Behavioral and neurophysiological effects of CNS expression of cytokines in transgenic mice.
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Animals↗
Biomedical subjects
C J Heyser
Publications and source records attributed to C J Heyser.
Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones.
The coloboma mutation (Cm) is a neutron-irradiation induced gene deletion located on the distal portion of mouse chromosome 2. This deletion region includes a gene encoding the synaptic vesicle docking fusion protein, synaptosomal-associated protein of 25 kDa (SNAP-25). The resulting mutation is semi-dominant with heterozygote mice exhibiting a triad of phenotypic abnormalities that comprise profound spontaneous hyperactivity, head bobbing and a prominent eye dysmorphology. Because the expression pattern of two SNAP-25 isoforms begins to change during the first postnatal week, neurobehavioral developmental milestones were examined in order to determine if the expression of the coloboma behavioral phenotype could be detected during this period of postnatal development. The early classification of coloboma mutant offspring may help to further describe the penetrance of this mutation as well as the contribution of developmental changes to the adult behavioral phenotype. The coloboma mutation resulted in delays in some tests of complex motor skills including righting reflex and bar holding. In addition, coloboma mutants were characterized by body weight differences (first appearance day 7) and hyperreactivity to touch (day 11) and head bobbing (day 14). These data demonstrate disruptions in the time course of attaining developmental milestones in coloboma mutants and provide further evidence supporting the hypotheses that alterations in Snap gene expression are associated with functional behavioral consequences in developing offspring.
Aging↗
Effects of prenatal exposure to cocaine on Morris water maze performance in adult rats.
The spatial memory of adult rats prenatally exposed to cocaine and that of control offspring was assessed using the Morris water maze. Offspring were derived from Sprague Dawley dams that received subcutaneous injection of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on gestational Days 8-20, pair-fed dams injected with saline, or nontreated control dams. After acquisition, the platform was moved to a new location (reversal phase). Probe trials were conducted at the end of acquisition and reversal training. On the 1st acquisition day, adult male and female offspring prenatally exposed to cocaine required significantly more time and traversed a greater distance to find the hidden platform than did control offspring. Despite these initial differences observed in C40 offspring performance, all of the rats were performing at equivalent levels at the time probe trials were conducted.
Animals↗
Chronic variable stress enhances the stimulatory action of a low dose of morphine: reversal by desipramine.
Adult male rats were exposed to a chronic variable stress treatment, an animal model of depression, with or without concurrent daily administration of desipramine. Animals given chronic and variable stress were submitted daily to a different stressor following an injection of either saline or desipramine (5 mg/kg, i.p.), whereas control animals were unmanipulated except for the injection process. One day after the last event of the chronic procedure, control and stressed animals were administered saline or morphine (0.75 or 1.5 mg/kg, i.p.) and their locomotion assessed for 90 min. In an additional experiment, 24 h after the last stressor, stressed and control rats were challenged with either saline or one of two higher doses (behaviorally suppressant) of morphine (5 and 10 mg/kg, i.p.). A significantly greater increase in locomotor activity following a low dose (1.5 mg/kg) of morphine was observed in chronically stressed rats as compared to control rats. This potentiated locomotor response to morphine in stressed rats was prevented by desipramine pretreatment. The chronic and variable stress treatment did not modify the sedative response to the high doses of morphine. These data support the suggestion that a chronic and variable stress procedure results in sensitization to the stimulant effect of opioid stimulation, and that pretreatment with the antidepressant agent desipramine blocks the development of this sensitization.
Animals↗
Effects of prenatal exposure to cocaine on heart rate and nonassociative learning and retention in infant rats.
Nonassociative learning and retention were assessed in terms of habituation of a heart-rate (HR) orienting response (bradycardia) to a tone in 16-day-old male and female rats prenatally exposed to cocaine and in control offspring. Offspring were derived from Sprague-Dawley dams given daily subcutaneous injections of 40 mg/kg/3 cc cocaine HCI (C40) from gestational days 8-20, pair-fed control dams given saline injections (PF), and nontreated control dams (LC). Each pup was adapted to the test apparatus for 15 min prior to being given 10 presentations of a pulsing tone, each separated by a 65-sec intertrial interval, with HR measured during a 5-sec pretone period and throughout the 10-sec tone for each trial. To assess retention, subjects were given 10 additional tone trials either 1, 2, 4, or 6 hr later. C40 male offspring displayed significantly lower basal HR following the initial 15-min isolation period than either LC or PF offspring, whereas prenatal treatment had no effect on basal HR among females. Although no differences were seen in rate of habituation, prenatal cocaine exposure was observed to affect retention of the habituated orienting response. Whereas LC and PF offspring retained habituation of the orienting response for less than 4 hr, C40 offspring exhibited no forgetting after a 4-hr interval, and showed significant loss of the habituation response only after a 6-hr interval.
Animals↗
Responsiveness to cocaine challenge in adult rats following prenatal exposure to cocaine.
Adult rats that were gestationally exposed to cocaine and control offspring were examined for their sensitivity to challenge doses of cocaine. Offspring were derived from Sprague-Dawley dams that had received subcutaneous injections of 40 mg/kg per 3 cc cocaine hydrochloride daily on gestational days 8-20, pair-fed dams that were injected with saline, and nontreated control dams. In order to investigate the sensitivity to challenge doses of cocaine, offspring were assessed in adulthood for locomotor activity, cocaine drug discrimination, and the time course of cocaine in brain tissue following acute cocaine challenge. Adult offspring prenatally exposed to cocaine were observed to exhibit a reduced sensitivity to the discriminative stimulus effects of cocaine as evidenced by a significant shift to the right in the dose-response curve of cocaine discrimination. No prenatal treatment effects were observed in terms of the temporal patterns of cocaine discrimination or with regard to brain levels of cocaine. In addition, baseline locomotor activity and locomotor responses to challenge doses of cocaine were comparable across the prenatal treatment groups. Thus, prenatal cocaine exposure reduced sensitivity of offspring to the discriminative stimulus properties of cocaine without altering either the distribution of cocaine to the brain or the sensitivity of the offspring to the locomotor stimulant effects of cocaine.
Animals↗
Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone.
The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hippocampal cell firing correlates of delayed-match-to-sample performance in the rat.
Hippocampal CA1 and CA3 neurons were recorded in rats performing a delayed-match-to-sample (DMTS) task. Complex spike cells showed significant firing peaks following sample and match responses and during delivery of water reward. Individual cells were classified into 4 subtypes according to the presence or absence of firing in each of these 3 phases. There were significant differences in delay interval firing among the 4 subtypes, but firing during the delay did not predict the correct response: 34% of the cells showed a linear change in firing during the delay. Further analyses revealed significant lever position firing biases in approximately 70% of the cells tested irrespective of subtype. The complexity of firing correlates of the neurons recorded in this DMTS task suggests that the hippocampus divides specific aspects of the performance demands of the task across different cell subtypes, which together provide sufficient information to resolve the matching-to-sample problem on any given trial.
Animals↗
Effects of delta-9-tetrahydrocannabinol on delayed match to sample performance in rats: alterations in short-term memory associated with changes in task specific firing of hippocampal cells.
The effects of delta-9-tetrahydrocannabinol (delta-9-THC) were studied during performance of a delayed match to sample (DMTS) task in rats. Correlated hippocampal cellular activity was also assessed in terms of the effects of cannabinoids on well characterized task specific changes in firing rate which occurred during various phases of a DMTS trial. Results show a surprising correlation between the delay and dose (0.75-2.0 mg/kg)-dependent behavioral deficit produced by delta-9-THC in this task and similar effects produced by damage to the hippocampus and related structures. However, unlike the effects of hippocampal lesions or neurotoxic damage, the effects of delta-9-THC were completely reversible within 24 hr of injection. Neither control injection of the vehicle nor equivalent concentrations of the nonpsychoactive cannabinoid, cannabidiol, produced alterations in DMTS performance levels. Simultaneous recordings from identified hippocampal complex spike cells at the highest dose of drug indicated that the DMTS deficit was associated with a specific decrease in hippocampal cell discharge during the Sample (but not the Match) phase of the task. In nine identified neurons (including four observed during both control and drug conditions) recorded from six different animals in which the effects of delta-9-THC were manifested, no indication of Sample phase firing was observed. Although there were slight but significant reductions in Match and Reinforcement phase related firing during THC sessions, highly significant increases in firing in these phases were still present, indicating that elimination of Sample phase firing did not reflect a nonspecific effect of delta-9-THC on hippocampal cell activity. These findings strongly suggest that performance of the DMTS task was selectively impaired by the lack of Sample phase discharge of hippocampal neurons during the DMTS trial, and that this effect could serve as the basis for the well characterized short-term memory and other cognitive deficits reported in humans after smoking marijuana.
Action Potentials↗
Prenatal cocaine exposure attenuates cocaine-induced odor preference in infant rats.
In order to further examine whether prenatal cocaine exposure alters the later reward efficacy of cocaine, exposed offspring were tested for cocaine-induced odor preference early in life. Test offspring were derived from Sprague-Dawley dams that received daily SC injections of 40 mg/kg/3 cc cocaine hydrochloride (C40) from gestational day 8-20, nutritional control dams receiving daily SC saline injections (NC), and nontreated control dams (LC). At testing on postnatal day 8 (P8), both LC and NC offspring were observed to exhibit a preference for the odor that had been paired on P7 with 2.0, 5.0, or 10.0 mg/kg cocaine. In contrast, C40 offspring exhibited a significant odor preference only when the odor had been previously paired with 5.0 or 10.0 mg/kg cocaine. These results, combined with previous work from our laboratory showing that adult offspring exposed gestationally to cocaine did not exhibit a cocaine-induced conditioned place preference, provide evidence that offspring exposed prenatally to cocaine are less likely to develop a preference for stimuli associated with cocaine. Further studies are needed to determine whether these alterations in cocaine preference reflect a learning deficit, pharmacokinetics factors, or an attenuation in the rewarding properties of cocaine.
Animals↗
Effects of prenatal exposure to cocaine on conditional discrimination learning in adult rats.
Adult male rats that were gestationally exposed to cocaine and control offspring were trained on an instrumental conditioning task for assessment of the acquisition and reversal of an appetitive conditional discrimination based on olfactory cues. Offspring were derived from Sprague-Dawley dams that had received subcutaneous injections of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on Gestational Days 8-20, pair-fed (PF) dams that were injected with saline, nutritional control dams (NC) that had received saline injections, and nontreated control dams (LC). There were no differences among the prenatal treatment groups in acquisition of the barpress response or response rate throughout all phases of training. All prenatal treatment groups required approximately the same number of sessions to criterion on the initial odor discrimination. In contrast, adult C40 offspring required more sessions to acquire the reversal of the conditional discrimination than did animals from the other treatment groups (PF, NC, and LC). In addition, even at criterion performance for acquisition of the reversal discrimination, C40 animals exhibited lower accuracy on the first 10 responses and made significantly more errors before the first reward. Taken together with previous results, these findings suggest that gestational exposure to cocaine results in long-lasting alterations in performance on conditioning tasks that are evident early in life and that persist into adulthood.
Animals↗
Age-related differences in sensory conditioning in rats.
Four experiments tested rats 8, 12, or 21 days postnatal for sensory conditioning in terms of the association acquired between two odors presented simultaneously or sequentially. The sensory conditioning of 8- and 12-day-old rats exceeded that of rats 21 days of age when the odors were presented simultaneously. When one odor was presented immediately followed by another, however, 21-day-old rats conditioned as effectively as the younger animals, and with a sufficiently long interval between odors (20 min), the sensory conditioning of the 21-day-old rats surpassed that of the rats 12 days of age. Although consistent across a variety of procedures, in previous experiments and within the present study, the age-related differences in sensory conditioning after simultaneous presentation of two odors are difficult to understand. Increasing knowledge of the ontogeny of orienting may lead to an explanation in terms of Thompson's (1972) theory linking sensory conditioning with orienting and sensitization.
Aging↗
Prenatal cocaine exposure induces deficits in Pavlovian conditioning and sensory preconditioning among infant rat pups.
Offspring derived from Sprague-Dawley dams that received daily subcutaneous injection of 40 mg/kg.3 cc-1 cocaine hydrochloride (C40) or saline (LC) from Gestational Days 8-20 were tested for first-order Pavlovian conditioning and sensory preconditioning at Postnatal Days 8 (P8), P12, and P21. Although C40 dams gained significantly less weight than LC dams, pup body weights did not differ between the two groups. Significant sensory preconditioning was obtained at P8 and P12 (but not at P21) in LC offspring, confirming previous reports of decline in performance in this task during ontogeny. In contrast, C40 offspring failed to exhibit sensory preconditioning at any test age. In addition, C40 pups tested at P8 did not display significant first-order conditioning. Taken together these results suggest a more general deficit in cognitive functioning rather than a delay in cognitive development in prenatally cocaine-exposed offspring.
Animals↗
The effects of delta-9-THC on mechanisms of learning and memory.
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Animals↗
Prenatal exposure to cocaine disrupts cocaine-induced conditioned place preference in rats.
Cocaine-induced conditioned place preference (CPP) was tested in adult offspring of Sprague-Dawley dams that had been injected subcutaneously with 40 mg/kg/3cc cocaine HCl (C40) daily from gestational days 8-20, pair-fed (PF) dams injected with saline, and nontreated control (LC) dams. C40 and PF dams gained significantly less weight than LC dams, although offspring body weights did not differ among the three prenatal treatment groups at birth or in adulthood. Significant place conditioning was obtained in LC and PF offspring when either 2.0 or 5.0 mg/kg of cocaine was paired with the designated place. In contrast, C40 offspring did not exhibit place conditioning at either training dose. Yet, all animals exposed to 5 mg/kg of cocaine during conditioning exhibited less activity during the test (when no cocaine was given) than controls given unpaired exposures to the apparatus and cocaine and C40 offspring did not differ from LC and PF offspring in this respect. Therefore, despite their lack of a conditioned place preference for cocaine, rats that had been exposed gestationally to cocaine nevertheless revealed an effect of cocaine during conditioning in one aspect of their test behavior. Possible explanations for the lack of cocaine-induced place preference in these animals include a learning deficit or a change in cocaine's effectiveness as a reward.
Animals↗
A fostering study of the effects of prenatal cocaine exposure: I. Maternal behaviors.
The effect of rearing condition and prenatal exposure to cocaine on maternal behaviors was examined. Sprague-Dawley dams were given SC injections of 40 mg/kg/3cc cocaine HCl (C40) or saline (LC) daily from gestational days 8-20. Maternal behavior was assessed in treated dams rearing their biological pups (LC/LC; C40/C40), treated dams rearing untreated pups (LC/FOS; C40/FOS), and foster dams rearing treated pups (FOS/LC; FOS/C40). All dams were monitored for home cage behavior (time eating, drinking, and with pups) for 2 h during both the light and dark cycle on postnatal day 4 (P4), pup retrieval on P5-P9, and maternal aggression to a female intruder (latency to the first attack, number of attacks, boxing, pins, intruder time spent submissive and motionless) on P10. No differences were observed in nest behavior or in tests of pup retrieval among the six groups. Dams rearing their biological litter (LC/LC and C40/C40) were significantly quicker to initiate the first attack when compared to all other groups. This increased aggression was maintained throughout the test session in the C40/C40 dams who made significantly more intruder attacks than all other groups, with the intruder spending significantly more time in a submissive posture (lying on back). In contrast, LC/LC dams did not exhibit an increased number of attacks during the test, apparently responding to an increased freezing in their intruders with a reduction in aggressive behavior. Taken together these findings suggest that prior cocaine exposure results in alterations in maternal aggression that is evident when these dams rear their own pups.
Aggression↗
A fostering study of the effects of prenatal cocaine exposure: II. Offspring behavioral measures.
The impact of rearing condition was assessed in Sprague-Dawley dams given 40 mg/kg cocaine (C40) or saline (LC control) subcutaneously (SC) from gestational days 8-20 and their offspring. Treated pups reared by their biological dams (LC/LC; C40/C40), treated pups reared by surrogate dams (FOS/LC; FOS/C40), and foster pups raised by treated dams (LC/FOS; C40/FOS) were examined. On postnatal day 7 (P7), pups received either 0 (unpaired) 2, 3, or 4 pairings of an odor and footshock and were tested for their aversion to this odor. Foster and LC pups, regardless of rearing condition, exhibited significant odor aversions following either 2, 3, or 4 training trials. In contrast, C40 pups reared by surrogate dams required 4 trials to acquire the aversion, and C40 pups reared by their own dams did not exhibit conditioning even after 4 trials. At P17, no differences were seen among the groups in the aversion formed to an auditory or an olfactory stimulus that was paired with footshock. At P60, shock-elicited aggression among pairs of siblings was examined. Regardless of prenatal exposure condition, offspring reared by dams given cocaine showed a decreased latency to the first aggressive contact, an effect that was evident without any alteration in shock sensitivity. Together these data suggest that being reared by a dam previously exposed to cocaine has an impact on offspring behavioral function apart from the effects of prenatal cocaine exposure per se. The implications of the data regarding the cognitive performance of pups exposed prenatally to cocaine are also discussed.
Acoustic Stimulation↗
Is use of a cellulose-diluted diet a viable alternative to pair-feeding?
Pair-feeding (PF) has been traditionally used as a nutrition control for drugs that reduce food intake during pregnancy. This method of dietary restriction has been shown to induce alterations in the behavior and physiology of the dams, with some consequent effects on their offspring. Dams treated with cocaine typically exhibit a transient reduction in food intake lasting 3-5 days. A novel nutritional control, using a cellulose-diluted diet, was developed to control for this transient anorexia without requiring explicit food restriction. Daily body weights and food and water intake were measured in Sprague-Dawley dams that received subcutaneous injections of 40 mg/kg/3 cc of cocaine hydrochloride (C40) daily on gestational day 8-20, pair-fed (PF) dams that were injected with saline, and nontreated control dams (LC). In addition, another group of dams were placed on a powdered chow diet diluted with cellulose (40% by weight) and were injected with saline from gestational day 8-20 (NC). Both the food intake and body weight gain of NC and PF dams closely matched that of C40 dams. NC dams were more similar in water intake to cocaine-treated dams than PF dams. However, offspring of NC dams exhibited a significant reduction in pup body weight on postnatal day 1 when compared to PF, LC, and C40 offspring, a finding which limits the usefulness of this novel nutritional control procedure. Thus, pair-feeding still appears to be the best available method for controlling the nutritional consequences of developmental toxicants.
Animals↗