Social isolation and individual differences: behavioural and dopaminergic responses to psychomotor stimulants.
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Animals↗
Biomedical subjects
G H Jones
Publications and source records attributed to G H Jones.
Behavioural rigidity and rule-learning deficits following isolation-rearing in the rat: neurochemical correlates.
Isolation-reared rats were compared to those reared in social groups on the acquisition of a conditional visual discrimination (Expt. I), a simultaneous (simple) light/dark discrimination and serial reversal learning (Expt. II). In Expt. I, rats reared in social isolation made more errors during the acquisition of the conditional discrimination but did reach a level of accurate performance which was comparable with that of socially-reared rats. Discrimination performance in isolates was less disruptable by manipulations of the task requirements. Reducing the number of stimulus lights or the introduction of a distracting stimulus increased the number of errors committed by socially-reared rats but did not significantly affect accuracy in isolates. Performance in isolated rats was also remarkably resistant to changes in motivational variables. Isolates responded more frequently during conditions of extinction and were virtually unaffected by pre-feeding prior to testing. In Expt. II, isolation-reared rats were not impaired in the acquisition of a simultaneous discrimination but unlike socially-reared rats isolates failed to show improvement with successive reversals of this discrimination. Isolates exhibited stronger position habits than socially-reared rats following reversal of the contingencies. These results of these two experiments combined have demonstrated a specific impairment in rule learning in isolates. Isolated rats were not impaired on a simultaneous discrimination in which accurate performance can be achieved simply by approaching the stimulus associated with reinforcement, but performed worse than controls on both the conditional discrimination and on serial reversal learning, another form of conditional task. In both of these latter tasks each stimulus becomes equally associated with reward and therefore performance can be improved by learning a rule. Post-mortem neurochemical measurements made at the completion of Expt. II revealed selective alterations in dopaminergic, serotoninergic and cholinergic markers in isolated rats. Correlational analyses indicated specific relationships between neurochemical and behavioural measurements.
Animals↗
Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine.
The relationship between a rat's locomotor response to a novel environment and its behavioral and dopaminergic responses to cocaine was examined. Subjects were divided into two groups based on their locomotor response to a novel environment. Subjects who had a novelty response above the median were classified as high responders (HR), while those with a novelty response below the median were classified as low responders (LR). Following administration of cocaine-HCl (0, 2.5, 5.0, 10.0, or 15.0 mg/kg), HR rats showed a greater locomotor response than LR rats. Moreover, there was a significant correlation between a subject's locomotor response to the novel environment and the locomotor response to either 10.0 (r = 0.65) or 15.0 (r = 0.92) mg/kg cocaine. In a separate experiment, the extracellular concentration of dopamine in the nucleus accumbens (NACC) was monitored using microdialysis procedures. Following cocaine administration (15.0 mg/kg) HR rats showed a larger NACC dopamine response and greater locomotor activity than LR rats. In addition, there was a threefold greater locomotor activity to dopamine ratio in HR rats than in LR rats. A correlation between a subject's locomotor response to a novel environment and the dopaminergic response to cocaine was also evident. These results suggest that differences in the locomotor response to cocaine can, to some degree, be predicted by a rat's locomotor response to a novel environment, and that variations in dopamine-dependent mechanisms of the NACC may underlie these individual differences.
Animals↗
Individual differences in locomotor activity and sensitization.
Male rats were screened for locomotor activity in a novel environment and divided into high (HR) and low (LR) responders based on whether their locomotor activity score for the first hour was above or below the median locomotor activity for the subject sample. Subsequently, the locomotor response to repeated administration of either amphetamine (AMPH; 0.5 mg/kg), cocaine (10 mg/kg), scopolamine (0.5 mg/kg) or saline was monitored in separate groups of HR and LR rats. HR rats had significantly higher overall activity scores than LR rats for all 3 drugs. Both HR and LR rats developed tolerance at the same rate to repeated scopolamine administration. In contrast, only HR rats showed pronounced sensitization to the locomotor stimulating properties of AMPH and a direct correlation was evident between the locomotor response to novelty and the magnitude of sensitization. These results suggest that an individual's response to a novel environment can, to a certain extent, predict drug-induced locomotor activity and that individual differences in the response to novelty and sensitization to AMPH may result from individual variations in a common neural mechanism.
Amphetamine↗
Sensitization of amphetamine-stereotypy reduces plasma corticosterone: implications for stereotypy as a coping response.
The potential coping functions of amphetamine-induced stereotypy were investigated using a physiological index of stress or arousal, plasma corticosterone level. A series of five injections of d-amphetamine was used to enhance stereotyped behavior in control animals as well as in rats with bilateral dopamine-depleting lesions of the caudate-putamen. This regimen of amphetamine injections significantly increased stereotyped behavior and also reduced the normal elevation in corticosterone produced by treatment with d-amphetamine. This effect was apparent in both control and lesioned animals. These results support the hypothesis that amphetamine-induced stereotyped behavior functions to reduce stress or arousal and additionally suggest that this effect is largely independent of underlying dopaminergic mechanisms.
Adaptation, Psychological↗
Pleiotropic effects of a relC mutation in Streptomyces antibioticus.
Ochi (Agric. Biol. Chem. 51:829-835, 1987) has isolated a relaxed mutant of Streptomyces antibioticus, designated relC49, relC49 accumulates significantly lower levels of ppGpp than the parent stain, IMRU3720. At its maximum, the ppGpp level in relC49 was only one-fourth that observed in strain IMRU3720. Interestingly, a burst of ppGpp synthesis between 18 and 22 h of growth in IMRU3720 coincided with the onset of actinomycin production in that strain. As shown previously, the activity in protein synthesis of ribosomes from strain IMRU3720 decreases with the age of the culture. The decrease in activity was less pronounced in cultures of relC49. relC49 mycelium contains reduced levels of phenoxazinone synthase, a key enzyme involved in actinomycin biosynthesis. The rel mutation prevents the normal increase in the activity of one of the other enzymes required for production of the antibiotic, 3-hydroxyanthanilate-4-methyltransferase, and a third enzyme, actinomycin synthetase I, appears to be completely absent from relC49 mycelium. Levels of phenoxazinone synthease mRNA were examined by RNA dot blotting with the cloned phenoxazinone synthase gene as a probe. mRNA levels for phenoxazinone synthase were dramatically reduced in relC49 compared with strain IMRU3720. These results are discussed in terms of the possible regulation of the onset of actinomycin production by ppGpp.
Dactinomycin↗
P300 and reaction-time measures in senile dementia of the Alzheimer type.
Auditory evoked potentials were recorded in a choice reaction-time task. This test paradigm elicited the attention-related P300 component and was used to study cognitive processing. Compared with age-matched controls, 17 patients with dementia of the Alzheimer type were shown to have significantly longer reaction times as well as delayed latencies of several components of the auditory evoked potentials. The fractional increase in the reaction times was much greater than that of the P300 peak latency. The latter is commonly accepted as an index of stimulus-evaluation time. These findings suggest a delay in both response selection and stimulus evaluation.
Aged↗
Head circumference in elderly long-stay patients with schizophrenia.
The head circumference of a long-stay population with schizophrenia was compared with that of a population with dementia, matched for sex and year of birth. Schizophrenics had a smaller head circumference, even after correction for height and weight. This confirms earlier but inconclusive and controversial reports, and might be taken as supporting a neurodevelopmental hypothesis of the aetiology of schizophrenia.
Aged↗
Effects of dopamine depletion from the caudate-putamen and nucleus accumbens septi on the acquisition and performance of a conditional discrimination task.
Three experiments compared the effects of dopamine depletion from the caudate-putamen (CAUD; dorsal striatum) or nucleus accumbens septi (NAS; ventral striatum), or a systemically administered dopamine receptor antagonist (alpha-flupenthixol) on the acquisition and performance of a conditional discrimination task involving temporal frequency. In Expt. 1, rats receiving 6-hydroxydopamine (6-OHDA) lesions of the CAUD were impaired in the acquisition of a visual version of the task, and rats with 6-OHDA lesions of the NAS were not reliably impaired. Even when the rats with CAUD lesions had acquired the discrimination, they were still significantly slower to collect earned food pellets. Both CAUD and NAS lesions reduced a bias to respond to the faster of the two discriminative stimuli. In Expt. 2, rats with 6-OHDA lesions of CAUD were markedly impaired in their accuracy and speed of responding when they had been trained to criterion preoperatively. These effects could not be mimicked in controls by prefeeding (which had only minor effects on performance). Rats with 6-OHDA-induced lesions of the NAS were unimpaired in either visual or auditory discrimination performance, but were slower to extinguish responding than controls. In Expt. 3, alpha-flupenthixol (0.1-0.56 mg/kg, i.p.) produced dose-dependent impairments in both latency to respond and choice accuracy in visual and auditory versions of the task. In conjunction with other results, these data suggest that (1) dopamine receptor blockade and central dopamine depletion can impair discrimination performance under certain conditions (2) dopamine depletion from the ventral and dorsal striatum, respectively, have dissociable effects on behaviour controlled by conditioned reinforcers and discriminative stimuli and (3) the disruption of discrimination performance by dorsal striatal dopamine depletion is probably attributable to several factors.
Animals↗
Increased sensitivity to amphetamine and reward-related stimuli following social isolation in rats: possible disruption of dopamine-dependent mechanisms of the nucleus accumbens.
These experiments compared isolation-reared and socially-reared rats in two complementary paradigms for measuring responding to signals of reward, both undrugged and following either systemic or intraaccumbens d-amphetamine (AMPH). In experiment 1, locomotor activity conditioned to food presentation was measured in rats exposed to a restricted feeding schedule. The interaction between this conditioned activity, AMPH administration (0.5, 2.0, 3.5, 5.0 mg/kg IP) and motivational state was measured. In experiment 2, hungry rats were trained to associate a compound light/noise stimulus with sucrose reward and were then implanted with guide cannulae in the nucleus accumbens. In the test phase, responding on one of two novel levers produced the compound stimulus (conditioned reinforcer; CR). Responses on the other lever had no effect. Each rat received four counterbalanced intra-accumbens infusions of AMPH (0, 3, 10, 20 micrograms). In both experiments, isolated rats responded more with stimuli associated with reward and this differential rearing effect was further exaggerated by AMPH. The isolation-induced sensitivity to these stimuli and to AMPH was critically dependent on motivational variables. Thus, in experiment 1 there were no differences between the groups when sated or during extinction and in experiment 2 the increased responding was restricted to the lever providing CR. Measurements of the locomotor response to intra-accumbens AMPH (0, 3, 10 micrograms) also revealed that isolated rats were more sensitive to a low dose of the drug when tested food-deprived in a relatively novel environment. These results suggest that the experience of isolation-rearing interacts either directly or indirectly with dopamine-dependent mechanisms of the nucleus accumbens to enhance the effects of reward-related stimuli.
Animals↗
Comparison of the effects of Alzheimer's disease, normal aging and scopolamine on human transient visual evoked potentials.
Transient visual evoked potentials elicited by the onset of a patterned stimulus were recorded in patients suffering from Alzheimer's disease (AD), in healthy elderly controls and in healthy young individual. The latencies and amplitudes of both the components studied were adversely affected by normal aging and one of the components, CI, but not the other, CII, showed further deterioration in AD. These changes occurred over a range of stimulus contrast levels. The changes found in AD, but not those seen in normal aging, could be mimicked by administration of the cholinergic antagonist scopolamine to young volunteers.
Adult↗
Emission of viable bacteria in the exhaust flue from a waste incinerator.
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Air Pollutants, Occupational↗
The effects of excitotoxic lesions of the basal forebrain on the acquisition, retention and serial reversal of visual discriminations in marmosets.
The effects of N-methyl-D-aspartate-induced lesions of the basal forebrain (which included the cholinergic cells of the nucleus basalis of Meynert) were studied on three aspects of visual discrimination; learning, retention and reversal performance, in the marmoset. Neurobiological investigations revealed that the lesion produced large reductions in choline acetyltransferase activity within anterior regions of cortex, particularly prefrontal. In Experiment 1 lesioned animals showed impaired retention, one week after surgery, of a visual discrimination learned immediately prior to surgery and subsequently showed impaired performance over a series of reversals. The reversal deficit could be characterized as a tendency to perseverate on the previously correct stimulus on the first reversal and as a failure to show serial reversal learning on subsequent reversals. Acquisition of a novel discrimination was not impaired five weeks after surgery. As time of testing may have been a confounding factor, in Experiment 2 the effects of the same lesion on new learning were examined immediately following surgery and the effects on retention a month later. The lesion was found to disrupt new learning but did not affect retention. From the two experiments it is clear that, whereas disruption of retention and new learning was relatively transient, the impairments in reversal performance were more long lasting. In addition, lesioned animals exhibited behavioural hyperactivity and elevations in consummatory and schedule-controlled licking. The disinhibitory and preservative effects observed following lesions of the basal forebrain in this study are similar to those following lesions of the orbitofrontal cortex while the disruption of serial reversal learning is commonly seen following damage to the amygdala. Therefore, these results are consistent with the hypothesis that the range of behavioural effects of the lesion result from damage to the cholinergic afferents to orbitofrontal cortex and to the amygdala, two structures intimately connected to one another.
Animals↗
Cortical, hippocampal, and striatal mediation of schedule-induced behaviors.
The sequential occurrence of licking, locomotor activity, entries into the food magazine (panel pressing), and nonreenforced lever pressing engendered by a periodic schedule of food presentation were measured in each 60-s interreenforcement interval in normal and brain-damaged rats. The development of these responses was measured over 20 days in different groups of food-deprived rats that had received aspirations of the hippocampus, small lesions of the cortex overlying the hippocampus (hippocampal-operated control group), decortication, or 6-hydroxy-dopamine lesions of the caudate nucleus or nucleus accumbens. All lesions produced distinctive patterns of change in the measured behaviors, and dissociations as well as similarities in their effects were evident. These results are discussed with respect to dissociations in the motor and motivational effects of the various lesions and in terms of contemporary hypotheses of schedule-induced behavior.
Animals↗
Molecular cloning and in vitro expression of a silent phenoxazinone synthase gene from Streptomyces lividans.
Phenoxazinone synthase (PHS) catalyzes a step in actinomycin D biosynthesis in Streptomyces antibioticus. Two sequences from Streptomyces lividans that hybridize to the phs gene of S. antibioticus have been cloned in Escherichia coli K-12 using the plasmid pBR322. Although there was some similarity in the restriction maps of the two cloned fragments, neither insert appeared to be a direct subset of the other nor of the S. antibioticus phs gene. In vitro expression studies, in a streptomycete coupled transcription-translation system, showed that a 3.98-kb SphI fragment encoded a PHS-related protein. These observations provide additional support for the existence of silent genes for antibiotic production in streptomycetes.
Blotting, Southern↗
Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes.
Two experiments examined the effects of excitotoxic lesions of the substantia innominata on cholinergic activity in the neocortex and on performance in a paradigm measuring selective attention in the rat. In Expt. 1, ibotenate-induced lesions produced approximately 30% reductions in cortical choline acetyltransferase (ChAT) activity, and damage to wide regions of the substantia innominata and ventral pallidum. The rats were impaired in their ability to localize brief visual targets in a serial reaction time task, as measured by reduced choice accuracy. This impairment was particularly evident at short stimulus durations, but the lesioned rats did not exhibit evidence of primary visual sensory dysfunction and exhibited only minor deficits when the stimuli were presented unpredictably. The deficit was exacerbated when distracting white noise was interpolated into the task. The rats with lesions were also slower to respond correctly, probably resulting partly from the adoption of a speed/error trade-off strategy, and were slower to collect earned food pellets, although they made no more errors of omission than controls. In Expt. 2, quisqualate-induced lesions produced fewer signs of non-specific damage and 50% reductions in cortical ChAT activity. This lesion produced generally qualitatively similar, but weaker effects to those of ibotenate-induced lesions. It was notable that many of the deficits following either ibotenate- or quisqualate-induced lesions lasted for several months after surgery. The results are discussed in terms of the cholinergic hypothesis of cognitive dysfunction. It is argued that lesions of the substantia innominata, including the magnocellular cholinergic neurons of the nucleus basalis of Meynert, produce deficits in attentional processing, which may not result from damage specifically to cholinergic cells. However, the longevity of the effects makes these preparations suitable for further exploration of the restorative effects of cholinergic treatments.
Animals↗
Co-administration of Ro 15-1788 prevents diazepam-induced retardation of recovery of function.
Following unilateral lesions of the anteromedial cortex, recovery from somatosensory asymmetry reliably occurs within about 10 days. Chronic exposure to diazepam significantly delays this recovery. In the present study, co-administration of Ro 15-1788, a benzodiazepine antagonist (i.e. it blocks the negative and positive allosteric modulation of GABA), prevented diazepam-induced retardation of recovery from somatosensory asymmetry. Nocturnal ambulatory (motor) activity was not different between rats receiving diazepam-alone and those receiving Ro 15-1788 in combination with diazepam. These data suggest that the benzodiazepine receptor is importantly involved in the detrimental effects of diazepam on recovery, and that non-specific behavior sedation plays little or no role.
Animals↗