The orexin-1 antagonist SB-334867 blocks antipsychotic treatment emergent catalepsy: implications for the treatment of extrapyramidal symptoms

We have previously shown that the orexin-1 antagonist SB-334867 blocks the electrophysiological effects of haloperidol and olanzapine on the activity of A9 and A10 dopamine neurons. To evaluate if orexin-1 antagonists might block other effects of antipsychotic drugs in animals, we examined the effects of SB-334867 on behavioral, neurochemical, and neuroendocrine effects of antipsychotic drugs. Pretreatment with SB-334867 (0.01-10 mg/kg, intraperitoneal [IP]) significantly decreased the catalepsy produced by the administration of haloperidol (1 mg/kg, subcutaneous [SC]), risperidone (2 mg/kg, SC), and olanzapine (10 mg/kg, SC). Administration of SB-334467 also reversed catalepsy after it had been established in animals pretreated 2 hours earlier with haloperidol. However, pretreatment with SB-334867 (1-10 mg/kg, IP) did not block the decreases in exploratory locomotor activity produced by administration of haloperidol (0.1 mg/kg, SC) or risperidone (0.3 mg/kg, SC). In addition, pretreatment with SB-334867 (1-10 mg/kg, IP) neither blocked the increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or striatum nor the elevation in serum prolactin produced by administration of haloperidol (0.1 mg/kg, SC) and risperidone (1 mg/kg, SC). Administration of SB-334867 alone neither changed locomotor activity and DOPAC or prolactin levels nor produced catalepsy. These results show that orexin-1 antagonists block the catoleptogenic effects of antipsychotics but do not block other locomotor, neurochemical, or neuroendocrine effects of antipsychotics. Because catalepsy is thought to be a good predictor of extrapyramidal symptoms in humans, treatment with orexin-1 antagonists might decrease the occurrence or severity of antipsychotic treatment-emergent extrapyramidal symptoms in humans.     

Anorexia and weight loss in male rats 24 h following single dose treatment with orexin-1 receptor antagonist SB-334867

Acute systemic treatment with the selective orexin-1 receptor antagonist SB-334867 (30 mg/kg, i.p.) has been reported not only to inhibit food intake and to accelerate behavioural satiety in rats, but also to produce a significant loss of bodyweight over the 24 h period post-dosing. The present studies were designed to test the hypothesis that the inhibition of weight gain following acute treatment with SB-334867 is due to a persistent anorectic action of the compound. In Experiment 1, the acute effects of SB-334867 (30 mg/kg, i.p.) on food intake and behaviour in a 1 h test with palatable mash were assessed as a function of injection-test interval. Results confirmed that, when administered 30 min prior to testing, SB-334867 significantly suppressed mash intake and accelerated behavioural satiety. More importantly, significant anorexia and behavioural change were also observed when animals were tested 24 h, but not 48 h, post-dosing. As previously reported, all animals treated with the orexin-1 receptor antagonist lost bodyweight over the 24 h period following acute treatment. The generality of these findings was confirmed in Experiment 2, where acute treatment with SB-334867 (30 mg/kg, i.p.) significantly suppressed home cage chow consumption over the 24 h period post-dosing, an effect also accompanied by a significant loss of bodyweight. The results of Experiment 3 showed that, following i.p. administration of 30 mg/kg, SB-334867 has good CNS penetration, reaches peak plasma and brain concentrations at 30 min, and maintains good exposure over 4 h post-dosing. Overall, current data support the hypothesis that a persistent anorectic action contributes to the significant loss of bodyweight observed 24 h following acute dosing with SB-334867. As the compound is virtually undetectable in plasma or brain beyond 8 h post-dosing, and since nothing is known about potentially active metabolites, we consider the possibility that single dose treatment with SB-334867 results in enduring alterations to the orexin-1 receptor and/or downstream signalling pathways.     

Satiety enhancement by selective orexin-1 receptor antagonist SB-334867: influence of test context and profile comparison with CCK-8S

Acute systemic treatment with the selective orexin-1 (OX1R) antagonist SB-334867 reduces food intake in rats, an effect associated with an acceleration in behavioural satiety and unrelated to gross behavioural disruption, alterations in palatability, or toxicity. However, as enhanced satiety is behaviourally indexed by an earlier-than-normal transition from eating to resting, and since orexin-A has been implicated in mechanisms of arousal, it remains possible that sedation contributes to the anorectic effect of acute OX1R blockade. Previous work has shown that, when treated with SB-334867 (30 mg/kg, i.p.) 30 min before a 1h test with palatable food, rats begin to show appreciable levels of resting 10-15 min earlier than under control conditions (i.e. around 20 min versus 30-35 min into the session). The present results demonstrate that a 20 min increase in the injection-test interval (i.e. 50 min) had no significant impact on the anorectic, behavioural or weight gain effects of SB-334867 in non-deprived male rats. Most importantly, this altered treatment regimen led to a temporal profile of resting virtually identical to that previously observed with the more conventional 30 min injection-test interval. Although parallel studies indicated that the OX1R antagonist accelerated the onset of resting (and suppressed most active behaviours) even in the absence of food, an equianorectic dose of the natural satiety-related signal cholescystokinin octapeptide (CCK-8S; 5 microg/kg, i.p.) also produced very similar behavioural effects regardless of the presence of food. Together with evidence that SB-334867 preserves the structural integrity of natural feeding behaviour, does not induce nausea/illness or alter taste/palatability and fails to influence EEG measures of arousal/sleep, the present findings are consistent with the view that acute OX1R antagonism selectively enhances satiety. However, unlike the immediate short-circuiting of the satiety sequence induced by CCK-8S, the slower response to SB-334867 implies a more indirect mechanism of action.     

Role of the 5-HT1A somatodendritic autoreceptor in the dorsal raphe nucleus on salt satiety signaling in rats

We investigated the possible role of 5-HT_1A somatodendritic autoreceptors in the dorsal raphe nucleus (DRN) on salt intake response during basal conditions and following natriorexigenic challenge aroused by sodium depletion in rats. Acute systemic administration (76–1520 nmol/kg s.c.) of 8-OH-DPAT, a selective 5-HT_1A somatodendritic autoreceptor agonist, induced a clear and dose-dependent preference for salt intake through free choice between water and 0.3 M NaCl simultaneously offered under basal conditions. Acute intra-DRN microinjection (7.5 nmol/rat) of 8-OH-DPAT significantly mimicked the acute systemic protocol in sodium-replete rats. Interestingly, microinjection of 8-OH-DPAT into the DRN raised an additional long-lasting increase of 0.3 M NaCl intake in sodium-depleted rats despite a high volume ingested 30 min after central injection. Conversely, chronic systemic treatment (1520 nmol/kg s.c.) with 8-OH-DPAT for 2 and 3 weeks or repeated intra-DRN microinjection (7.5 nmol/rat) evoked a significant long-term decrease in 0.3 M NaCl intake in sodium-depleted rats given only water and a sodium-deficient diet over the course of 24 h after furosemide injection. These results show a clear-cut involvement of the DRN 5-HT_1A somatodendritic autoreceptors in sodium satiety signaling under basal conditions and during the consummatory phase of salt intake in sodium-depleted rats.     

The selective 5-HT(1A) receptor antagonist p-MPPI antagonizes sleep--waking and behavioural effects of 8-OH-DPAT in rats

Systemic administration of the selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT) increases waking and reduces slow wave sleep (SWS) and rapid eye movement (REM) sleep in the freely moving rat. The selective 5-HT(1A) antagonist 4-(2'-methoxy-phenyl)-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido]-ethyl-piperazine (p-MPPI) induces a dose-related decrease in REM sleep. The present study examined p-MPPI's potential as an antagonist of the sleep and waking responses elicited by 8-OH-DPAT. Also, the experiments explored the ability of p-MPPI to block behavioural reactions of the 5-HT syndrome induced by 8-OH-DPAT, and whether p-MPPI induced any behavioural effects of its own. This study demonstrated that pre-treatment with p-MPPI (5 mg/kg intraperitoneal (i.p.)) 30 min before 8-OH-DPAT (0.375 mg/kg subcutaneously (s.c.)) reduced the effect of 8-OH-DPAT on waking and REM sleep. Also, p-MPPI (5 and 10 mg/kg i.p.) reduced the effect of 8-OH-DPAT on locomotion and partially or completely antagonized hindlimb abduction and flat body posture. No overt behavioural change was produced by p-MPPI alone. Thus, p-MPPI behaved as a true 5-HT(1A) antagonist.     

代谢型谷氨酸受体1亚型选择性拮抗剂LY367385对抗大鼠缺血性脑水肿

目的研究代谢型谷氨酸受体1亚型（mGluR1）选择性拮抗剂LY367385对大鼠缺血性脑水肿的影响.方法Wistar雄性大鼠（280～320g）线栓法复制大脑中动脉闭塞（MCAO）脑缺血模型.动物随机分为生理盐水（NS）对照组、LY367385给药组及MK-801给药组,于MCAO后1min,侧脑室内注射NS或LY367385（500nmol）5μl,或腹腔注射MK-801（1mg/kg）.各组动物分别于MCAO 6、24h进行神经病学评分、脑含水量测定及脑梗死面积测定.结果LY367385明显改善大鼠脑缺血引起的神经症状,而MK-801在MCAO 6h增加神经病学评分.LY367385降低大鼠MCAO引起的脑含水量增加,MK-801无明显作用.LY367385及MK-801均降低脑梗死面积百分率,且LY367385作用优于MK-801.结论LY367385能对抗大鼠脑缺血性脑水肿,作用明显优于MK-801.     

AM251, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats

Long-term potentiation (LTP) has a long history as putative mechanism of memory formation, specially in the hippocampus, a structure essential for memory formation. Endocannabinoids are one of the endogenous systems that modulate this plasticity event: the activation of hippocampal CB1 receptors may inhibit local GABA release. Here, we have studied both (1) the role of the selective CB1 antagonist AM251 upon LTP induction in a hippocampal slice preparation, and (2) the effect of its intrahippocampal administration in the step-down inhibitory avoidance (IA) and the open field habituation tasks (OF). Standard extracellular electrophysiology techniques were used to record field excitatory postsynaptic potentials from the dendritic region of CA1 neurons in response to a high frequency stimulation of Schaffer's collaterals; a micropipette ejected 0.2 microM of AM251 (in DMSO/PBS) 2 min before the stimulus: LTP was induced and lasted more than 30 min in the control, but not in the AM251-treated group. Immediately after training, either in IA (footshock, 0.5 mA) or OF, animals received a bilateral infusion of 0.55 or 5.5 ng/side of AM251 or its vehicle in the CA1 region, and test was performed 24 h later. AM251 has caused a significative decrease in the test step-down latency when compared to the control group, but no differences were detected in the OF task, including the number of crossings, i.e., there were no motor effects. The LTP supression could be caused by AM251 acting over GABAergic interneurons that modulate the LTP-bearing glutamatergic neurons. Endocanabinoids would then be the natural dis-inhibitors of local plasticity in the dorsal hippocampus, and the amnestic action of AM251 would be due to a disruption of this endogenous modulatory system.     

Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition

The 5-hydroxytryptamine₇ (5-HT₇) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT₇ receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT₇ receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT_2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT₇ receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.     

Effects of adrenalectomy and of mineralocorticoid receptor/glucocorticoid receptor ligands in female Brown Norway and Fischer 344 rats and f1 hybrids

Our previous studies suggested that the mineralocorticoid receptor (MR) of Brown Norway (BN) male rats is active independently of the presence of its ligands (i.e. constitutively active), and that glucocorticoid receptor (GR)-mediated mechanisms are more efficient in BN than in Fischer 344 (F344) male rats. Such functional differences in corticosteroid receptors led us to compare the effect of adrenalectomy (ADX) and MR/GR-mediated actions (treatments with deoxycorticosterone, DOC and RU 28362, respectively) on female rats from both strains, and, within the framework of a genetic study, to investigate how these differences were inherited in rats of the first generation (F1) born from the crossbreeding between BN and F344 inbred rats. This study extends our previous hypotheses of a constitutive activation of MR and of a greater efficiency of GR in males to females of the BN strain. In both strains, female rats were less sensitive to ADX and to treatments with DOC or RU 28362 than males. Globally, F1 hybrid BNxF344 rats inherited the functional characteristics of MR and GR of BN rats.     

Evaluation of behavioural effects of a selective NMDA NR1A/2B receptor antagonist in the unilateral 6-OHDA lesion rat model

The degeneration of the dopaminergic nigrostriatal pathway in Parkinson's disease (PD) is associated with altered transmission at striatal NMDA receptors containing NR2B subunits. We investigated a potential novel therapeutic compound, 4-trifluoromethoxy-N-(2-trifluoromethyl-benzyl)-benzamidine (BZAD-01), a selective NMDA NR1A/2B receptor antagonist for PD and compared it with levodopa, the standard treatment for PD. This study also evaluated whether combining levodopa and BZAD-01 gave better improvements of parkinsonian symptoms. Parkinsonism was induced by microinjection of the toxin, 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) of 40 Sprague-Dawley rats. Parkinsonism and the efficacy of drugs were assessed using a battery of behavioural tests including balance beam, apomorphine-induced rotation, body axis bias or "curling", head position bias and disengage sensorimotor latency test. Immunohistochemistry was performed on post-mortem tissue to estimate the loss of dopaminergic neurons. The main effects were that BZAD-01 co-administration prevented chronic levodopa-induced potentiation of apomorphine rotation. However levodopa-treated rats were slower than either controls or BZAD-01-treated rats in the locomotor test. The improvement in the apomorphine rotation test suggests that BZAD-01 may be a useful adjunct to levodopa monotherapy.     

Effects of an adenosine A2A receptor blockade in the nucleus accumbens on locomotion,feeding, and prepulse inhibition in rats

The nucleus accumbens (NAc) subserves behaviors governed by natural rewards, i.e., feeding or exploration, and has been implicated in control of prepulse inhibition (PPI), a measure of sensorimotor gating. The present study sought to determine whether a tonic stimulation of adenosine A(2A) receptors in the rat NAc is involved in control of spontaneous locomotor activity, feeding behavior, and PPI. To this end, bilateral microinfusions of a prodrug (MSX-3) (3 microg and 5 microg in 1 microl per side) of the selective A(2A) receptor antagonist MSX-2 or vehicle (1 microl per side) were administered into the NAc. Results show that blockade of intra-NAc adenosine A(2A) receptors by a high (5 microg), but not by a low (3 microg), dose of MSX-3 increased locomotor activity in an open field, reduced food intake, and delayed intake onset in food-deprived rats examined in a test cage with standard laboratory chow. Furthermore, PPI was significantly disrupted after intra-NAc infusion of 5 microg, but not 3 microg, MSX-3. These findings suggest that locomotor activity as well as intact PPI and feeding behavior rely on tonic activation of intra-NAc A(2A) receptors. The data add further support to the view that adenosine is a tonically active modulator of striatal function through actions on A(2A) receptors.     

Selective corticotropin-releasing factor type 1 receptor antagonist blocks conditioned fear-induced release of noradrenaline in the hypothalamic paraventricular nucleus of rats

The effects of conditioned fear on the release of noradrenaline in the hypothalamic paraventricular nucleus (PVN) and the involvement of corticotropin-releasing factor (CRF) receptor type 1 (CRFR1) in conditioned fear-induced changes in noradrenaline release were examined by intracerebral microdialysis in rats. Conditioned fear was produced by placing animals into a box where they had previously been exposed to a 5-min period of electric footshock, 135 min prior to the start of experiment. Conditioned fear for 20 min produced a significant increase in the release of noradrenaline in the PVN. Intraperitoneal preadministration of a selective nonpeptidic CRFR1 antagonist, CRA1000, completely blocked the conditioned fear-induced release of noradrenaline. These results suggest that CRFR1 is involved in the release of noradrenaline in the hypothalamic PVN induced by conditioned fear.     

Aging and SB-269970-A, a selective 5-HT7 receptor antagonist, attenuate circadian phase advances induced by microinjections of serotonergic drugs in the hamster dorsal raphe nucleus

Aging leads to many changes in the circadian timekeeping system, including reduced sensitivity to phase-resetting signals such as systemic administration of the serotonergic agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In previous studies, we observed an age-related decrease in 5-HT7 receptor binding sites, one of the receptor subtypes that is activated by 8-OH-DPAT, in the dorsal raphe nucleus. In this study, we tested the hypotheses that (1) aging reduces circadian phase shifts induced by local administration of 8-OH-DPAT (30 microM, i.e., 1.97 ng) or 5-carboxamidotryptamine (5-CT, 100 nM, i.e., 6.39 pg), another serotonin agonist, into the dorsal raphe and (2) 5-HT7 receptors mediate the phase shifts induced by administration of 5-CT and 8-OH-DPAT into the dorsal raphe. Young (3-5 months), middle-aged (12-13 months) and old hamsters (17-19 months) were surgically implanted with chronic guide cannulae aimed at the dorsal raphe, and were housed in cages equipped with running wheels. Aging significantly inhibited (P<0.01) the phase advances in running-wheel rhythms induced by 8-OH-DPAT microinjected during the midsubjective day. 5-CT induced phase advances tended to decrease with aging, but this effect was not significant (P<0.12). Microinjection of the selective 5-HT7 receptor antagonist, SB-269970-A (50-5000 nM, i.e., 0.39-390 pg), 15 min before microinjection of 5-CT or 8-OH-DPAT into the dorsal raphe of young hamsters, significantly inhibited phase shifts. In conjunction with our previous study, these findings indicate that an age-related reduction in 5-HT7 receptors in the dorsal raphe nucleus is an important neurochemical mechanism leading to aging deficits in the circadian timekeeping system.     

A novel water-soluble selective CRF1 receptor antagonist,NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats

The stress response involves the activation of two corticotropin-releasing factor (CRF) receptor subtypes. We investigated the role of CRF1 in stress-related visceral responses. A novel water-soluble tricyclic CRF1 antagonist, NBI 35965 was developed that displayed a high affinity for CRF1 (Ki approximately 4 nM) while having no binding affinity to CRF2. This antagonist also inhibited the stimulation of cAMP induced by sauvagine in CRF1 transfected cells. NBI 35965 administered per orally (p.o.) in rats (1, 3, 10 or 30 mg/kg) inhibited dose-dependently [125I]sauvagine binding selectively at brain sites of CRF1 distribution as shown by ex vivo receptor autoradiography. At the highest doses, NBI 35965 completely prevented [125I]sauvagine labeling in the cortex. NBI 35965 (10 mg/kg) administered p.o. or subcutaneously (s.c.) 1 h before intravenous CRF completely blocked the 81% shortening of distal colonic transit time induced by CRF. NBI 35965 (20 mg/kg s.c.) significantly reduced the defecation in response to water avoidance stress but not that induced by s.c. carbachol. In adult male Long-Evans rats that had undergone maternal separation, acute water avoidance stress significantly increased the visceromotor response to colorectal distention (20-80 mmHg) by 42+/-19% compared with the response before stress. Stress-induced visceral hyperalgesia was abolished by NBI 35965 (20 mg/kg, s.c.). The data show that NBI 35965 is a novel water-soluble selective CRF1 antagonist with bioavailability to the brain upon peripheral administration and that CRF1 receptor signaling pathways are involved in water avoidance stress-induced hyperalgesia to colorectal distention and stimulation of colonic transit.     

Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats

BACKGROUND: Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on beta-adrenergic receptor (beta(1) and beta(2)) expression in the amygdala. METHODS: Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last betaxolol injection. Following behavioral testing, betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. RESULTS: Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore, treatment with betaxolol during early cocaine withdrawal significantly decreased beta(1)-adrenergic receptor protein expression in the amygdala to levels comparable to those of control animals. CONCLUSIONS: The present findings suggest that the anxiolytic-like effect of betaxolol on cocaine-induced anxiety may be related to its effect on amygdalar beta(1)-adrenergic receptors that are up-regulated during early phases of drug withdrawal. These data support the efficacy of betaxolol as a potential effective pharmacotherapy in treating cocaine withdrawal-induced anxiety during early phases of abstinence.     

Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia.     

Meal patterns and food selection during the development of obesity in rats fed a cafeteria diet

(1) Offering preferred foods in addition to laboratory chow led immediately to a marked increase in both mean meal size (MMS) and meal frequency (MF). (2) As body weight increased over a 5 months period, MF declined to a low level but MMS remained high. (3) Within a majority of meals there was substantial consumption of only one food item. Nonetheless, when “mixed” meals were eaten these were usually larger than “exclusive” meals. (4) With more than one preferred food available there was a significant tendency to alternate consumption of food types from one meal to the next. This disappeared at inter-meal intervals longer than 90 minutes. (5) With one preferred food available, only MMS (and not MF) was increased and the degree of hyperphagia and obesity were reduced. The findings suggest the following conclusions: Both palatability (preference value for a particular food) and variety (availability of different types of food) have incremental, but distinguishable, effects on food consumption and meal parameters. Palatability mainly influences meal size, whereas variety exerts an effect on meal size and inter-meal interval. However, the potential effect of variety on overall intake is probably somewhat reduced by the tendency to eat only one type of food in each meal. Obesity has an inhibitory influence on feeding, operating primarily through a reduction in meal frequency.     

Meal patterns and food selection during the development of obesity in rats fed a cafeteria diet

(1) Offering preferred foods in addition to laboratory chow led immediately to a marked increase in both mean meal size (MMS) and meal frequency (MF). (2) As body weight increased over a 5 months period, MF declined to a low level but MMS remained high. (3) Within a majority of meals there was substantial consumption of only one food item. Nonetheless, when “mixed” meals were eaten these were usually larger than “exclusive” meals. (4) With more than one preferred food available there was a significant tendency to alternate consumption of food types from one meal to the next. This disappeared at inter-meal intervals longer than 90 minutes. (5) With one preferred food available, only MMS (and not MF) was increased and the degree of hyperphagia and obesity were reduced. The findings suggest the following conclusions: Both palatability (preference value for a particular food) and variety (availability of different types of food) have incremental, but distinguishable, effects on food consumption and meal parameters. Palatability mainly influences meal size, whereas variety exerts an effect on meal size and inter-meal interval. However, the potential effect of variety on overall intake is probably somewhat reduced by the tendency to eat only one type of food in each meal. Obesity has an inhibitory influence on feeding, operating primarily through a reduction in meal frequency.     

Protective effect of the interleukin-1 receptor antagonist (IL-1ra) on experimental allergic encephalomyelitis in rats

Cytokines such as interleukin-1 (IL-1) are thought to contribute to the inflammatory response associated with autoimmune diseases like multiple sclerosis. We assessed the role of IL-1 in an animal model of MS, experimental allergic encephalomyelitis (EAE), by testing the effects of treatment with an IL-1 receptor antagonist (recombinant human IL-1ra) on the clinical course of EAE in Lewis rats. Treatment with rhIL-1ra every day starting on Day 9 post-immunization with myelin basic protein (MBP) during the effector phase of EAE significantly inhibited clinical signs of EAE. rhIL-1ra delayed the onset, reduced the severity of paralysis and weight loss, and shortened the duration of disease. These data suggest that IL-1 is a mediator of the inflammation resulting from active immunization with MBP, and that inhibitors of IL-1 may prove beneficial for the treatment of autoimmune or inflammatory diseases of the central nervous system.