the Laboras Test to record locomotor activity, and the Conditioned Place Preference and Self-administration test to examine drugseeking behavior. However, it seems that prenatal drug exposure can sensitize animals not only to the locomotor-stimulating and conditioning effects of drugs, but may also be responsible for modified responses to various drug effects.
Methamphetamine (MA) is an addictive psychostimulant with significant potential for abuse. Previous rat studies have demonstrated that MA use during pregnancy impairs maternal behavior and induced delayed development of affected pups. The
offspring of drug-addictive mothers were often neglected and exposed to neonatal stressors. The present study therefore examines the effect of perinatal stressors combined with exposure to prenatal MA on the development of pups and maternal behavior. Dams were divided into three groups according to drug treatment during pregnancy: controls (C); saline (SA, s.c., 1 ml/kg); MA (s.c., 5 mg/ml/kg). Litters were divided into four groups according to postnatal stressors: controls (N); maternal separation (S); maternal cold-water stress (W); maternal separation plus cold-water stress (SW). The pup-retrieval test showed differences among postnatally stressed mothers and non-stressed controls. The righting reflex on
a surface revealed delayed development of pups prenatally exposed to MA/SA and postnatal stress. Negative geotaxis and Rotarod results confirmed that the MA group was the most affected. Overall, our data suggests that a combination of perinatal stress and prenatal MA can have a detrimental effect on maternal behavior as well as on the sensorimotor development of pups. However, MA exposure during pregnancy seems to be the decisive factor for impairment.
The aim of the present study was to compare effect of three low doses of morphine (MOR) and delta9-tetrahydrocannabinol (THC) on social behavior tested in Social interaction test (SIT). 45 min prior to testing adult male rats received one of the drugs or solvents: MOR (1; 2.5; 5 mg/kg); saline as a solvent for MOR; THC (0.5; 1; 2 mg/kg); ethanol as a solvent for THC. Occurrence and time spent in specific patterns of social interactions (SI) and non-social activities (locomotion and rearing) was video-recorded
for 5 min and then analyzed. MOR in doses of 1 and 2.5 mg/kg
displayed decreased SI in total. Detailed analysis of specific patterns of SI revealed decrease in mutual sniffing and allo-grooming after all doses of MOR. The highest dose (5 mg/kg) of MOR decreased following and increased genital investigation. Rearing activity was increased by lower doses of MOR (1 and 2.5 mg/kg). THC, in each of the tested doses, did not induce any specific changes when compared to matching control group (ethanol). However, an additional statistical analysis showed differences between all THC groups and their
ethanol control group when compared to saline controls. There was lower SI in total, lower mutual sniffing and allo-grooming, but higher rearing in THC and ethanol groups than in saline control group. Thus, changes seen in THC and ethanol groups are seemed to be attributed mainly to the effect of the ethanol. Based on the present results we can assume that opioids affect SI more than cannabinoid.
Olfactory bulbectomy in rodents is considered a putative model of
depression. Depression is often associated with drug addiction. Our previous studies demonstrated that methamphetamine (MA) administration to rat mothers affects both, mothers and their pups. The aim of the present study was to examine the effect of bulbectomy, as a model of depression, and MA administration on behavior of rat mothers and postnatal development of their pups. Adult female Wistar rats were randomly divided into two groups: bulbectomized (OBX) and sham-operated (SH). A period of 20 days was allowed for the development of the depressive-like phenotype. Animals were tested in the motor activity test and 2 % sucrose preference for anhedonia and hyperactive locomotor response to a novel environment, respectively. After then females were impregnated. Pregnant females were exposed to daily subcutaneous (s.c.) injection of MA (5 mg/kg) or saline (SA) during the entire gestation period. Postnatally, maternal behavior and pup development was examined. The effect of a challenge dose of MA (1 mg/kg, s.c.) on behavior was further examined in adult male offspring. Our results showed no differences in the maternal behavior as a matter of bulbectomy, only OBX rats slept more than all the SH controls. Pups from OBX mothers were born with lower birthweight and gained less weight during the postnatal development than pups from SH controls. Both, bulbectomy and MA administration, delayed the eyes opening. As a matter of functional development of the pups, maternal OBX procedure impaired the performance in the Bar-holding test, but only in saline group. OBX/SA group was the worst in the Bar-holding test relative to all the other groups. In addition, pups
from OBX mothers dropped more boluses during the Bar-holding test, suggesting that they were more stressed. In adult male offspring, bulbectomy increased immobility only in the SA/SA group. Prenatal MA exposure increased locomotion, while decreasing immobility. In addition, challenge dose of MA in adulthood increased distance traveled, locomotion, rearing, and average and maximal velocity, while decreasing immobility and grooming. In conclusion, our results suggest that depressive-like phenotype of rat mothers induces impairment in somatic and functional development of their male offspring.
Psychostimulants, as well as cannabinoids, have been shown to
significantly affect a great variety of behaviors in both humans
and laboratory animals. Our previous studies have repeatedly
demonstrated that the application of the vehicle for
psychostimulants, i.e. saline, to control groups, generated
different behavioral test results compared to absolute naïve
controls (i.e. without any injection). Therefore, our present study
has set three goals: (1) to evaluate the effect of three different
psychostimulant drugs, (2) to evaluate the effect of three doses
of delta 9-tetrahydrocannabinol (THC), and (3) to evaluate the
effect of saline and ethanol injections vs sham injections and no
injection on spontaneous behavior of adult male rats. The
LABORAS test (Metris B.V., Netherlands) was used to examine
spontaneous locomotor activity and exploratory behavior in an
unknown environment over 1 h. In Experiment 1,
psychostimulant drugs were tested: single subcutaneous (s.c.)
injections of amphetamine (5 mg/kg), cocaine (5 mg/kg), and
3,4-methylenedioxymethamphetamine (MDMA) (5 mg/kg) were
applied prior to testing. Control animals received the same
volume (1 ml/kg) of s.c. saline. In Experiment 2, the effect of
three doses of THC (1, 2, and 5 mg/kg, s.c.) were examined.
An s.c. injection of vehicle (ethanol) was used as a control. In
Experiment 3, injections of saline and ethanol were compared to
the group receiving a sham s.c. injection and to a group of
absolute “naïve” controls. Our results demonstrated that (1) all
psychostimulants increased locomotion time, distance traveled,
and speed while decreasing immobility time of adult male rats
relative to saline controls. The most prominent effect was
associated with MDMA; (2) The effect of THC was dosedependent and was most apparent within the first 10 min of the
LABORAS test. (3) With regard to the effect of injection: absolute
controls (without injection) compared to animals injected with
ethanol, saline, or sham-injected displayed reduced immobility
time, traveled longer distances, and had increased speed. In
conclusion, our data showed drug dependent behavioral changes
in adult male rats after application of psychostimulants and
cannabinoids. Our findings also suggest that not only drugs but
the actual single injection per se also affects the behavior of
laboratory animals in an unknown environment. This effect
seems to be associated with the acute stress associated
with the injection.