Effects of dexfenfluramine on dopamine dependent behaviours in rats

5-hydroxytryptamine (5-HT) inhibits the synthesis and release of dopamine (DA) from rat nigrostriatal DAergic neurons. Dexfenfluramine releases 5-HT from brain 5-HTergic neurons. The present study was undertaken to determine whether dexfenfluramine, through the released 5-HT, modulates the intensity of the behaviours dependent on the functional status of the nigrostriatal DAergic system. The effect of pretreatment with dexfenfluramine on dexamphetamine and apomorphine stereotypies of the oral movement variety and on catalepsy induced by haloperidol and small doses (0.05 and 0.1 mg/kg ip) of apomorphine was studied in rats. We also investigated whether dexfenfluramine induces catalepsy in rats. Dexfenfluramine at 2.5, 5 and 10 mg/kg ip did not induce catalepsy and did not antagonise apomorphine stereotypy. However, 1 h pretreatment with 5-HT releasing doses of dexfenfluramine ie 5 and 10 mg/kg ip, antagonized dexamphetamine stereotypy and potentiated catalepsy induced by haloperidol and small doses of apomorphine. Our results, that dexfenfluramine at 2.5, 5 and 10 mg/kg ip neither induced catalepsy nor antagonised apomorphine stereotypy, indicate that dexfenfluramine at these doses does not block the postsynaptic striatal D2 and D1 DA receptors. They also indicate that the 5-HT released by 5 and 10 mg/kg dexfenfluramine does not exert an inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptor sites. However, 5 and 10 mg/kg doses of dexfenfluramine, through the released 5-HT, inhibit the synthesis and release of DA from the nigrostriatal DAergic neurons and thus antagonise dexamphetamine stereotypy and potentiate catalepsy induced by haloperidol and small doses of apomorphine.     

Effects of yohimbine on dopamine dependent behaviours in rats and mice

In the present study we have investigated the effect of yohimbine on dopamine-dependent behaviours in rats and mice. Yohimbine (1.25 to 10 mg/kg, ip) failed to block the conditioned avoidance response in rats, to inhibit the traction response in mice and to induce catalepsy in rats and mice. Pretreatment with yohimbine (1.25 to 10 mg/kg, ip) had no significant effect on apomorphine stereotypy in rats and apomorphine induced cage climbing behaviour in mice. However, pretreatment with yohimbine (1.25 to 10 mg/kg. ip) significantly increased the intensity of methamphetamine stereotypy and antagonised haloperidol catalepsy in rats. Our findings indicate that yohimbine does not possess postsynaptic striatal and mesolimbic D-2 dopamine receptor blocking activity.     

Effects of buspirone on fixed interval responding in rats

Buspirone is a novel anxiolytic which does not share the muscle relaxant, anticonvulsant and sedative properties of classical anxiolytics such as the benzodiazepines. Its effects in different animal models of anxiety are also variable. The present experiments investigated the effects of buspirone on a fixed interval 60 s schedule of reinforcement (FI). In experiment 1, four doses of buspirone (10, 3.3, 1.1 and 0.3 mg/kg, i.p.) and two doses of chlordiazepoxide (5 and 20 mg/kg, i.p.) were administered to separate groups of rats throughout acquisition of the FI task. In experiment 2, four doses of buspirone (1.1, 0.3, 0.1 and 0.03 mg/kg, i.p.) and a single dose of chlordiazepoxide (5 mg/kg, i.p.) were used. Chlordiazepoxide generally released responding. At higher doses (1.1 mg/kg and above) buspirone suppressed responding in the later parts of the FI interval. The effects of lower doses were variable but included some response release in the later parts of the FI interval. At no dose did buspirone release responding at the beginning of the FI interval. The experiments show that buspirone differs qualitatively as well as quantitatively from chlordiazepoxide and that current animal models based on behavioural inhibition may need to be used with considerable care if detection of novel anxiolytics is to be ensured.     

Effects of sibutramine on anxiety-related behaviours in rats.

Sibutramine is an anorexiant drug that inhibits the reuptake of noradrenaline and serotonin, a pharmacological property shared with drugs clinically effective in treating anxiety pathologies. However, the effects of this compound on experimental and clinical anxiety have not been assessed yet. In this study, we evaluated the effects of sibutramine on anxiety-related behaviours which have been related to specific anxiety disorders. Acute injection of sibutramine (5, 10 or 20 mg kg(-1); intraperitoneally) in male Wistar rats impaired inhibitory avoidance in the elevated T-maze (ETM) and in the light/dark transition test, indicative of an anxiolytic effect. The drug also inhibited one-way escape in the ETM. Sibutramine, however, was ineffective in changing rat performance in the elevated plus-maze. Therefore, sibutramine decreased the expression of defensive behaviours that have been associated with generalized anxiety disorder (inhibitory avoidance) and with panic disorder (one-way escape). Yet, in contrast to what has been reported with drugs such as the tricyclic anti-depressants that also inhibit monoamine reuptake, the anxiolytic effects of sibutramine were revealed after a single administration.     

褪黑素对海洛因依赖大鼠的作用

目的 :观察褪黑素 (MT)对海洛因 (Her)依赖大鼠的作用。方法 :将 15 0只大鼠随机分为海洛因依赖模型组、海洛因依赖MT保护组和溶媒对照组。分别用海洛因、海洛因加MT或溶媒处理大鼠。 4 2d后将海洛因模型组大鼠随机分为MT治疗组、美沙酮治疗组、海洛因依赖组、自然戒断组、纳洛酮催促戒断组。然后观察自然戒断或ip纳洛酮催促戒断症状 ;进行淋巴细胞增殖反应和亮氨酸脑啡肽 (L -EK)以及β内啡肽 (β -EP)的测定。结果 :MT保护组及MT治疗组均显示 :MT可缓解大鼠的戒断症状 ;促进海洛因依赖大鼠脾淋巴细胞增殖 ;提高海洛因依赖大鼠脑L -EK和 β-EP水平。 结论 :MT可部分控制海洛因依赖大鼠的戒断症状 ;对海洛因造成的细胞免疫功能低下可能有预防和逆转的作用     

Effects of dopamine supersensitivity on lateral hypothalamic self-stimulation in rats

Dopamine (DA) receptor supersensitivity was demonstrated by potentiated d-amphetamine stereotypy after a three-day treatment regimen in which the DA receptor blocker pimozide (4.0 mg/kg) was administered twice daily. Similarly-induced DA supersensitivity produced a significant increase in the rate of lever-pressing for lateral hypothalamic (LH) intracranial self-stimulation (ICSS) and a significant decrease in ICSS thresholds. No change from pretreatment baselines was observed in vehicle-treated control animals. Following three-day treatment with the noradrenaline-(NA) and DA-receptor blocker, haloperidol (4.0 mg/kg twice daily), a single injection of the alpha-adrenergic agonist clonidine (0.15 mg/kg) caused increased running behavior. In contrast clonidine decreased running in rats pretreated with chronic pimozide or vehicle. These results indicate an increase in the sensitivity of central NA receptors following chronic haloperidol but not chronic pimozide. Taken together, these findings were interpreted as a potentiation in the reinforcing properties of LH-ICSS after chronic pimozide treatments due to increases in the sensitivity of DA and not NA receptors.     

Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats

The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1?mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10?min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.     

Effect of buspirone on rat plasma prolactin levels and striatal dopamine turnover

Buspirone, an effective antianxiety compound, produced a dose-dependent, relatively prolonged increase in rat plasma prolactin (PRL) levels. The stimulation of PRL secretion by buspirone was additive with the effect of -methyl-p-tyrosine (AMPT) or -butyrolactone. In vitro, buspirone itself had no effect on the release of PRL from rat pituitary glands but it blocked the inhibitory action of dopamine (DA). Buspirone also increased DA turnover in the striatum as measured by the AMPT-induced depletion of striatal DA levels. These results demonstrate the ability of buspirone to block pituitary and striatal DA receptors.     

Effects of buspirone and chlordiazepoxide on plasma catecholamine and corticosterone levels in stressed and nonstressed rats

The effects of intragastric administration of the prototypical benzodiazepine (BDZ) anxiolytic drug chlordiazepoxide (CDP) and the non-BDZ anxiolytic agent buspirone (BUSP) on basal and stress-elevated plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) contents were investigated. Acute dosing of CDP (1-27 mg/kg) produced dose-related increases in basal CS secretion but was without effect on basal NA levels. The high dose of CDP caused a slight short-term A increase. Dose-dependent increases in plasma A, NA and CS contents were observed after acute treatment with BUSP (2 and 20 mg/kg). A medium dose of CDP (9 mg/kg) attenuated the stress-induced CS and A elevations. High doses of CDP that elevated basal CS release prevented a further increase of CS by stress and inhibited the NA and A response to stress. BUSP (2 and 20 mg/kg) was not effective in decreasing the stress-elicited rise of CS, NA or A. Conversely, the 20 mg/kg dose of BUSP enhanced the stress-induced A response. Repeated administration of CDP (9 mg/kg/day for six days) produced tolerance to the elevation of basal CS triggered by acute CDP treatment, but increased the efficacy of the drug's CS and A attenuating action in stressed rats. Repeated administration of BUSP (2 mg/kg/day for six days) also produced tolerance to the acute BUSP-induced effect on basal CS release, but did not affect the stress-induced CS, NA and A responses. It is concluded that the clinically effective anxiolytic BUSP does not have the BDZ-like property to inhibit stress-induced elevations in CS, NA and A. Furthermore, the present data support other evidence that activation of 5-HT1A receptor mechanisms increases plasma catecholamine and corticosterone concentrations.     

Effects of central dopamine depletion on thed-amphetamine discriminative stimulus in rats

The discriminative stimulus properties ofd-amphetamine, cocaine, and apomorphine were assessed in rats trained in a two-lever, food-reinforced drug discrimination paradigm to discriminate 1.0 mg/kgd-amphetamine from saline. After determination of these dose-response relationships, the rats were divided into two groups. One group (6-OHDA) was given injections of desmethylimipramine (DMI, 30 mg/kg, IP) and 6-hydroxydopamine (6-OHDA, 100 g/10 l each ventricle), while the other group (sham) was given the same dose of DMI and 6-OHDA vehicle (intraventricularly). Beginning approximately 45 days after intraventricular injections, dose-response relationships were redetermined for all three drugs. Larger doses ofd-amphetamine were required to elicit the same response in the 6-OHDA group (i.e. the dose-response relationship was shifted to the right), while no change was observed in the sham group. Any changes in the dose-response relationships for cocaine and apomorphine were comparable in the 6-OHDA and sham group. The rate-decreasing effects were not altered in either group for any of the drugs. Upon sacrifice, dopamine (DA) was found to be significantly depleted in the accumbens, caudate and rest of brain of the 6-OHDA group. Levels of norepinephrine and serotonin were unaltered. These data suggest that central DA-containing neurons play a role in the discriminative stimulus properties of psychomotor stimulants in rats.     

Effects of dopamine receptor antagonists on ongoing maternal behavior in rats

The effects of different peripheral doses of four dopamine (DA) receptor antagonists on general activity and maternal behavior were examined in lactating female rats. Administration of the classic D1-like and D2-like DA receptor blocker haloperidol (0.1 and 0.05 mg/kg) disrupted pup retrieval and nest-building behaviors and reduced motor activity. Pimozide (0.5 and 0.2 mg/kg), which has more affinity for DA D2-like receptors, mildly disrupted pup retrieval while showing no significant influence on open-field behaviors. The putative DA D(4) receptor blocker, clozapine (1.5 and 1.0 mg/kg) reduced motor activity significantly, while only 1.0 mg/kg dose significantly decreased percent of rats displaying nest building. The DA D1-like receptor blocker SKF-83566 (0.2 and 0.1 mg/kg) significantly reduced pup retrieval, nest building and motor activity. These results suggest a role for DA receptors in ongoing maternal behavior that correlates directly with general activity.     

L-四氢巴马汀对吗啡依赖大鼠阿片肽含量的影响

目的　观察L 四氢巴马汀 (L THP)对吗啡依赖大鼠血浆、下丘脑 β EP和纹状体LEK含量的影响。 方法　用放射免疫法测定 β EP和LEK含量。 结果　L THP 40mg·kg-1ip可拮抗吗啡依赖大鼠 β EP释放减少的作用 (P <0 0 1)。与自然戒断组比较 ,L THP可显著加速血浆中 β EP水平的恢复 (P <0 0 5 ) ,并部分拮抗戒断 2d时下丘脑 β EP含量的下降 (P <0 0 5 ) ,对纹状体LEK含量无影响。结论　L THP能促进吗啡依赖大鼠 β EP释放 ,这可能是它抑制吗啡戒断症状的机制之一。     

Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats

The spontaneous open-field behavioural effects of 10 days of chronic treatment with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100 mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered subcutaneously by implanted osmotic pumps) were examined in rats. Central and peripheral arena locomotor and rearing activities were recorded simultaneously, and the data were assessed during the first hour as well as during the following 24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg daily exhibited lower peripheral locomotor and rearing activities than the other groups during the first test hour. The ratio between central and peripheral activity increased in a dose-dependent non-proportional manner during the first test hour, indicating a general increase in the central arena activity exerted by the rats when treated with citalopram. No major differences were observed between any of the four groups in overall behavioural activities over the 24-hr period. This study indicated that the open-field locomotor and rearing behaviours in normal rats were affected by increasing doses of racemic citalopram, particularly during the first hour of adaptation.     

Effects of intrathecal and systemic administration of buspirone on genital reflexes and mating behavior in male rats

Buspirone was studied to determine whether the detailed profile of male sexual behavior observed following treatment with the prototypical 5-HT1A ligand, 8-OH-DPAT, can be generalized to other 5-HT1A agonist drugs. Systemic and intrathecal (IT) routes of administration were compared. Like DPAT, significant reduction in intromission frequency followed IT infusion of buspirone (80-160 micrograms) as did intraperitoneal (IP) injection (1-4 mg/kg). IT doses of 80-160 micrograms and all IP doses significantly reduced ejaculation latency. Intercopulatory interval significantly decreased following IP buspirone but not after IT infusion although there were trends in that direction. All IP doses and 80 micrograms IT significantly shortened the postejaculatory interval. Buspirone inhibited erection and/or ejaculation in the ex copula reflex test. A decrease in percentage of rats displaying erections and ejaculation occurred following either route of administration. Ejaculation was significantly inhibited at the low IT dose of 40 micrograms. We conclude that buspirone affects sexual behavior very much like DPAT or other 5-HT1A drugs, to the extent known. Sexual effects of buspirone were generally similar regardless of route of administration, but the effective doses were clearly lower with IT treatment.     

丁螺环酮对地西泮抗焦虑作用的影响

应用大鼠 Vogel冲突饮水实验和群居接触焦虑模型 ,观察丁螺环酮 (Bus)对地西泮抗焦虑作用的影响 .结果发现 ,以低于有效剂量的 Bus与低于有效剂量的地西泮合用 ,能显著促进大鼠的抗冲突饮水次数和群居接触时间 .而以低于有效剂量的Bus与有效剂量的地西泮合用 ,则能使地西泮的抗焦虑作用消失 .结果表明 ,Bus在不同条件下能加强或减弱地西泮的抗焦虑作用 ,提示中枢 5- HT与γ-氨基丁酸 -苯二氮艹卓 系统之间存在着相互作用 ,并可能共轭调节焦虑的病理生理过程 .     

Comparison of effects of buspirone and gepirone with benzodiazepines and antagonists of dopamine and serotonin receptors on punished behavior of rats

Lever-press responding of male Sprague-Dawley rats was maintained under a conflict procedure in which every tenth response produced both food and electric shock (punished responding); every thirtieth response produced only food in the presence of a separate stimulus. The benzodiazepines, diazepam and chlordiazepoxide, increased responding 4- to 6-fold. Buspirone and its structural analog, gepirone, only moderately and inconsistently increased responding (1.5- and 2-fold, respectively). The dopamine-2 (D-2) receptor antagonist, sulpiride, but not haloperidol had effects similar to buspirone. The D-1 antagonist SCH 23390 was not active. The non-selective serotonin (5HT) antagonists, cyproheptadine and methysergide, consistently increased responding 2-fold, but the 5HT-2 antagonists, ketanserin, pirenperone, ritanserin, R-56 413, and LY 53857 and the 5HT-1A agonist, 8-OH-DPAT, were inactive. In pigeons, serotonergic compounds have been shown to increase punished responding. The present results suggest that exploitation of this species difference may be helpful in evaluating new chemicals for novel anxiolytic activity and for investigation of their mechanisms of action.     

Dose-response analysis of the effects of buspirone on rearing in rats

The effects of buspirone were tested on rearing in an open field. Six different doses of buspirone (10, 3.3, 1.1, 0.3, 0.1 and 0.04 mg/kg) and a single dose of chlordiazepoxide (5 mg/kg) were administered i.p. to separate groups of rats. Buspirone produced a dose-dependent decrease in rearing in the range 0.04-10 mg/kg, whereas only the higher doses (10 and 3.3 mg/kg) decreased ambulation significantly. Chlordiazepoxide reduced rearing to an extent equivalent to 1 mg/kg of buspirone. Together with data in the literature, the results suggest that 5-HT1A agonists affect rearing at lower doses than ambulation; that the effects of buspirone in the open field are similar to classical anxiolytics; and that changes in rearing may be more closely related to anxiolytic than muscle relaxant, anti-convulsant and other GABA-mediated effects of the classical anxiolytics.     

甲基苯丙胺对大鼠行为和脑组织多巴胺及其代谢产物含量的影响

甲基苯丙胺（methamphetamine，MA）属于苯丙胺类兴奋剂，其盐酸盐为无色透明的晶体，状如冰，俗称“冰毒”。MA最初是作为减肥药、抗疲劳剂使用，随后发现其具有精神依赖性。上世纪50年代，欧美国家出现MA滥用。近年国际上的滥用呈上升趋势，国内大中城市的滥用情况也十分严峻。MA除对心、肝、肺、肾和骨骼肌等有毒性作用外，还有较强的神经毒性。