Neurocognitive abnormalities in offspring of mothers with systemic lupus erythematosus.

Offspring of systemic lupus erythematosus (SLE) patients delivered during follow-up in the lupus clinic from 1973 to 1998 were assessed for SLE and by age-appropriate neurocognitive tests. Nine domains were evaluated. Controls, matched for age, sex, race and socio-economic status, underwent the same neurodevelopmental/neuropsychological evaluation. A domain was considered 'abnormal' if at least one of the tests in the domain yielded abnormal results. The number of offspring with normal/abnormal results was compared in each of the nine domains using McNemar test for matched analysis. In addition, an unmatched analysis using chi-square tests was performed. Logistic regression was run on both the matched pairs and unmatched groups to adjust for possible gender differences. A total of 106 children, 49 pairs of SLE offspring and matched controls (20 male and 29 female) and an extra eight offspring (three male and five female) of SLE patients without a control match were included. Of the 57 SLE offspring, none were diagnosed with SLE. The matched analyses of the neuropsychological domains revealed impairment in SLE children compared with matched controls in two of the nine domains: learning and memory and behaviour.

Amphetamine-induced perseverative behavior in a radial arm maze following DSP4 or 6-OHDA pretreatment.

Mice permitted to explore an 8-arm radial maze tended to visit those arms least recently entered. Treatment with D-amphetamine engendered a perseverative tendency, wherein mice repeatedly visited two arms of the maze. Administration of the norepinephrine (NE) neurotoxin, N-2-chloroethyl-N-ethyl-2-bromo-benzylamine (DSP4), appreciably reduced NE in the hippocampus and cortex, moderately reduced NE in the locus coeruleus, and had only a small effect on hypothalamic NE. The DSP4 treatment resulted in a decrease of locomotor activity among amphetamine-treated mice, coupled with an increase of stereotyped response patterns. Although the NE depletion did not affect the pattern of exploration that mice ordinarily displayed, DSP4 appreciably increased the perseverative tendency provoked by amphetamine. Reduction of dopamine (DA) and NE by intraventricular administration of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), antagonized the effects of amphetamine, such that the frequency of alternation responses was increased and the proportion of perseverative responses was reduced. The effectiveness of the 6-OHDA treatment in antagonizing the amphetamine-induced perseveration was not reduced among mice that were pretreated with desmethylimipramine, which resulted in partial prevention of the NE reduction by 6-OHDA administration. It is suggested that DA neuronal activity contributes to the amphetamine -provoked perseveration , whereas NE stimulation modifies the perseverative tendency by influencing exploration or habituation.

Acute and chronic amphetamine treatment: differential modification of exploratory behavior in a radial maze.

Mice permitted to explore an 8-arm radial maze displayed high levels of spontaneous alternation as measured by the frequency of visiting (a) the 4 least recently entered arms, (b) the 2 least recently visited arms, and (c) sequences of arms which are adjacent to one another. Acute treatment with low doses of amphetamine (1.0 mg/kg) eliminated the alternation tendency. Higher doses (5.0-7.0 mg/kg) also produced marked stimulus perseverance, such that mice tended to revisit the two arms that had been most recently entered. With repeated amphetamine treatment the perseverance tendency was attenuated. The abatement of perseverance in the radial maze did not appear to reflect simply the reduction in the potency of the drug. That is, the reduction of perseverance after chronic exposure to amphetamine was not accompanied by recovery of normal exploratory patterns. In fact, the alternation and adjacent alternation patterns typical of naive animals were absent in mice chronically treated with amphetamine even when tested in the nondrug state. It was suggested that the attenuation of amphetamine induced perseverance after chronic amphetamine administration may reflect a breakdown of normal behavior patterns rather than the development of a genuine tolerance.

Attenuation of perseverative behavior after repeated amphetamine treatment: tolerance or attentional deficits?

When permitted to explore an 8-arm radial maze, animals exhibited a systematic pattern of exploration characterized by preference for the most novel arms (spontaneous alternation) and entry into immediately adjacent arms (adjacent alternation). Acute treatment with moderate dosages of amphetamine reduced the proportion of both types of alternation responses and induced marked stimulus perseverance, i.e., consecutive entries between pairs of arms. Prior exposure to the apparatus enhanced the degree of perseverance ordinarily observed, and provoked perseverance after low doses of the drug. In contrast to acute drug treatment, perseverance was reduced after chronic amphetamine administration. However, chronic amphetamine treatment did not appear simply to reduce the potency of the drug. In contrast to the effects of apparatus pre-exposure on the degree of perseverance induced by acute amphetamine treatment, the degree of perseverance was not enhanced by pre-exposure to the maze in mice with a history of chronic amphetamine administration. Moreover, the exploratory pattern evident in chronically treated animals differed from that of control animals even when tested in the nondrug state. That is, animals chronically treated with amphetamine and tested with saline exhibited alternation scores which did not deviate from chance. These data suggest that chronic amphetamine treatment alters the way in which organisms attend, or respond, to environmental stimuli.

Alterations of exploratory patterns induced by uncontrollable shock.

A series of studies evaluated the effects of footshock on subsequent patterns of exploration in an eight-arm radial maze. When permitted to explore an eight-arm maze freely, mice typically exhibited a characteristic pattern of exploration in which they tended to enter arms of the maze that were least recently visited (spontaneous alternation). Moreover, animals frequently made successive entries into immediately adjacent arms of the maze (adjacent alternation). Following exposure to escapable shock the alternation performance is not appreciably altered; however, an identical amount of uncontrollable shock disrupted the adjacent alternation tendency. The disruption was evident immediately after shock, but was absent if mice were tested 24 hr after the inescapable-shock treatment. Interestingly, when mice were reexposed to a small number of shocks, a treatment which itself has no effect, the disturbance of adjacent alternation was reinstated. It is suggested that the alterations of exploratory patterns may be related to catecholamine alterations provoked by stressors, and that the behavioral disturbance could potentially influence performance in tasks involving associative processes.

Adaptation to the tumor-enhancing effects of stress.

Growth of P815 mastocytoma in syngeneic DBA/2J male mice was evaluated following several stress regimens. Although escapable shock did not enhance tumor growth, an equivalent amount of inescapable shock applied in a yoked paradigm markedly augmented tumor development. If mice received repeated stress sessions on 5-10 consecutive following tumor cell transplantation, the tumor-enhancing effects of an acute session were abrogated. This effect was not due to an antitumor effect exerted by a shock session applied several days after cell transplantation. It seems that the tumorigenic effects of stress are subject to adaptation since stress exposure prior to cell transplantation also inhibited the effects of an acute stress session. The data were discussed in relation to stress-induced neurochemical alterations.