Behavioral analysis of the effect of substance P injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat

In the present experiments the behavioral response to substance P (SP) microinfusion into the ventral tegmental area (VTA), substantia nigra (SN), and sensorimotor cortex (CX) was investigated in detail. The experiments were carried out using an eight-hole box to measure exploratory behavior and a video monitor for the analysis of spontaneous motor behavior. When infused into the VTA, SP (0.125, 0.5, 3.0 g) augmented the frequency and total duration of hole-pokes, and tended to diminish the mean duration of hole-pokes. The strategy and organization of responses, as measured by the order of hole-visits and hole-switching, were unchanged by SP and there was no indication of stereotypy, measured by the number of hole-pokes per hole-visit. The open-field analysis revealed a marked increase in locomotion and rearing, both in the periphery and center of the arena; grooming was decreased by SP. The behavioral profile following SN infusions of SP (3.0 g) was similar to that elicited by VTA infusions, with the exception that center rearing was not enhanced. SP administration into cortex (3 g) had no significant effect on any behavioral measures. It is hypothesized that SP infused into the ventral mesencephalon results in an enhancement of approach response tendencies, suggesting that endogenous SP in this region may regulate spontaneous behavior. The possibility of an interaction between SP and meso-telencephalic dopamine neurons is discussed.     

Behavioral analysis of the effect of neurotensin injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat

The present experiments examined in detail the behavioral response to microinfusions of neurotensin (NT) into the ventral tegmental area (VTA), substantia nigra (SN) and hippocampus (HPC). The behavioral apparatus consisted of an eight-hole box in which investigatory and spontaneous motor behavior were recorded. Three doses (0.175, 0.5, 4.0 g) of NT were injected into the VTA. The main effect of NT was a strong augmentation of rearing (frequency and duration) both in the periphery and center of the arena, accompanied by a small increase in locomotion and decreased grooming. NT had no effect on the strategy, organization, or duration of exploration but did augment frequency of hole visits towards the end of the session. NT injected into the SN and HPC had no effect on investigatory and spontaneous behavior with the exception of an increase in peripheral locomotion after HPC-NT injections. The results are discussed in terms of a modulatory role of endogenous NT on mesolimbic dopamine neurons.     

Effects of thioridazine on apomorphine-elicited stereotypic behavior and motor activity

Bilaterally injected thioridazine (10 μg) into the striata of rats augmented the stereotypic behavior elicited by apomorphine. The enhancing effect was attenuated by pretreatment with α-methyl-p-tyrosine. At 48 hr postinjection of thioridazine (1.0 mg/kg, IP), motor suppression from a low dose of apomorphine (0.2 mg/kg, IP) was enhanced; however, motor response to a high dose of apomorphine (1 mg/kg, SC) was not affected. Possible mechanisms of action of thioridazine are discussed.     

Pars compacta of the substantia nigra modulates motor activity but is not involved importantly in regulating food and water intake

Summary Precise, bilateral radio-frequency lesions of pars compacta of the substantia nigra in rats resulted in the immediate and sustained appearance of hyperactivity, but such lesions did not produce significant alterations in food or water intake. These behavioral effects were correlated with considerable, histochemically assessed loss of dopamine terminals in the caudate-putamen complex, but dopamine innervation in nucleus accumbens and other forebrain areas was only slightly affected. The magnitude of motor activity increase was positively correlated with the degree of pars compacta involvement. Animals with lesions in the median raphe and adjacent reticular formation also displayed chronic hyperactivity. In contrast to rats receiving discrete radio-frequency lesions of pars compacta, animals with bilateral mesencephalic ablations produced by 6-hydroxydopamine (6-OHDA, 8 g/4 l or 4 g/2 l in combination with desipramine pretreatment) displayed poverty of movement. Furthermore, significant, dose-dependent decrements in food and water intake were seen after 6-OHDA. The nonselective component of such lesions was frequently large and irregular in shape. Occasional ablations produced by this neurotoxin, however, appeared more selective in that damage was confined primarily to pars compacta. Nonetheless, the best correlate of aphagia and adipsia associated with 6-OHDA treatment was lesion size, regardless of the extent of pars compacta or other nigral involvement. We conclude that aphagia and adipsia concomitant to 6-OHDA lesions of the substantia nigra result from the incidental destruction of extra-nigral systems. Virtually complete, but precise, lesions of pars compacta do not produce aphagia and adipsia. While our results are consistent with the notion that the substantia nigra serves an important role in the regulation of motor activity, they provide no support for the conjecture that it is importantly involved in mediating ingestive behaviors.     

Behavioral and neurochemical effects of dietary tyrosine in young and aged mice following cold-swim stress

The effects of dietary supplements of L-tyrosine on aggressive behavior, locomotor activity, and brain neurochemical changes were assessed in young and aged mice following cold-swim stress. Male CF-1 mice, ages 3 months and 21 months, were maintained on a semi-synthetic basal diet for one week, pretested for aggressive behavior and locomotor activity, then switched to diets modified by the addition of tyrosine or casein (control). After one week on the diet supplements, half of the mice were stressed by cold water swim and all were again subjected to behavioral testing. Members of each group were sacrificed for analysis of amino acids and monoamines in brain tissue and corticosterones in blood. It was found that tyrosine supplementation induced a marked increase in aggressive behavior in young, nonstressed mice but not in aged mice. Stress decreased the aggressiveness of both young and aged mice, and tyrosine prevented this stress-induced decrease in both groups. Young mice exhibited no changes in locomotion as a function of stress or diet. However, tyrosine prevented decreases in locomotion observed on second testing of both stressed and nonstressed older mice. The effect of stress was to lower levels of brain norepinephrine (NE) and dopamine (DA) in both young and aged mice. Tyrosine supplementation increased brain tyrosine and DA in both groups. Brain serotonin levels were lower in the aged mice compared to the younger ones, and this was associated with relatively higher concentrations of 5-hydroxyindoleacetic acid. It appears that tyrosine supplementation was effective in reducing the effects of stress in the aged animals, possibly by virtue of its relationship to catecholamine metabolism.     

Attenuation of paraquat-induced dopaminergic toxicity on the substantia nigra by (-)-deprenyl in vivo

(-)-Deprenyl (DEP) had been shown to slow of progression of Parkinson's disease (PD). The present study sought to determine whether DEP would attenuate the nigrostriatal system damage induced by intranigral administration of the herbicide paraquat (PQ) as a model of parkinsonism in vivo. Neurochemical and behavioral observations of Wistar rats were the focus of our study. In the neurochemical observation, the PQ injected in the rats caused dose-dependent depletion of dopamine (DA) in the ipsilateral striata. The coadministration of DEP with PQ partially increased the striatal DA level. The prediction of the striatal DA levels was calculated by regression coefficients obtained from multiple linear regression (r(2) = 0.82): DA level (% of control) = 103.34 - 9.58 PQ (nmol) + 0.79 DEP (nmol). It was demonstrated that the high dose of 20 nmol DEP could significant attenuate the PQ (5 nmol)-elicited dopaminergic toxicity (p < 0.05). In the behavioral observation, the intranigral injection of PQ into the rats caused a rotation behavior contralateral to the lesioned side in response to apomorphine administration (0.5 mg/kg, sc). This apomorphine-induced rotational behavior could also be attenuated significantly by coadministration of DEP (20 nmol) and PQ (5 nmol) compared with PQ-treated (5 nmol) animals (p < 0.05). The above observations indicate that DEP could provide a protective effect on the moderate injury elicited by PQ toxicity of the nigrostriatal dopaminergic system. DEP might be a useful therapeutic agent in treating patients with early-stage PD.     

Dose-dependent dissociable effects of haloperidol on locomotion, appetitive responses, and consummatory behavior in water-deprived rats

We studied whether a cascade of different phases of ingestive behavior were governed by different doses of the dopamine D2 receptor system. A wide spectrum of doses (0, 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg) of a D2 receptor antagonist, haloperidol, were administered to 6 groups of water-deprived rats. 45 min following administration of the drug a 15 min water intake session was allowed to assess the effect on (a) locomotion, (b) appetitive response and (c) consummatory responses. The procedure was repeated for 5 days. Results: The doses of 0.025 to 0.1 mg/kg had no effects on any measured behavior compared with the control group. The 0.2 mg/kg dose induced catalepsy during sessions 3 and 5 and impaired consummatory (decreased lick numbers and intake volume) behaviors during sessions 1-5. The 0.4 mg/kg dose affected appetitive behavior (increased latency to contact the water tube) during session 2 and consummatory behavior during all five water sessions. The 0.2 mg/kg dose appeared to dissociate appetitive and consummatory behavior, and the 0.4 mg/kg dose locomotor activity and motivational behavior (including consummatory and appetitive responses). These results, that the three elements of ingestive behavior (locomotion, appetitive responses, and consummatory behavior) have different sensitivity to haloperidol, suggest that separable D2 mechanisms are involved in governing the ingestive behavior.     

Interaction of dietary tryptophan and social isolation on territorial aggression,motor activity,and neurochemistry in mice

This study examined the interaction of dietary tryptophan (TRP) and differential housing on territorial-induced aggression, locomotor activity, and monoamine neurochemistry in mice. Groups of male CF-1 mice were singly-housed or group-housed and administered a semisynthetic basal diet supplemented with TRP (0.25–1.0%). Behavioral measures were taken at various intervals up to 2 weeks after dietary administration was instituted. Separate groups of mice were given the same experimental treatment and sacrificed for whole brain determination of the monoamines and their metabolites. Isolated mice were consistently more aggressive than grouped animals, suggesting that territorial-induced aggression is synergistic with intermale aggression based on social isolation. The combination of isolation and 0.50% TRP was particularly effective in producing increases in aggression that reached maximal levels after 10 days of diet administration. However, motor activity of singly-housed mice was unaffected by TRP, while that of grouped mice was decreased after 5 days of 0.50% TRP. By day 14 of administration behavioral changes tended to return to baseline levels. Neurochemical measures indicated increased DA and 5-HT turnover in isolated mice, with the 5-HT system most affected by dietary TRP. Because housing conditions were a prominent factor in the aggression and neurochemistry, the results suggest the involvement of both transmitter systems in this behavior. However, there were no changes in monoamine turnover that could account for the development of behavioral tolerance.     

Dissociation of the effects of ethanol on memory, anxiety, and motor behavior in mice tested in the plus-maze discriminative avoidance task

Rationale Several studies have shown the amnestic effects of ethanol (ETOH). However, while memory tasks in rodents can be markedly influenced by anxiety-like behavior and motor function, ETOH induces anxiolysis and different effects on locomotion, depending on the dose. Objective Verify the effects of ETOH in mice tested in the plus-maze discriminative avoidance task (PMDAT) concomitantly evaluating memory, anxiety-like behavior, and motor behavior. Methods ETOH acutely or repeatedly treated mice were submitted to the training session in a modified elevated plus-maze with two open and two enclosed arms, aversive stimuli in one of the enclosed arms, and tested 24 h later without aversive stimuli. Learning/memory, locomotion, and anxiety-related behavior were evaluated by aversive arm exploration, number of entries in all the arms and open arms exploration, respectively. Results Acute ETOH: (1) either increased (1.2–1.8 g/kg) or decreased (3.0 g/kg) locomotion; (2) decreased anxiety levels (1.2–3.0 g/kg); and (3) induced learning deficits (1.2–3.0 g/kg) and memory deficits (0.3–3.0 g/kg). After repeated treatment, sensitization and tolerance to hyperlocomotion and anxiolysis induced by 1.8 g/kg ETOH were observed, respectively, and tolerance to the amnestic effect of 0.6 (but not 1.8) g/kg ETOH occurred. Conclusion Neither the anxiolytic nor the locomotor effects of ETOH seem to be related to its amnestic effect in the PMDAT. Additionally, data give support to the effectiveness of the PMDAT in simultaneously evaluating learning, memory, anxiety-like behavior, and motor activity by different parameters. Possible relationships between the behavioral alterations found are discussed.     

Inhibition of circling behavior by neuroleptic drugs in mice with unilateral 6-hydroxydopamine lesions of the striatum

The development of circling behavior to apomorphine, amphetamine and l-Dopa in mice with unilateral 6-hydroxydopamine lesions of the dopaminergic nerve terminals in the striatum has been studied, and the effect of a range of neuroleptic and sedative drugs on this circling behaviour has been investigated. Circling induced by all the stimulant drugs was inhibited in a dose-dependent manner by haloperidol, pimozide, chlorpromazine, metoclopramide and clozapine (in descending rank order of potency), but not by phenoxybenzamine, diazepam, promethazine and pentobarbitone sodium. This relatively simple animal model appears useful for screening neuroleptic drugs which may block striatal dopamine receptors, thereby predicting their potency to cause unwanted extrapyramidal effects but not their antipsychotic efficacy.     

Effects of repeated exposure to cocaine on group II metabotropic glutamate receptor function in the rat medial prefrontal cortex: behavioral and neurochemical studies

Rationale  Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Enhanced excitatory output from the medial prefrontal cortex (mPFC), which can be modulated by group II metabotropic glutamate receptors (mGluR), is thought to play a key role in the development of sensitization to cocaine. Objectives  The present studies were designed to determine whether the ability of intra-mPFC injections of the group II mGluR agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit cocaine-induced motor activity and dopamine release in the nucleus accumbens is reduced in sensitized animals. Results  Initial studies demonstrated that injection of APDC (0.015–15 nmol/side) into the mPFC dose dependently reduced cocaine-induced (15 mg/kg, i.p.) motor activity. The lowest dose in the present studies that significantly reduced the acute motor-stimulant response to cocaine was 1.5 nmol/side. The specificity of the effects of APDC was confirmed by demonstrating that intra-mPFC co-injection of LY341495 (1.5 nmol/side), a group II mGluR antagonist, prevented the inhibitory actions of APDC. Finally, it was shown that intra-mPFC injection of APDC was able to prevent the initiation of behavioral and neurochemical sensitization to cocaine. Intra-mPFC APDC was also observed to block the expression of cocaine-induced sensitization after short (1 day), but not prolonged (7 and 30 days), abstinence from cocaine. Conclusions  Taken together, these data suggest that mPFC group II mGluR function is reduced following extended abstinence from repeated cocaine.     

5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: A comparative study using in vivo microdialysis

Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150–290%) but remarkably increased 5-HT levels (540–900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC₅₀ values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.     

Intrahypothalamic and intrastriatal dopamine and norepinephrine injections in relation to motor hyperactivity in rats

High doses of dopamine (59 g) and norepinephrine (65 g) injected directly into the striatum and hypothalamus induced motor hyperactivity in rats. The motor activity recorded on the Animex for a period of 60 min after injection of 65 g of norepinephrine into the hypothalamus, showed a significant increase (p<0.005) in comparison with the controls. The increase in motor activity after dopamine (intrahypothalamic) and norepinephrine and dopamine (intrastriatal) was distinctly lower, although there was an initial large increase of motor activity after intrastriatally injected dopamine. Pre-treatment with reserpine or parachlorophenylalanine (intraperitoneal injection) to lower the serotonin level in the brain, followed by intracerebral injection of norepinephrine or dopamine failed to produce fighting or mounting behaviour.     

Behavioural,biochemical and electrophysiological studies on the motor depressant and stimulant effects of bromocriptine

Summary Bromocriptine (BRC) produced a biphasic behavioural effect in mice; an early depressant phase which lasted for about 1 h and a later stimulant phase which lasted from about 1 to 5 h. The stimulation was blocked with SCH23390. Both phases of activity were accompanied by marked striatal DA autoreceptor effects as indicated by reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and by a reduction in the accumulation of DOPA (after inhibition of nigrostriatal DA nerve firing and DOPA decarboxylase). However, while the autoreceptor effects were still evident during the behavioural stimulant phase, there was a gradual rise in DOPAC and HVA from 1 to 4 h after injection, indicating a gradually increasing DA turnover. We were unable, using a variety of behavioural and biochemical paradigms, to demonstrate any change in DA autoreceptor sensitivity after one dose of BRC. In electrophysiological studies, however, it was found that prior exposure of rats to one dose of BRC rendered them subsensitive to the rate-inhibiting effects of a second dose of BRC, as measured in anaesthetized animals using extracellular single cell recordings of identified DA neurons in the substantia nigra pars compacta. It is concluded firstly, that the stimulant phase of BRC in mice occurs despite continued occupation of the DA autoreceptors by BRC because adequate endogenous DA is available to provide the required D1 receptor stimulation and secondly, that the terminal autoreceptors in the striatum (as assessed in mice using biochemical techniques) may be regulated differently to the somatodendritic autoreceptors (as assessed electrophysiologically in rats). Send offprint requests to: D. M. Jackson at the above address     

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP⁺), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP⁺ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 µM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 µM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 µM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.     

Effect of fusaric acid on aggression,motor activity,and brain monoamines in mice

The effects of fusaric acid (FA), a dopamine-β-hydroxylase (DβH) inhibitor, were determined on aggression, motor activity, and brain monoamines at doses of 3.2 to 60 mg/kg following administration of dietary supplements of L-tyrosine or balanced protein to male albino mice. Compared to saline injected control animals, both aggression and motor activity were reduced by the highest doses of FA. Somewhat more reduction in aggression was observed in animals administered dietary supplements of casein compared to those given the tyrosine supplement. Treatment with FA at doses of 30 to 60 mg/kg decreased brain norepinephrine and dopamine, and decreased brain tyrosine in animals fed the tyrosine supplement. In contrast, FA increased 5-hydroxytryptamine, and caused marked increases in 5-hydroxyindoleacetic acid at the highest doses. The data suggest that the neurochemical effects of FA may not be the same in rats and mice.     

双重血浆分子吸附系统治疗百草枯所致肝脏损害的效果观察与护理

目的　探讨双重血浆分子吸附系统（double plasma molecular absorb system,DPMAS）应用在治疗百草枯中毒所致肝脏损害中的效果与护理技术。方法　选取2018年1月至2020年1月间由广州市第十二人民医院急诊科收治的百草枯中毒患者68例,以随机数字表法分为对照组和观察组,各34例。对照组男12例,女22例,年龄（44.26±8.48）岁;观察组男13例,女21例,年龄（45.33±8.26）岁。两组均采取DPMAS治疗,分别采取常规护理及针对性护理,比较护理后两组患者检验指标、治疗效果及并发症发生率。符合正态分布的计量资料以（x±s）表示,组间比较采用独立样本t检验,计数资料以例（%）表示,组间比较采用卡方校验。结果　护理后,两组患者血液中百草枯浓度、总胆红素（TBIL）、总胆汁酸（TBA）、谷丙转氨酶（ALT）、谷草转氨酶（AST）、血氨（NH₃）、白蛋白（Alb）、白细胞介素6（IL-6）均明显小于护理前（均P<0.05）,两组患者各项指标对比,差异均无统计学意义（均P>0.05）。观察组有效率88.2%（30/34）,高于对照组的76.5%（26/34）,但差异无统计学意义（P>0.05）;观察组置管处血肿或出血、肺部感染、低血压、寒战、凝血的总发生率均明显低于对照组（P<0.05）。结论　DPMAS作为人工肝支持系统的一种,应用在百草枯中毒所引起的肝脏损害治疗中,能够有效清除血液中的百草枯及其他毒性物质,改善肝脏功能,在治疗时配合以针对性的护理,能降低并发症的发生,提高治疗的安全性。     

Circling behavior induced by intranigral injections of GABA and muscimol in rats

Circling behavior induced by unilateral intranigral injections of GABA or muscimol was studied in rats. Both GABA (10–400 g) and muscimol (1–100 ng) evoked the same kind of contralateral circling behavior dose-dependently when injected into the substantia nigra. Muscimol was much more potent than GABA and its effect lasted longer. Neither GABA nor muscimol induced any ipsilateral circling. Pretreatment with bicuculline (3 mg/kg IP) significantly attenuated the intensity of circling behavior induced by intranigral injections of GABA or muscimol. Pretreatment with haloperidol (0.5 and 1.0 mg/kg SC) also significantly antagonized the circling behavior induced by GABA and muscimol. Pretreatment with atropine (10 mg/kg IP) significantly increased the intensity of circling behavior induced by intranigral injections of muscimol and tended to increase the intensity of circling behavior induced by intranigral injections of GABA. Pretreatment with strychnine (0.25 mg/kg IP) did not modify circling behavior induced by GABA, but did to some extent increase that induced by muscimol. These results indicate that the contralateral circling behavior induced by intranigral injections of GABA and muscimol seems to be dependent both on the activation of the dopaminergic nigrostriatal system and on the nondopaminergic nigral output system.     

Correlation between lipid peroxidation and morphological manifestation of paraquat-induced lung injury in rats

Biochemical and morphological studies of rat lung were performed to determine the role of lipid peroxidation in the in vivo lung toxicity of paraquat. Two injections of 20 mg/kg paraquat were administered intraperitoneally every other day. While notable epithelial damage in the lungs was observed on the day after the second paraquat injection and progressed through the 5th day, the concentration of lipid peroxides in the rat lungs did not increase by the 3rd day after the injection. The lipid peroxide concentrations increased after the 5th day post-injection, and reached the maximum concentrations on the 7th day, when the damaged alveolar surface had been mostly repaired by regenerative pneumocytes. On the other hand, the delayed increase of lung lipid peroxides in paraquattreated rats paralleled the increased number of macrophages in the lung, which reached maximum numbers on the 7th day. Glutathione peroxidase activity in the lungs also increased with a similar time course. Macrophages from the lungs contained a large amount of engulfed degradation products and cellular debris, and immunohistochemical study showed high glutathione peroxidase content on the 5th and 7th days. These results suggest that lipid peroxidation is a relatively late event in the in vivo paraquat-treated lung and that the delayed increase of lipid peroxides in the lungs occurs from the phagocytic activities of macrophages rather than from toxic cell injury.