Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-6 mediates brain-immune interactions, influences the survival of postnatal mesencephalic and basal forebrain cells, influences mesocorticolimbic dopamine and serotonin neurotransmission, and is linked with various central nervous system disorders. In the present study, single injections of IL-6 (1 or 2 microg/Long-Evans rat, i.p.) induced modest elevations of locomotor activity. The locomotor increases were not augmented by repeated intermittent injections of IL-6 (five daily injections; 1 microg/rat), however. Nonetheless, repeated IL-6 treatment increased sensitivity to the locomotor-stimulating effects of 1.0 and 0.5 mg/kg amphetamine, when tested 5, 7, or 14 days following interruption of the cytokine treatment. The ability of acute IL-6 injections to alter locomotor activity and the ability of repeated IL-6 injections to produce long-lasting sensitization to the locomotor-stimulating effects of amphetamine suggest an interaction of this cytokine with the mesolimbic dopamine system, a system implicated in aspects of schizophrenia, addiction, and movement disorders. The fact that IL-6 caused a lasting change in responsiveness to amphetamine implies a mechanism by which immunogenic stimuli can alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli or events.
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PMID:Interleukin-6 increases sensitivity to the locomotor-stimulating effects of amphetamine in rats. 1057 98

Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Reported strain and supplier-based differences in sensitivity to PPI-disruptive effects of DA agonists presumably reflect the differential impact of genetics and/or environment on DAergic substrates regulating PPI. In 2000, Harlan Laboratories established a Texas Sprague-Dawley line (SDHt; facility 211) using breeders from Indianapolis (SDHi; facility 202A). SDHi rats had been used, approximately 11 years earlier, to establish a colony in San Diego (SDHsd; facility 235). SDHt and SDHi rats are thus genetically similar, but raised in distinct environments; approximately 11 years of genetic "drift" separates SDHsd rats from both SDHi and SDHt rats. Harlan Long-Evans hooded rats (LEH; Madison, WI; facility 207) are genetically distinct from albino SDH. All except SDHsd rats were shipped to our facility by air freight. We used SDHt, SDHi, SDHsd, and LEH rats to assess genetic and environmental contributions to the DAergic regulation of PPI. Acoustic startle/PPI were assessed in rats treated with the D1/D2 agonist apomorphine (APO), the D2 agonist quinpirole, or the D1 agonist SKF 82958. The relative sensitivities to the PPI-disruptive effects were: APO: SDHt=SDHsd=SDHi>>LEH; SKF 82958: SDHt=SDHsd=SDHi (LEH not sensitive); quinpirole: SDHt=SDHsd=SDHi; SDHi>LEH. Strain/supplier differences in sensitivity to drug effects on startle magnitude did not correspond to patterns of PPI sensitivity. In these rats, strain differences in the DAergic regulation of PPI are most easily explained by genetic, rather than environmental influences that differentially impact both D1 and D2 substrates. This finding is consistent with published reports in other strains. Pharmacogenetic studies of PPI in rats may identify a genetic basis for a model of deficient sensorimotor gating in schizophrenia.
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PMID:Sensitivity to the dopaminergic regulation of prepulse inhibition in rats: evidence for genetic, but not environmental determinants. 1170 Nov 91

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating and is reduced in neuropsychiatric disorders such as schizophrenia. Isolation rearing of rats is a developmentally specific, nonpharmacological manipulation that leads to deficits in sensorimotor gating that mimic those observed in schizophrenia patients. This study examined the effects of an added stressor (water deprivation) on the magnitude of the isolation rearing effect on PPI and locomotor activity. At the time of weaning, male (n = 80) and female (n = 80) rats were assigned to either social housing or isolation housing and were subsequently assigned to the water-deprived or non-water-deprived groups. Rats were tested for acoustic startle and PPI at 3, 5 and 7 weeks postweaning. Isolated rats showed a significant decrease in PPI that was apparent at all 3 weeks. Water deprivation did not significantly affect PPI, nor was there a significant interaction between housing and water treatment or between sex and housing. When tested in the Behavior Pattern Monitor to assess locomotor activity, isolated rats displayed decreased habituation across the 1-h test session. Water deprivation did not affect locomotor activity in any significant, independent manner, nor did it potentiate the effects of isolation rearing on locomotor habituation. In these studies, both male and female Long-Evans rats were sensitive to the PPI-disruptive and locomotor-activating effects of social isolation. Isolation rearing significantly disrupts PPI and locomotor habituation independent of any effects of water deprivation.
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PMID:Isolation rearing-induced deficits in prepulse inhibition and locomotor habituation are not potentiated by water deprivation. 1221 2

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We reported heritable differences in sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine (APO) in Harlan Sprague-Dawley (SDH) and Long-Evans (LEH) rats, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. In this study, we assessed the neurochemical specificity of this heritable phenotype across parental SDH and LEH strains, and their F1 and N2 offspring, based on their sensitivity to the PPI-disruptive effects of the indirect DA agonist D-amphetamine (AMPH) and the 5HT2A agonist DOI. AMPH sensitivity followed a gradient of SDH>N2>F1>LEH, consistent with past findings with APO. DOI sensitivity did not differ across strains or generations. These findings demonstrate that the heritable phenotype in this model is not specific to a particular compound (APO), and reflects physiological differences in the DAergic, but not serotonergic, regulation of PPI.
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PMID:Heritable differences in the effects of amphetamine but not DOI on startle gating in albino and hooded outbred rat strains. 1275 27

Rearing rats in social isolation from weaning into adulthood leads to deficits in prepulse inhibition and alterations in monoamine systems that modulate prepulse inhibition. For example, rats reared in social isolation have elevated dopamine levels in the nucleus accumbens. Previous studies in rats have shown that nucleus accumbens dopamine depletion with 6-hydroxydopamine blocks the prepulse inhibition-disruptive effects of amphetamine, an indirect dopamine agonist. We tested the hypothesis that prepulse-inhibition deficits in isolation-reared rats are dependent on elevated dopamine levels in the nucleus accumbens. Specifically, we examined whether nucleus accumbens dopamine depletion would attenuate the isolation-induced disruption of prepulse inhibition. Isolation-housed female Long-Evans rats exhibited deficient prepulse inhibition. At 9 weeks post weaning, bilateral injections of 6-hydroxydopamine (8 microg/side) or ascorbic acid vehicle (0.1%) into the nucleus accumbens of social and isolation-reared rats were performed (8-10 rats per group). One week after surgery, prepulse inhibition deficits were exhibited by isolation-reared rats that received vehicle infusion into the nucleus accumbens, but not by those that received 6-hydroxydopamine infusions into the nucleus accumbens. 6-Hydroxydopamine infusions did not significantly change prepulse inhibition in socially reared rats. Behavioral and neurochemical evidence of nucleus accumbens dopamine depletion included: 1) a blockade of amphetamine-stimulated locomotor activity in nucleus accumbens 6-hydroxydopamine-infused isolated and socially reared rats; and 2) high performance liquid chromatography measurements demonstrating a significant depletion of accumbens dopamine and its major metabolites, in addition to decreases in dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid levels in the frontal cortex and anterior caudate. These data indicate that dopamine in the nucleus accumbens plays an essential role in the prepulse inhibition deficits associated with isolation rearing in female Long-Evans rats. The implication of a central role of nucleus accumbens dopamine in prepulse inhibition deficits in an animal model provides further evidence for a link between overactive dopamine function and sensorimotor-gating deficits in patients with schizophrenia.
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PMID:Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats. 1276 84

Although subchronic phencyclidine (PCP) administration is recognized as a probative method to model schizophrenia-like symptoms in animals, only a few sets of data support the hypothesis of a cognitive prefrontal cortex (PFc) dysfunction in PCP-treated monkeys and rodents. Two experiments were here conducted to further test the integrity of prefrontal function in two versions of a memory for temporal order (MTO) task administered to rats. Original versions of this task elaborated by Kesner repeatedly yielded moderate to severe performance deficits in PFc lesioned rats. MTO assessment in an eight-arm radial maze consisted in a recency discrimination between two arms previously explored in the context of sequential forced choices. In Experiment 1, 16 naive Long-Evans rats were pre-trained on a variable version of the MTO task involving randomly re-mixed sequences until they reached a group criterion. Then, rats were treated daily for 21 days with PCP (10mg/kg) or saline vehicle and were tested on the same task approximately 20 h after an injection. The performance of the groups did not differ. In Experiment 2, 16 naive Long-Evans rats untrained prior to treatment received 27 daily injections of either PCP (10mg/kg) or saline vehicle and were tested, 20 h after each injection, on a constant version of the MTO task. This time, a fixed set of four sequences of successive arm entries was repeated within each daily session as well as across days. Again, prolonged PCP exposure failed to impair discrimination of temporal order despite the stability of sequential information over time. These negative results are not consistent with long-lasting hypofrontality, a major landmark of human schizophrenia, in the PCP rat model.
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PMID:Schizophrenia-like syndrome inducing agent phencyclidine failed to impair memory for temporal order in rats. 1293 31

Prepulse inhibition (PPI) of acoustic startle is decreased in unmedicated schizophrenia patients and similar deficits can be induced in rats through pharmacological, environmental, or neuroanatomical manipulations. Recently, we reported that Brattleboro (BB) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in PPI homologous to those observed in schizophrenia patients. We also reported that PPI deficits in BB rats could be reversed by chronic but not acute administration of 0.5 mg/kg haloperidol. No other dose or drug was tested in that experiment. In this study, we tested the effects of acute subcutaneous administration of several doses of haloperidol as well as the second-generation antipsychotic, clozapine, and the putative novel antipsychotic, PD149163, a neurotensin mimetic that crosses the blood-brain barrier. Consistent with our previous report, BB rats exhibited PPI deficits compared to LE rats and none of the doses of haloperidol produced a significant effect on this PPI deficit. In contrast, 10 and 15 mg/kg of clozapine and all the doses of PD149163 tested reversed the PPI deficits in BB rats. In addition, haloperidol, but not clozapine or PD149163 produced significant catalepsy in BB rats, supporting the notion that PD149163 has a profile consistent with atypical antipsychotics and providing support for the predictive validity of the PPI results. These results further strengthen the notion that the BB rat is a useful predictive model of antipsychotic efficacy and suggest that this model may differentiate between antipsychotics belonging to different therapeutic categories, for example, first- and second-generation agents.
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PMID:Reversal of sensorimotor gating deficits in Brattleboro rats by acute administration of clozapine and a neurotensin agonist, but not haloperidol: a potential predictive model for novel antipsychotic effects. 1476 Mar 94

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI disruptive effects of the D(1)/D(2) agonist apomorphine in Harlan Sprague-Dawley (SDH) versus Long Evans (LEH) rats. In the present study, we assessed the generational pattern of this phenotypic difference across parental SDH and LEH strains under in- and cross-fostering conditions, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. Apomorphine sensitivity followed a gradient across generations that suggested relatively simple additive effects of multiple genes. Cross fostering studies confirmed that SDH>LEH apomorphine sensitivity did not reflect post-natal maternal influences. Generational patterns of PPI apomorphine sensitivity were not associated with albino versus hooded phenotypes per se, but apomorphine sensitivity in hooded N2 rats was strongly related to body surface area of fur pigmentation. The association between pigmentation and PPI apomorphine sensitivity may provide an important clue to specific biochemical and genetic substrates responsible for population differences in the regulation of sensorimotor gating.
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PMID:Heritable differences in the dopaminergic regulation of sensorimotor gating. I. Apomorphine effects on startle gating in albino and hooded outbred rat strains and their F1 and N2 progeny. 1530 Mar 58

Prenatal administration of synthetic estrogens in humans as well as lower mammals was reported to alter behavior in adulthood. The alterations remain to be characterized according to specific pathophysiological hypotheses. In this study, three common behavioral models of schizophrenia were tested, i.e., latent inhibition (LI), prepulse inhibition of the startle response (PPI) and hyperlocomotion under amphetamine. Female Long-Evans rats were injected i.p. with a solution of 17alpha-ethinylestradiol (15 microg kg(-1)) everyday from day 9 to 14 of pregnancy, and behavioral characteristics of their offspring, raised by Wistar foster mothers, were compared to those of rats born from dams injected with the vehicle only, over the same gestation period. LI was tested in a conditioned taste aversion and a conditioned passive avoidance paradigm followed by a parametric study of PPI and an evaluation of locomotion in an open field under saline or amphetamine (1.5 mg kg(-1)). Histological brain measurements were also carried out in a subset of the same rats. Neither LI nor PPI was altered using methods that had proven sensitive in previous pharmacological studies. Treated rats' locomotion was impaired, but amphetamine did not elicit a differential enhancement. A thinner Amon's horn layer was observed in their hippocampus. This indicates that standard models of schizophrenia did not fit to the behavioral abnormalities found by others and confirmed in this study. They were not due to the abnormal maternal care to pups elicited by the treatment.
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PMID:Prenatal exposure of Long-Evans rats to 17alpha-ethinylestradiol modifies neither latent inhibition nor prepulse inhibition of the startle reflex but elicits minor deficits in exploratory behavior. 1535 6

Abnormal activity in corticolimbic circuits during development may be a predisposing factor for schizophrenia. Permanent or temporary lesions of limbic structures such as the ventral hippocampus and basolateral amygdala in rats on postnatal day (PND) 7 result in functional changes similar to some behavioural and cognitive signs of schizophrenia. The present experiments tested whether transient increases in the neural activity of corticolimbic circuits on PND 7 would result in similar behavioural changes. Long-Evans rats were treated with either kainic acid (KA, 1.5 mg/kg, i.p.) or saline on PND 7 and tested for prepulse inhibition (PPI) of the acoustic startle response and spontaneous locomotor activity both in a novel environment and following amphetamine treatment before puberty (PND 35) and in early adulthood (PND 56). In subgroups of animals PPI was also measured following apomorphine administration (0.2 mg/kg) and spatial learning and memory were tested in the water maze. Rats treated with KA were indistinguishable from saline-treated animals on PND 35. However, on PND 56, KA-treated animals showed a subtle consistent decrease in PPI relative to control animals, but did not show increased sensitivity to the disruptive effects of a low dose of apomorphine on PPI. Locomotor responses to novelty or amphetamine were not reliably altered in the KA-treated animals. KA- and saline-treated animals performed similarly in the water maze. These results support the hypothesis that neural hyperactivity on PND 7 in rats causes behavioural changes in early adulthood that resemble some symptoms of schizophrenia. These pharmacological data suggest that the changes are not mediated by postsynaptic alterations in mesolimbic dopamine transmission.
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PMID:Delayed onset of prepulse inhibition deficits following kainic acid treatment on postnatal day 7 in rats. 1554 7


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