Antidepressants in chronic unpredictable mild stress (CUMS)-induced deficit of fighting behavior

Chronic unpredictable stress (CUS) is one of the behavioral models resembling in some respects (loss of normal aggresiveness) human depression. In the present study, consistent with the ethical principles for scientific experiments on animals, we have decided to modify the CUS procedure. In this new modified model named chronic unpredictable mild stress (CUMS), we have introduced mild stressor (14 h period of 45 degrees cage tilt) instead of one severe stressor (20 s exposure to electric footshock). The purpose of the present study was to determine whether this new procedure CUMS, similarly to CUS, affected the footshock-induced fighting behavior. We have also investigated the effect of antidepressant drugs with different pharmacological profiles (imipramine, mianserin, fluoxetine, moclobemide, tianeptine) and anxiolytic drug (oxazepam) on fighting behavior in rats submitted to CUMS. It was found that in rats subjected to CUMS procedure the number of fighting attacks was significantly reduced (by about 80%). Prolonged treatment (once daily, for 14 days) with imipramine (10 mg/kg/day), tianeptine (12.5 mg/kg/day), mianserin (10 mg/kg/day), moclobemide (50 mg/kg/day), fluoxetine (10 mg/kg/day), but not oxazepam (5 mg/kg/day) prevented the deficit in fighting behavior in rats subjected to CUMS. In conclusion, the results of the present study indicate that CUMS, similarly to CUS procedure, induced behavioral deficit in rats which was normalized by antidepressants with a different pharmacological profile.     

N-乙酰半胱氨酸对抑郁模型大鼠行为及神经递质的影响

目的 观察 N-乙酰半胱氨酸（NAC）对抑郁模型大鼠行为、各脑区单胺递质的影响, 探讨 NAC 潜在的抗抑郁作用及机制。 方法 选取成年雄性 SD 大鼠 32 只, 随机分为模型组、氟西汀（FLX）组、NAC 组、对照组, 每组 8 只;前 3 组单笼孤养, 釆用连续 6 周慢性轻度不可预见性应激（CUS）的方法建立慢性抑郁大鼠模型, 并于第 3 周末至第 6 周末对 NAC 组和 FLX 组分别给予 NAC 和 FLX 灌胃, 模型组和对照组给予同体积生理盐水灌胃。 CUS 前、后及干预后以体质量测量、糖水消耗实验、旷场实验对大鼠行为进行评估; 以库仑阵列电化学高效液相色谱法测定各组大鼠前额叶（PFC）、纹状体（ST）、杏仁核（AM）和海马（HIP）单胺神经递质去甲肾上腺素（NE）、5-羟色胺（5-HT）、多巴胺（DA）水平。 结果 （1）干预后对照组、NAC 组、FLX 组较模型组大鼠体质量增加多、糖水消耗量多、水平运动距离长、直立次数多、粪便粒数少（均 P < 0.05）。（2）与对照组相比, 模型组大鼠前额叶、纹状体、杏仁核、海马等脑区单胺神经递质 NE、DA 和 5-HT 水平明显降低（均 P < 0.05）;与模型组相比, NAC 组、FLX 组前额叶、纹状体、杏仁核、海马等 NE、DA、5-HT 浓度显著升高（均 P < 0.05）。 结论 NAC 和 FLX 均可有效改善抑郁模型大鼠的抑郁行为, 并在总体上提高前额叶、纹状体、杏仁核、海马等脑区单胺神经递质的水平。     

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats.

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.     

Effect of long-term caffeine administration on depressive-like behavior in rats exposed to chronic unpredictable stress

Chronic unpredictable stress (CUS) was used to study the effects of a long-term treatment with either caffeine (8 mg/kg, orally) or desipramine (DMI) (10 mg/kg, intraperitoneally) in Wistar rats. The CUS procedure was applied for 6 weeks. Animals underwent a 2-week drug-free CUS procedure. Drugs were administered for 4 weeks alongside the stress and both drug and stress were continued throughout the behavioral testing period. CUS-exposed rats showed depressive-like behavior with reduced weight gain, reduced consumption of sucrose solution, increased immobility in the forced swimming test, and hypolocomotion in an open field. For the open field and elevated plus maze, calculation of an anxiety index confirmed that CUS increased anxiety, which was accompanied by an increase in the core temperature. DMI counteracted these physical and behavioral changes. Caffeine caused similar effects to DMI on weight gain, motor activity, anxiety level, and core temperature. In CUS-exposed rats, caffeine showed antidepressant and anxiolytic activity, accompanied by increased hippocampal dopamine and serotonin levels. However, no significant change in weight gain or core temperature was observed after caffeine treatment in CUS-exposed rats. These results suggest that, similar to the antidepressant DMI, long-term caffeine exposure exerts an antidepressant and anxiolytic effect in the CUS model. The involvement of the dopaminergic and serotonergic systems is discussed.     

Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment

RATIONALE: Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning. MATERIALS AND METHODS: Mice (C57BL/6) were exposed to CMS for 6 weeks and anhedonia was evaluated by weekly monitoring of sucrose intake. Paroxetine (10 mg kg(-1)day(-1) i.p.) or saline were administered the last 3 weeks of CMS and continued for 2 weeks thereafter. Behavioral tests were performed over the last week of CMS (acute effects) and 1 month later (long-term effects). RESULTS: Mice exposed to CMS displayed both acute and long-term decreased sucrose intake, increased immobility in the forced swimming test (FST) and impaired memory in the novel object recognition test. It is interesting to note that a correlation was found between the cognitive deficits and the helpless behavior in the FST induced by CMS. During the CMS procedure, paroxetine treatment reverted partially recognition memory impairment but failed to prevent the increased immobility in the FST. Moreover, it decreased on its own sucrose intake. Importantly, the long-term effects of CMS were partially prevented by chronic paroxetine. CONCLUSIONS: CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.     

Reduction of submissive behavior in rats: a test for antidepressant drug activity.

Randomly paired rats were food deprived overnight and placed in an apparatus compelling them to compete for a food reward. About half of these pairs developed a dominant-submissive relationship measured as a significant difference in time spent on the feeder by each rat. This relationship developed over a 2-week period and remained stable for at least the next 5 weeks. Treatment of the submissive subjects, for at least 2 weeks, with imipramine, desipramine, or fluoxetine (10 mg/kg) significantly reduced submissive behavior. The effect faded after cessation of treatment with desipramine. Fluoxetine was further tested at 2.5- and 5-mg/kg doses and showed a dose-dependent reduction of submissive behavior. Treatment of submissive rats with the anxiolytic diazepam (1 mg/kg) was ineffective. The prevalence of dominant-submissive relationships and the effect of desipramine and imipramine on submissive behavior were gender independent. The predictive, face, and construct validity of the behavioral test is discussed.     

慢性不可预知应激诱导的抑郁大鼠血清中神经递质含量的动态变化

目的观察慢性不可预知应激(CUS)并配合孤养诱导模型大鼠抑郁样行为过程中神经递质水平的变化,探讨神经递质作为诊断抑郁症的客观、可量化标志物的可能性。方法 利用CUS并配合孤养模型建立抑郁大鼠动物模型,以体质量、糖水偏爱率和旷场实验(穿格数和直立次数等)结果评定大鼠行为学的动态变化;采用高效液相-荧光法(HPLC-FD)测定血清中5-羟色胺(5-HT)、去甲肾上腺素(NE)、肾上腺素(E)、多巴胺(DA)、左旋多巴(L-DOPA)、5-羟基吲哚乙酸(5-HIAA)、高香草酸(HVA)、3,4-二羟基苯乙酸(DOPAC)、酪氨酸(Tyr)和色氨酸(Trp)等10种神经递质的含量;应用SPSS软件对体质量、糖水偏爱率和旷场数据等行为结果进行主成分分析,并采用回归分析方法分析行为学与神经递质变化间的相关性。结果 ①与正常对照组相比,造模期间第14天,模型组直立次数显著降低(P<0.05);造模期间第22天,模型组体质量、糖水偏爱率、穿格数和直立次数均显著降低(P<0.05)。②与正常对照组相比,造模期间第6天,模型组Tyr和5-HIAA的含量显著降低(P<0.05);造模期间第9天,NE的含量显著降低(P<0.05);造模期间第22天,NE和5-HT的含量显著降低(P<0.05);造模期间第15和22天,NE,5-HIAA,HVA和5-HT的含量显著降低(P<0.05)。③NE,HVA和5-HT的变化趋势为降低的程度逐渐增大,与行为学结果变化趋势接近;而Tyr的变化趋势为先升后降,5-HIAA,L-DOPA,DA,DOPAC,Trp和E呈波动性变化。主成分分析结果显示,第一主成分可代表93.47%的信息,结果可靠;相关性分析结果表明,5-HT,NE和HVA与第一主成分的相关性好。结论 血清中神经递质在CUS诱导抑郁样行为过程中呈动态变化,其中NE,5-HT和HVA的变化可以在一定程度上反映大鼠的抑郁状态和程度,可作为诊断抑郁症的临床辅助指标。     

L-NAME prevents anxiety-like and depression-like behavior in rats exposed to restraint stress

Stressful life events contribute to the development of many neuropsychiatric disorders including depression and anxiety. Animal studies based on the relationship of stress and depression or anxiety are scarce and controversial. Moreover, neither the neurobiological basis of anxiety and depression nor the mechanisms responsible for neurochemical regulation by stressful stimuli are well understood. This study was designed to investigate the possible contribution of both acute (2 h) and chronic (2 h X 15 d) restraint stress in the generation of anxiety and depression, and also to find out whether nitric oxide (NO) has a modulatory role in these behavioral reactions. Elevated plus-maze and forced swimming test (FST) were chosen for assessment of anxiety and depression, respectively, and N(G)-nitro L-arginine methyl ester (L-NAME, 10 mg/kg), a NO synthase (NOS) inhibitor, and L-arginine (50 mg/kg), a NO precursor, were used to evaluate the role of nitrergic system in restraint exposed rats. The results showed that acute and chronic stress caused depression-like and anxiety-like behaviors in rats and the acute inhibition of NOS by L-NAME prevented these acute and chronic stress-induced anxiogenesis and depression. These data lead to the conclusion that stress and NO seem to be involved in the generation of anxiety and depression.     

Chronic antidepressant drug regimes and food and water intake in rats

Food and water consumption were measured in rats prior to and during a course of antidepressant drug administration. Desmethylimipramine (DMI, 10 mg/kg/day), clorgyline (1.0 mg/kg/day) or saline were injected IP for 30 days. Food and water intake in the DMI- and clorgyline-treated rats was initially and significantly decreased but progressively returned towards pretreatment levels over the course of the drug administration. The effects of these antidepressant drug treatments on food and water intake appeared to consist of two components: (a) a rapid suppressive effect, possibly associated with an acute central action of these drugs (and perhaps a slight initial stress effect related to the drug administration) and (b) an adaptive effect over the course of the treatment which may involve changes in monoaminergic neurotransmitters or receptor status in those brain regions associated with feeding behavior. The similarities of the results of these treatments and those seen with chronic stress are discussed.     

Effects on drug disposition, brain monoamines and behavior after chronic treatment with the antidepressant venlafaxine in rats with experimental hepatic encephalopathy.

Patients with chronic hepatic encephalopathy (HE) may present affective symptoms and antidepressant drug treatment in this condition is not uncommon. The present microdialysis study investigated treatment with the chronic antidepressant venlafaxine (VEN) in experimental HE with regard to tentative changes in pharmacokinetic and/or pharmacodynamic parameters. Three weeks after portacaval shunt (PCS) or sham operation in rats, VEN (10 mg/kg daily) was administered by implanted osmotic minipumps. VEN treatment for 14 days resulted in higher concentrations of VEN in PCS rats than in sham controls in serum and brain compartments, and the VEN levels in serum and brain were strongly inter-correlated. The serum N-desmethylvenlafaxine concentration did not differ between the groups, but correlated with the serum VEN levels. The other VEN metabolites were below the quantification limits. VEN treatment for 9-12 days significantly stimulated locomotion and rearing in the open field in sham controls, but failed to do so in the PCS rats. The concentrations of noradrenaline, dopamine, 5-HT, and 5-HIAA in neocortical dialysates were higher in PCS than in sham rats after 14 days of VEN treatment, but the elevations reached statistical significance only in the case of dopamine and 5-HIAA. In summary, there were significant pharmacokinetic and pharmacodynamic alterations in rats with experimental HE as compared to controls. The described experimental HE model may be useful for continued pharmacokinetic/pharmacodynamic interaction studies to unravel the pathophysiological consequences of HE on the CNS.     

Adriamycin-related anxiety-like behavior, brain oxidative stress and myelotoxicity in male Wistar rats

Chemotherapeutic regimens have been indicated to negatively impact the quality of life for patients. Adriamycin (ADR) is an effective chemotherapeutic agent widely employed for the treatment of human's malignancies; however, it may cause serious side effects. The present study was aimed at investigating the effects of acute administration of ADR on cognitive alterations, brain oxidative status and immune dysregulation in male Wistar rats. Treated animals received a single intraperitoneal injection of ADR (7 mg/kg). Control ones received physiological saline only. Behavioral effects were tested in the elevated plus-maze and the open field which showed that drug-treated rats displayed anxious behavior and deteriorations in the locomotive and exploratory activities over the 72 h following ADR injection as compared to controls. Assessment of brain antioxidant capacity in ADR-injected animals revealed an increase in glutathione-S-transferase activities and malondialdehyde levels while a decrease in glutathione concentrations when compared with the vehicle-treated group. Our results indicated that ADR administration decreased total leukocyte, lymphocyte and granulocyte counts, while enhanced monocyte levels. Moreover, white blood cells (WBC) relative counts in ADR-treated rats showed a significant increase in monocytes and granulocytes and a decrease in lymphocytes as compared to controls. This study suggests that ADR-related cognitive impairments are associated with brain oxidative stress and myelosuppression.     

Social stress-induced hypothyroidism is attenuated by antidepressant treatment in rats

Although serotonergic system has been classically implicated in mood modulation, there has been relatively little study on the relationship between this system and thyroid hormones (TH) economy in stress models. When TH are studied, the effects of stress on thyroid function seems to be complex and depend on the kind and time of stress which counts for the elusiveness of mechanisms underlying changes in TH economy. Herein, we hypothesized that serum TH are affected in a time-dependent fashion after repeated social stressful stimuli and serotonergic system is implicated in these changes. Therefore, we aimed to investigate the possible alterations in thyroid hormone economy and type 1 (D1) and type 2 (D2) deiodinase activity in a model of social defeat stress. Thereafter, we tested the responsiveness of these changes to fluoxetine treatment. Both short (STS) and a long-term (LTS) stress were performed. Blood samples were drawn just before and 1 (STS) or 4 and 8 weeks (LTS) after the beginning of stress to assess serum T4, T3 and corticosterone. Deiodinases activity was assessed at the end of each protocol. Stress-induced behavior studied in open field arena and hypercorticosteronemia were mainly observed in LTS (week 4). Stress-induced behavior was associated to hypothyroidism which occurred before, since week 1 in stressed group. Serum TH was restored to control levels in week 8, when behavior changes were not observed anymore, and was mainly associated with high brown adipose tissue D2 activity since thyroid and liver D1 activity were low or normal in the STS and LTS respectively in stressed rats compared to control. Antidepressant study revealed that fluoxetine treatment (10mg/kg po during four weeks) fully reversed stress-induced behavior and normalized serum T4, but not T3 levels and hypercorticosteronemia in stressed group compared to control. The current work adds new concepts concerning TH metabolism changes induced by social stress and suggests that serotonergic system impairment may take part in the key events which ultimately lead to hypothyroxinemia and behavioral changes induced by chronic social defeat. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Hippocampal CLOCK protein participates in the persistence of depressive-like behavior induced by chronic unpredictable stress

Rationale

Circadian disturbances are strongly linked with major depression. The circadian proteins CLOCK and BMAL1 are abundantly expressed but function differently in the suprachiasmatic nucleus (SCN) and hippocampus. However, their roles in depressive-like behavior are still poorly understood.

Objectives

To investigate the alterations of CLOCK and BMAL1 in the SCN and hippocampus in rats subjected to chronic unpredictable stress (CUS) and to explore the relationship of circadian protein and the depressive-like behavior.

Results

Together with depressive-like behavior induced by CUS, CLOCK and BMAL1 in the SC were inhibited during the light period, and the peak expression of CLOCK in the hippocampus was shifted from the dark to light period. BMAL1 expression in the hippocampus was not significantly changed. Two weeks after the termination of CUS, abnormalities of CLOCK in the CA1 and CA3 endured, with unchanged depressive-like behavior, but the expression of CLOCK and BMAL1 in the SCN recovered to control levels. Knockdown of the Clock gene in CA1 induced depressive-like behavior in normal rats. CLOCK in the SCN and hippocampus may participate in the development of depressive-like behavior. However, CLOCK in the hippocampus but not SCN was involved in the long-lasting effects of CUS on depressive-like behavior. BMAL1 in the hippocampus appeared to be unrelated to the effects of CUS on depressive-like behavior.

Conclusion

CLOCK protein in the hippocampus but not SCN play an important role in the long-lasting depressive-like behavior induced by CUS. These findings suggest a novel therapeutic target in the development of new antidepressants focusing on the regulation of circadian rhythm.     

Chronic unpredictable stress, but not chronic predictable stress, enhances the sensitivity to the behavioral effects of cocaine in rats

RATIONALE: Chronic unpredictable stress, in which the type and timing of stress exposures are varied, alters protein levels in the mesolimbic DA system in a manner previously shown to be associated with enhanced behavioral responsiveness to cocaine. Chronic exposure to the same or predictable stress (restraint) does not. Thus, we examined the effects of chronic unpredictable and chronic predictable (restraint) stress on the locomotor activating and place conditioning effects to low cocaine doses. OBJECTIVE: To test whether chronic unpredictable stress enhances the sensitivity to the behavioral effects of cocaine. METHODS: Rats were exposed to 10 days of chronic unpredictable stress, of chronic predictable (restraint) stress, or were not stressed. One day following cessation of stress exposure, locomotor activity to cocaine (0 or 7.5 mg/kg) was assessed for 4 consecutive days and corticosterone levels on the last day were determined. In other experiments, the effects of the chronic stress procedures on cocaine (0.5 and 7.5 mg/kg) place conditioning using an unbiased procedure were assessed. RESULTS: Chronic unpredictable, but not chronic predictable, stress transiently increased the locomotor activating effects of cocaine and this was correlated positively with corticosterone levels. Chronic unpredictable, but not chronic predictable, stress also enhanced the place conditioning effects of cocaine: increased place preference was seen with the low dose and a pronounced place aversion occurred with the high dose. CONCLUSIONS: These data demonstrate that chronic unpredictable stress enhances the behavioral effects of cocaine, including its aversive effects, whereas chronic predictable stress (restraint) is without effect.     

Intermittent morphine administration induces dependence and is a chronic stressor in rats.

Although constant treatment with morphine (implanted pellets) does not activate the hypothalamic-pituitary-adrenal (HPA) axis, intermittent injections of morphine may constitute a chronic stressor in rats. To test this hypothesis, we compared the effects of morphine in escalating doses (10-40 mg/kg, s.c.) or saline injected twice daily for 4 days on energy balance, hormones, HPA responses to novel restraint and central corticotropin-releasing factor (CRF) mRNA 12 h and 8 days after the last morphine injection in adult male Sprague-Dawley rats. Weight gain stopped at the onset of morphine, weight loss was marked 36 h postmorphine; thereafter, body weight gain paralleled saline controls. At 12 h, insulin, leptin, and testosterone concentrations were reduced but normalized by 8 days. Restraint and tail nicks caused facilitated ACTH responses at 12 h, under-responsiveness at 8 days. CRF mRNA, measured only at 12 h, was increased in the paraventricular (PVN) and Barrington's nuclei (BAR), decreased in the bed nuclei of the stria terminalis (BNST) and unchanged in the amygdala (CeA) in morphine-treated rats. After stress, CRF mRNA increased in PVN in both groups, increased in BAR and decreased in BNST in saline but not morphine groups, and was unchanged in CeA in both groups. Results from all variables characterize intermittent morphine injections as a chronic stressor. In contrast to constant treatment, injected morphine probably allows some withdrawal during each 12 h interval, causing repeated stress. Drug addicts treat themselves intermittently, and stress causes relapse after withdrawal. Thus, intermittent morphine, itself, may promote relapse.     

Increases in anxiety-like behavior induced by acute stress are reversed by ethanol in adolescent but not adult rats

Repeated exposure to stressors has been found to increase anxiety-like behavior in laboratory rodents, with the social anxiety induced by repeated restraint being extremely sensitive to anxiolytic effects of ethanol in both adolescent and adult rats. No studies, however, have compared social anxiogenic effects of acute stress or the capacity of ethanol to reverse this anxiety in adolescent and adult animals. Therefore, the present study was designed to investigate whether adolescent [postnatal day (P35)] Sprague-Dawley rats differ from their adult counterparts (P70) in the impact of acute restraint stress on social anxiety and in their sensitivity to the social anxiolytic effects of ethanol. Animals were restrained for 90 min, followed by examination of stress- and ethanol-induced (0, 0.25, 0.5, 0.75, and 1 g/kg) alterations in social behavior using a modified social interaction test in a familiar environment. Acute restraint stress increased anxiety, as indexed by reduced levels of social investigation at both ages, and decreased social preference among adolescents. These increases in anxiety were dramatically reversed among adolescents by acute ethanol. No anxiolytic-like effects of ethanol emerged following restraint stress in adults. The social suppression seen in response to higher doses of ethanol was reversed by restraint stress in animals of both ages. To the extent that these data are applicable to humans, the results of the present study provide some experimental evidence that stressful life events may increase the attractiveness of alcohol as an anxiolytic agent for adolescents.     

Effect of trimethylgallic acid esters against chronic stress-induced anxiety-like behavior and oxidative stress in mice

BackgroundMany studies have shown that the levels of oxidative stress (increased lipid peroxidation, decreased glutathione levels and endogenous antioxidant enzyme activities) and proinflammatory cytokines (e.g., TNF-α) are increased in patients with chronic fatigue syndrome. Gallic acid and other phenolic compounds are potent antioxidants and inhibitor of cytokine production. The present study was designed to investigate the effect of newly synthesized conjugated esters of trimethylgallic acid in an experimental model of chronic stress.MethodsThe animals were forced to swim individually for a period of 6 min every day for 15 days to induce chronic stress. The locomotor activity, anxiety-like behavior, and memory retention were evaluated in chronically stressed animals, followed by biochemical estimations and neuroinflammatory surge in the brain.ResultsChronic treatment with trimethylgallic acid esters for 15 days significantly reversed the chronic stress-induced behavioral (impaired locomotor activity, anxiety-like behavior, and decreased percentage of memory retention), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-α) in stressed mice.ConclusionsThe study revealed that trimethylgallic acid esters could ameliorate chronic stress-induced various behavioral and biochemical alterations in mice, showing protective effects against chronic stress.     

Reduced peripheral presynaptic adrenoceptor sensitivity following chronic antidepressant treatment in rats.

In view of the recent M1 and M2 subclassification of muscarinic receptors and the suggestion of separate populations of muscarinic receptors on oxyntic and histamine cells in the gastric mucosa, we have analysed the effects of McN-A 343, classified as an M1-selective agonist, on gastric acid secretion by the mouse, isolated, lumen-perfused stomach assay. Acid secretion stimulated by McN-A 343 was not inhibited by tetrodotoxin pretreatment, although it was competitively antagonized by atropine (pKB 7.90), suggesting a muscarinic site of action between postganglionic neurones and the final secretory event. Acid secretion stimulated by McN-A 343 was more sensitive than 5-methylfurmethide-stimulated secretion to H2-receptor blockade: the profile of inhibition was consistent with expectations for a model of indirect agonism, suggesting that McN-A 343 preferentially stimulated the release of endogenous histamine from mucosal histamine cells. In view of this selective action the McN-A 343-pirenzepine interaction was studied, the latter being classified as an M1-selective antagonist. Results were consistent with expectations for a competitive interaction but the pKB (6.69) was not significantly different from the value obtained at the oxyntic cell, using 5-methylfurmethide as agonist in the presence of H2-receptor blockade, in a previous study. We suggest that there is no need to postulate differences in oxyntic and histamine cell muscarinic receptors to account for the selective stimulant activity of McN-A 343 observed in this study and the relatively selective inhibition of gastric acid secretion by pirenzepine in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic antidepressant and clonidine treatment effects on conflict behavior in the rat

The present studies examined the effects of chronic treatment with several antidepressants and clonidine on conflict behavior. In daily ten-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25 or 0.5 mA). Electrification was signalled by a tone. Chronic desipramine (5 mg/kg, IP, b.i.d.) or clonidine (40 micrograms/kg, b.i.d.) treatment resulted in time-dependent anticonflict effects, with a latency to onset of approximately 3-4 weeks. In contrast, chronic buproprion (up to 10 mg/kg, IP, b.i.d.), mianserin (up to 10 mg/kg, IP, b.i.d.) or trazodone (up to 40 mg/kg, IP, b.i.d.) treatment resulted in at best only a weak anticonflict effect. The efficacy of these antidepressants and clonidine to increase punished responding when administered chronically correlates well with their efficacy as antipanic agents in man.