Serotonin neurons and aversive conditioning in the rat

The acute and long-term effects of p -chloroamphetamine (PCA) on one-way and two-way active avoidance (AA), passive avoidance (PA) learning, fear retention (FR) and on central monoamine concentrations were examined in the male rat. Acute PCA administration (0.63–5 mg/kg i.p.), which releases presynaptic 5-HT, produced a dose-related impairment of both one-and two-way AA acquisition, AA retention, PA and fear retention. The selective serotonin (5-HT) uptake inhibitor zimelidine, but not the noradrenaline (NA) uptake inhibitor desipramine, blocked the avoidance deficit induced by acute PCA. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2 × 10 mg/kg i.p.) failed to change AA and PA learning but blocked the avoidance deficit induced by acute PCA. Degeneration of locus coeruleus NA neurones with DSP4 (1 × 50 mg/kg), a selective NA neurotoxin, failed to block the acute PCA action. Thus, the acute avoidance learning impairment appears to be specifically related to the acute release of endogenous 5-HT. Both acute and long-term PCA treatment affected 5-HT neurones preferentially in the forebrain while marginal effects were observed in the midbrain and spinal cord. A marked impairment in the retention and retrieval of fear conditioning in the rat was also observed following acute PCA administration. The serotoninergic mechanisms underlying the retrieval deficit were found to be similar but not identical to those involved in AA acquisition. These results suggest an important role for central 5-HT neurones in aversive learning processes. The possible involvement of 5-HT neurones in learning, memorial and/or retrieval processes is discussed.     

Serotonin neurons and aversive conditioning in the rat

The acute and long-term effects of p-chloroamphetamine (PCA) on one-way and two-way active avoidance (AA), passive avoidance (PA) learning, fear retention (FR) and on central monoamine concentrations were examined in the male rat. Acute PCA administration (0.63–5 mg/kg i.p.), which releases presynaptic 5-HT, produced a dose-related impairment of both one-and two-way AA acquisition, AA retention, PA and fear retention. The selective serotonin (5-HT) uptake inhibitor zimelidine, but not the noradrenaline (NA) uptake inhibitor desipramine, blocked the avoidance deficit induced by acute PCA. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2 × 10 mg/kg i.p.) failed to change AA and PA learning but blocked the avoidance deficit induced by acute PCA. Degeneration of locus coeruleus NA neurones with DSP4 (1 × 50 mg/kg), a selective NA neurotoxin, failed to block the acute PCA action. Thus, the acute avoidance learning impairment appears to be specifically related to the acute release of endogenous 5-HT. Both acute and long-term PCA treatment affected 5-HT neurones preferentially in the forebrain while marginal effects were observed in the midbrain and spinal cord. A marked impairment in the retention and retrieval of fear conditioning in the rat was also observed following acute PCA administration. The serotoninergic mechanisms underlying the retrieval deficit were found to be similar but not identical to those involved in AA acquisition. These results suggest an important role for central 5-HT neurones in aversive learning processes. The possible involvement of 5-HT neurones in learning, memorial and/or retrieval processes is discussed.     

Combined effect of early life stress and acute stress on colonic sensory and motor responses through serotonin pathways: differences between proximal and distal colon in rats

Clinically, adults who have experienced stresses in childhood present with episodes of serious symptoms of irritable bowel syndrome that are associated with acute stress, but the mechanism is not well understood. This study aimed to investigate the colonic sensory/motor responses to acute water avoidance stress (WAS) in male adult rats subjected to neonatal maternal separation (NMS), and the underlying mechanism of sensory/motor responses. Effects of the combined acute and early life stress on visceral sensation, colonic motility, and the tissue and luminal content of serotonin (5-hydroxytryptamine, 5-HT) in the proximal and distal colon were evaluated using the abdominal withdrawal reflex test, faecal pellet output measurement and capillary electrophoresis analysis, respectively. Results showed that WAS significantly increased not only visceral sensitivity but also colonic motility in NMS rats compared to the normal rats. These alterations were accompanied by significant increase in 5-HT content in the proximal but not the distal colonic tissues; these alterations were also associated with increased density of enterochromaffin (EC) cells in the proximal segment. In contrast, the faecal content of 5-HT increased similarly in both segments. Consecutive administration of parachlorophenylalanine to NMS rats was more potent at 500 mg kg?1 day?1 than at 150 mg kg?1 day?1 in suppressing colonic sensory/motor responses to WAS, corresponding to the greater reduction of the tissue and faecal content of 5-HT and of EC cell density in the colon. These data indicate that combined early life stress and acute stress effectively induce visceral hyperalgesia and motility disorder through 5-HT pathways in the colon of rats, and the proximal and distal colon have different responses towards the combined stressors.     

Attenuation of 8-OH-DPAT-induced decreases in 5-Ht synthesis in brain regions of rats adapted to a repeated stress schedule

Previously it has been shown that single episode of 2 h restraint produced behavioral deficits in rats which were not observed following daily restraint period of 2h/day for 5 days. It was suggested that adaptation to a stress schedule develops when the similar stress is administered repeatedly. In view of a role of 5-hydroxytryptamine (5-HT) in adaptation to stress the present study concerns effects of a 5-HT-1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on the synthesis of 5-HT in brain regions of rats adapted to a repeated restraint stress schedule of 2h/day for 5 days. The drug injected systemically at a dose of 1 mg/kg decreased 5-HT synthesis in the hypothalamus, cortex, hippocampus, striatum and raphe regions of previously unrestrained rats. These decreases were either smaller (raphe) or not observed (hypothalamus, cortex and hippocampus) in most brain regions of rats adapted to the repeated restraint stress schedule of 2h/day for 5 days. These results suggest that a subsensitive negative feedback effect on the synthesis of 5-HT leading to an increase in synaptic 5-HT concentration might help coping with stress demand to produce adaptation to stress.     

Differential effects of a 5-HT2 receptor blocker on alcohol intake in rats selectively bred for high and low catecholamine responses to stress

The effect of the selective 5-HT2 receptor blocker ritanserin on alcohol consumption was investigated in two strains of rats selectively bred for high and low catecholamine responses to stress. Rats were forced to drink a 5% alcohol solution for 10 days. For the subsequent six days, animals were injected subcutaneously with 2.5 mg/kg/2 ml ritanserin or vehicle only, and both a 5% solution of alcohol and water were presented to the animals. Ritanserin affected neither water nor total fluid intake. Furthermore, no effect of ritanserin on alcohol consumption could be demonstrated in high-responding rats, whereas in low-responding rats a very pronounced ritanserin-induced reduction in alcohol intake was observed. Results are discussed in terms of mediating effects of serotonergic neurons on mesolimbic dopaminergic reward systems related to drug addiction.     

Ritanserin and voluntary alcohol intake in rats

In a previous study (Rammsayer & Vogel, 1991), rats selectively bred for high and low catecholamine responses to stress showed a selective response to the 5-HT2 receptor blocker ritanserin. However, it remained unclear whether selective breeding resulted in a decrease in 5-HT responsivity, as suggested by the lack of an effect in high stress responding rats, or in an increase in 5-HT responsivity, as suggested by ritanserin-induced reduction in alcohol intake in low-responding rats. To answer this question, nonselectively bred rats were forced to drink a 5% alcohol solution for 10 days. For the subsequent six days, animals were injected subcutaneously with 2.5 mg/kg/2 ml ritanserin or vehicle only, and both a 5% solution of alcohol and water were presented to the animals. Ritanserin neither affected alcohol nor total fluid intake suggesting that in the general population of N/NIH (Hansen) rats as well as in rats of the same strain selectively bred for high catecholamine responses, mesolimbic dopaminergic activity is not effectively modulated by specific blockade of 5-HT2 receptors. However, a very pronounced ritanserin induced difference in daily water intake between nonbred male and female rats became evident.     

Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms

The present study adopts an ethoexperimental approach to examine the deportment subsequent to alteration in serotonin (5-HT) neurotransmission following treatment with site-specific neuropharmacological probes. The impact of perturbation in (5-HT) neurotransmission on baseline behavior was analyzed employing three animal models of anxiety, i.e., hole-board, elevated plus maze, and bright/dark arena. Inbred male rats (Wistar strain, weighing between 150 and 200 g) were used in this study. The vivarium and the behavioral laboratory were specially designed to permit operation of reversed light-dark cycle and all experiments were performed during the dark period. Pharmacological tools selected to influence 5-HT levels include (1) a combination of tranylcypromine and tryptophan (TCP + TRYPT) (0.75 mg/kg + 40 mg/kg) which augments 5-HT biosynthesis; (2) p-chlorophenylalanine (PCPA: 200 mg/kg), an inhibitor of 5-HT biosynthesis; and (3) 5-HT reuptake blockers, namely zimelidine (ZIM) (40 mg/kg) and fluoxetine (FLU) (10 mg/kg). Rats under the influence of PCPA exhibited anxiolytic response, whereas those under treatments to raise 5-HT levels, viz., TCP + TRYPT, ZIM and FLU, displayed anxiogenic-like reactions. Several other agents known to specifically interact with 5-HT receptor subtypes were also tested. 5-HT2 receptor stimulants, such as quipazine (5 mg/kg) and MK 212 (0.5 mg/kg), were found to be anxiogenic. Buspirone (2 mg/kg), a 5-HT1 agonist, surmounted normal behavioral inhibition. However, another 5-HT1 stimulant, 8-OH-DPAT (0.025 mg/kg), had anxiogenic action. Pretreatment with 5-HT3 antagonists [zacopride (2 mg/kg) and GR 38032F (0.1 mg/kg)] and putative 5-HT1 antagonist [propranolol (10 mg/kg)] resulted in borderline disinhibition of normal behavioral inhibition to novel environments. In contrast, cyproheptadine (0.5 mg/kg), a 5-HT2 antagonist, provoked anxiogenic-like behavior. Altogether, uniform results were obtained for each probe in all the three models, suggesting that the battery of anxiety tests chosen in this study is reliable and sensitive to detect unknown pharmacological responses. The results support the hypothesis that stimulation of serotonergic neurotransmission heightens normal anxiety, whereas its blockade releases normal behavioral inhibition. Furthermore, this work establishes the validity of using the three paradigms in evaluating the involvement of multiple neurotransmitter receptors in the control of behavior of rodents under natural circumstances and also detects any aberration following exposure to novelty and stress.     

Active and passive avoidance following the administration of systemic DSP4, xylamine, or p-chloroamphetamine

Groups of rats were administered either DSP4 (50 mg/kg, ip), xylamine (50 mg/kg, ip), or p-chloroamphetamine (2 X 10 mg/kg, ip), either 2 weeks or 1 week before the testing of two-way active avoidance. DSP4 and xylamine, the selective noradrenaline (NA) neurotoxins, caused a two-way avoidance impairment but p-chloroamphetamine, the selective 5-hydroxytryptamine (5-HT) neurotoxin, did not do so. Pretreatment with desipramine (20 mg/kg, ip) blocked the avoidance impairment caused by DSP4 and xylamine treatment. Neither DSP4 nor xylamine caused any alteration of passive avoidance retention. The biochemical analyses indicated severe NA, but not 5-HT, depletions in the DSP4 and xylamine conditions and drastic 5-HT, but not NA, depletions in the p-chloroamphetamine conditions. These results confirm and extend earlier findings concerning the role of NA in avoidance behavior.     

Influence of housing on the consequences of chronic mild stress in female rats

The chronic mild stress (CMS) paradigm was developed to model anhedonia in animals. The repeated administration of a series of unpredictable, mild stressors attempts to mimic the daily stress associated with the onset of clinical depression in humans. Male animals are predominantly used in these investigations despite significant, well-documented sex differences in human depression. In this study, the CMS procedure was modified to be more ecologically relevant to female animals. The effects of stress on sucrose preference, social interaction, rate of weight gain, and regularity of the estrous cycle in female Sprague-Dawley (SD) rats were evaluated in both single- and paired-housed rats, during 3 weeks each of baseline, CMS, and post-CMS phases. The results indicate that only single-housed rats exposed to stressors have a reduced rate of weight gain, significantly attenuated sucrose preference levels, and increased social interaction scores during the CMS phase of the study. Housing condition more than exposure to stress appeared to contribute to the disruption of estrous cycling in some animals. These data suggest that housing affords some protection from the negative consequences of CMS, at least in female rats, and that lack of social interaction in the single-housing condition may render females more vulnerable to stress-related illnesses. The development of paradigms that model human depression should emphasize sex-specific differences.     

Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT(4) receptor agonist, into the nucleus basalis magnocellularis of the rat

The serotonin 5-HT4 subtype receptor is predominantly localized into anatomical structures linked to memory and cognition. A few experimental studies report that the acute systemic administration of selective 5-HT4 agonists has ameliorative effects on memory performance, and that these effects are reversed by contemporary administration of 5-HT4 receptor antagonists. To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area. The intra-NBM administration of RS67333 enhances the acquisition (200-500 ng/0.5 microL) and the consolidation (40-200 ng/0.5 microL) of the place recognition memory. These effects are reversed by pretreatment with the selective 5-HT4 receptor antagonist RS39604 (300 ng/0.5 microL). Conversely, the recall of memory is not affected by the 5-HT4 agonist. Our results indicate that 5-HT4 receptors located within the NBM may play a role in spatial memory and that the procognitive effect of RS67333 is due, at least in part, to the potentiation of the activity of cholinergic NBM-cortical pathways.     

Novel effect of chronic corticosterone treatment on escape behavior in rats

Chronic administration of corticosterone in rats (4-35 mg/kg/day) produces a marked dose-dependent increase in the frequency of escape behavior observed when animals are held by the tail on a flat surface. The effect is fully developed after 3 days treatment. It is not the result of an increase in spontaneous motor activity since the hormone tends to reduce the latter behavior. Adrenalectomy decreases the escape behavior and tends to do so to a greater degree in rats subjected to chronic stress (restraint) than in nonstressed controls. The results suggest that endogenous corticosterone serves to maintain the above escape behavior during chronic stress.     

Strain and gender specific effects in the forced swim test: effects of previous stress exposure

The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.     

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2?h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, na?ve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33?mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.     

Acute alcohol intoxication paired with appetitive reinforcement: effects upon ethanol intake in infant rats

A recent study suggested that infant rats process alcohol odor and/or taste during acute ethanol intoxication probably due to ethanol elimination via respiration and salivation. The present set of experiments was meant to analyze the possibility that this orosensory processing may act as a conditioned stimulus when an appetitive reinforcer is paired with the state of intoxication. In the first experiment it was observed that intragastric administration of a mildly intoxicating ethanol dose (1.5 g/kg), paired during postabsorptive time intervals with oral infusion of sucrose, was sufficient to promote a significant preference to ethanol. In Experiment 2 different doses of ethanol were either paired or explicitly unpaired with sucrose administration. The result reported in Experiment 1 was replicated and it was observed that a higher dose (3.0 g/kg) unpaired with the reinforcer resulted in alcohol aversions in terms of alcohol consumption patterns. However, when the reinforcer was paired with this dose, the aversion was inhibited. Finally, in the third experiment results indicated that preexposure to alcohol odor eliminates sucrose-conditioned alcohol preferences. These results indicate that, in physiologically immature rats, alcohol preference can be regulated by prior associative experiences involving the state of intoxication and consequences internal and/or inherent to this state.     

N-Methyl-D-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine

The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra-VTA administration of N-methyl-d-aspartate (NMDA) receptor agents on nicotine's effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 microg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.     

慢性应激诱导的抑郁大鼠纹状体par-4基因的表达

为研究慢性温和应激诱导的抑郁大鼠纹状体内前列腺凋亡反应蛋白(prostate apoptosis response-4, par-4)的表达, 及甲基化是否参与par-4基因表达的调控, 将10周龄大鼠随机分为实验组和对照组, 实验组接受慢性温和应激, 对照组不接受实验性处理。于大鼠13周龄时, 采用强迫游泳、糖水偏爱测验测定大鼠的抑郁水平, 以实时定量PCR检测纹状体par-4及多巴胺D2受体(Dopamine receptor D2, DRD2) mRNA表达水平, 免疫印迹法检测纹状体par-4蛋白质表达水平, 用亚硫酸盐测序法检测par-4基因启动子区甲基化水平。结果发现, 与对照组大鼠相比, 实验组大鼠漂浮时间延长, 糖水偏爱率降低, 脑纹状体par-4、DRD2 mRNA及par-4蛋白质表达水平均降低, par-4基因启动子区甲基化水平两组差异不显著。提示慢性温和应激诱导大鼠产生了抑郁样行为, 并能抑制纹状体par-4基因的表达, 而基因甲基化可能并不参与其调控机制。     

d-cycloserine reverses the detrimental effects of stress on learning in females and enhances retention in males

Exposure to acute, inescapable stress produces a facilitation of subsequent classical eyeblink conditioning in male rats. The same stress exposure produces a profound deficit in classical eyeblink conditioning in females. Activation of N-methyl-d-aspartate receptors (NMDAr) is necessary for the effect of stress on learning in males while the contribution of NMDAr activation to the deficit in learning after stress is unknown. Here, we tested the influence of d-cycloserine (DCS), a positive modulator of the NMDAr, in stressed or unstressed male and female rats. Groups of males and females were exposed to an acute stressful event. One day later, they began training with four sessions of trace eyeblink conditioning. Each day before training, they were injected with DCS (15 mg/kg) or saline. Females treated with DCS during training responded similarly to those that were untreated. However, those that were stressed and the next day treated with the drug during training did not express the typical learning deficit, i.e. they learned to time the CR very well. Because the drug was administered well after the stressor, these data indicate that DCS reversed the negative effects of stress on learning in females. In males, the effect of DCS was subtle, resulting in higher asymptotic responding, and enhanced retention in a drug-free retention test. Thus, as shown previously, training in the presence of an NMDA receptor agonist enhances associative learning and memory retention. In addition, it can reverse learning deficits that have already been induced.     

应激性抑郁样行为发生中海马5-羟色胺1A受体的作用及其对NMDA受体和AMPA受体的调节

为探讨慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)诱发抑郁样行为发生中海马5-羟色胺1A受体(5-hydroxytryptamine receptor 1A, 5-HT1AR)表达与作用, 及其对谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体和α-氨基羟甲基异恶唑丙酸(α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid, AMPA)受体的影响。通过建立CUMS动物模型, 给应激抑郁模型大鼠海马微量注射5-HT1A受体激动剂、给正常大鼠海马微量注射5-HT1A受体拮抗剂, 测量大鼠体重变化率, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用Western blot和ELISA方法检测大鼠海马组织中5-HT1AR和NMDAR和AMPAR的关键亚基的表达以及磷酸化水平。结果显示, 与对照组相比, CUMS组大鼠表现出抑郁样行为, 海马5-HT1AR、AMPA受体的GluR2/3亚基表达及磷酸化明显降低, NMDA受体的NR1和NR2B亚基表达及磷酸化显著增加; 正常大鼠海马微量注射5-HT1A受体拮抗剂WAY100635, 动物行为学表现及AMPA受体、NMDA受体表达及磷酸化水平均与CUMS组相同; 注射5-HT1A受体激动剂8-OH-DPAT能逆转应激诱导的上述改变。以上结果表明, CUMS诱发抑郁样行为与海马5-HT1AR表达下降, AMPAR表达量及磷酸化水平降低, NMDAR表达量及磷酸化水平升高有关。5-HT通过5-HT1AR产生抗抑郁作用。5-HT1AR激动剂抗抑郁作用与降低NMDAR表达量及磷酸化水平, 提高AMPAR表达量及磷酸化水平密切相关。     

Cytokine-Purine Interactions in Behavioral Depression in Rats

This paper reviews recent findings from our laboratories concerning metabolic and immune mediators of behavioral depression in rats. Specifically, a single injection of 6 mg/kg of reserpine substantially increases behavioral depression, as evidenced by an increase in the amount of time spent floating by independent groups of rats tested for swim performance at various times during the next week. The behavioral impairment consists of two components. An early component emerges one hour after reserpine treatment and persists for about 24 hours. The deficit is not reversed by intracranial ventricular infusion of the receptor antagonist for interleukin-1beta (IL-1beta). A second, late-component deficit appears approximately 48 hours after reserpine treatment and recovers within a week. Late-component depression is reversed by central infusion of the IL-1beta receptor antagonist, and is mimicked by central infusion of the proinflammatory cytokine. Importantly, both early and late components of reserpine-induced depression and IL-1beta induced depression are reversed by a systemic injection of the highly selective A2A adenosine receptor antagonist 8-(3-Chlorostyryl) caffeine. These data are discussed in terms of the overlap in the conservation-withdrawal reaction during sickness, traumatic stress, and major depression and the regional contribution of purines and cytokines to the organization of this reaction in the brain.     

Voluminous sucrose consumption in female rats: increased "nippiness" during periods of sucrose removal and possible oestrus periodicity

In a two-bottle paradigm in which water and 10% sucrose water were always available, female rats drank about 200 cc of the sugar water (about 65 g of sucrose/kg) per day for 4 wk. There were no significant decreases in consumption over this time. In Exp. 2 female rats singly housed were given two bottles containing water for 1 wk. and then a bottle containing water and a bottle containing 15% sucrose for the next week for 6 wk. When sucrose was available, the rats ate 33% more rat chow. When sucrose was removed, the rats displayed more episodes of biting a stimulus when the food cubes were being removed for daily measurements. Some females exhibited a marked 4- to 5-day periodicity in sucrose (7.5%) consumption. The persistent and voluminous consumption of sucrose water and enhanced agonistic-like behavior during periods of withdrawal suggests the presence of a robust phenomenon with potential dinical applications to the challenge of addiction.