苯佐卡因凝胶剂药效学实验研究

将苯佐卡因制成以卡波姆为基质的外用凝胶剂,进行了药效学实验、口腔粘膜刺激性实验和急性毒性实验。结果表明苯佐卡因凝胶药效明显,与对照组有显著差异;使用后口腔粘膜未见刺激性;口服及腹腔注射LD_(50)分别为1327.9 mg/kg及1222.6 mg/kg。     

甲硝唑阴道用原位凝胶的急性毒性及阴道刺激性研究

目的研究甲硝唑阴道原位凝胶的急性毒性和阴道刺激性。方法采用改良寇氏法对小鼠进行全身急性毒性试验,用大鼠进行局部给药急性毒性试验,采用Eckstein法对性成熟雌性家兔进行阴道刺激性研究。结果小鼠腹腔注射甲硝唑原位凝胶的半数致死量（LD50）为（128．6±12．0）mg／kg;大鼠阴道给药无明显的全身和局部毒性反应;阴道刺激性试验中,家兔阴道刺激炎症总分值为5．11分,电镜下阴道上皮细胞完整,形态无明显变化。结论在试验剂量下,甲硝唑原位凝胶的LD50在中等毒性范围,阴道刺激性在可接受范围内,值得进一步研发。     

肤福牌皮肤消毒护肤喷雾剂的急性、亚急性毒性实验和刺激实验

目的：评价肤福牌皮肤消毒护肤喷雾剂的毒性和刺激性。方法：按照消毒技术规范（2002年版）进行急性和亚急性毒性实验、完整和破损皮肤刺激实验、急性眼刺激实验以及微核实验。结果：急性灌胃毒性实验结果显示,该产品对雌、雄小鼠的LD50〉5000mg／kg;对家兔多次完整皮肤、一次破损皮肤刺激实验,以及急性眼刺激实验均属无刺激性;500～5000mg／kg微核实验结果呈阴性;亚急性经口毒性实验,对雌、雄SD大鼠未观察到有害作用的剂量为1000mg／kg。结论：该产品属实际无毒级,无刺激性,安全性良好。     

双氯灭痛搽剂皮肤刺激、皮肤过敏和急性毒性试验

10％双氯灭痛搽剂每天涂药一次，连用14天。在用药的第3～11天，对新西兰免的完整和破损皮联具有中度刺激性，继续用药呈轻度刺激或刺激消退，与市售1．5％吲哚美辛搭剂皮肤刺激性相似。10%双氯灭痛搽剂对豚鼠皮肤无致敏性。10％双氟灭痛搽剂一次涂于大鼠皮性，LD50及对95%可信艰为82．7(61．7～110．9)mg／kg；双氯灭痛水溶液给大鼠灌胃的LD50为104．6(83．3～131．4)mg／kg。经协方差分析，两种给药途经的LD50无差异．     

复方辛苯聚醇凝胶的急性毒性及阴道刺激性研究

目的:研究复方辛苯聚醇阴道凝胶的急性毒性和阴道刺激性。方法:采用Bliss法对小鼠进行急性毒性实验;采用Eckstein法对性成熟雌性家兔进行阴道刺激性研究。结果:复方辛苯聚醇凝胶的半数致死量(LD50)为95.88mg.kg-1,95%可信限为83.78～109.71mg.kg-1;阴道刺激性实验中阴道刺激炎症总分值为4.41。结论:在实验剂量下,复方辛苯聚醇凝胶的LD50在中等毒性范围,阴道刺激性在可接受范围内。     

口腔粘膜给药所用实验动物在特殊安全性试验研究中的认识

1847年,Sobrero等首先报道硝酸甘油可以经口腔粘膜吸收进入人体血液循环系统。近年来,口腔粘膜给药逐渐引起人们的重视。在我国,随着新药研究的发展,研制出了多种口腔用药剂型,相应的,伴随着GLP的快速发展,我们在进行此类药物特殊安全性试验研究中,对所用的实验动物有了更深的认识。1相关指导原则在口腔给药刺激性试验所用动物方面的发展《中药新药研究指南》在口腔用药的毒性及刺激性试验中仅规定,可参照滴鼻剂和吸入剂的局部刺激性试验进行,病理解剖学及病理组织学检查改为口腔喉及主要内脏,而滴鼻剂和吸入剂的局部刺激性试验中所用动物…     

盐酸洛美沙星急性毒性试验与临床疗效观察

目的了解洛美沙星的毒性大小及临床疗效。方法选用小鼠静脉注射及腹腔注射两种途径进行急性毒性试验，按Bliss法程序统计处理；选择慢性单纯性支气管炎患者60例进行疗效观察。结果盐酸洛美沙星小鼠静脉和腹腔注射的半数致死量（LD50）分别为287．14mg／kg（95％可信限为261．01～315．89mg／kg）和657．45mg／kg（95％可信限为597．60～723．30mg／kg）；盐酸洛美沙星对慢性单纯性气管炎的临床总有效率为93．3％。结论盐酸洛美沙星急性毒性与文献报道相近，临床疗效具有疗效好、症状控制所需时间短的优势。     

盐酸米诺环素缓释原位凝胶的安全性评价

<正>由于盐酸米诺环素原位凝胶为应用于牙周袋内的制剂,使用后与牙周袋内的黏膜直接接触,因目前尚无成熟的口腔黏膜刺激性实验模型及方法,故参照了成熟的家兔眼部刺激性实验方法,考察盐酸米诺环素缓释原位凝胶在黏膜上的刺激性。     

依沙吖啶凝胶皮肤局部给药毒性研究

目的了解依沙吖啶凝胶对局部皮肤的不良反应。方法将不同剂量的依沙吖啶凝胶用于白色豚鼠背部正常或破损去毛区皮肤,观察其产生的急性毒性情况;采用致敏与激发接触依沙吖啶凝胶,观察动物过敏情况;以一次给药和多次给药方法,将依沙吖啶凝胶外涂于白色豚鼠背部正常或破损去毛区皮肤,观察其皮肤刺激性反应。结果依沙吖啶凝胶小剂量(0.05g/cm2)和大剂量(0.2g/cm2)外用时未出现任何急性毒性反应;不产生过敏反应;对正常皮肤无刺激性,对破损皮肤有轻度刺激性。结论外用依沙吖啶凝胶未产生急性毒性和过敏反应,对豚鼠正常皮肤无刺激性,对破损皮肤有轻度刺激性,但给药后48h或72h,这种刺激性消失。     

脊椎外科手术术中唤醒试验的麻醉方法研究

目的研究脊椎外科手术中术中唤醒试验（wakeuptest,WUT）的麻醉方法。方法20例择期行脊椎外科手术病人,ASA Ⅰ～Ⅱ级,伞麻静脉诱导用咪达唑仑0．05mg／kg、异丙酚2mg／kg、芬太尼4μg／kg、阿曲库铵0．5mg／kg,气管插管前用1％丁卡因咽喉部局部表面麻醉,静脉恒速输注咪达唑仑0．4mg／（k·h）和阿曲库铵0．5mg／（kg·h）,同时吸入七氟醚1．5％～2．5％维持麻醉、肌松,手术切皮前追加芬太尼4μg／kg。需要唤醒前10min,停止所有用药,进行复苏。结果所有病人能够在预期内唤醒,唤醒成功用时为（417±82）s,唤醒后病人无异常躁动,能够完成四肢指令动作。结论这种麻醉方法用于唤醒试验平稳安全和可控性强,且技术成熟,操作方便。     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Involvement of 5-HT1C-receptors in drug-induced penile erections in rats

Drug-induced penile erections (PE) were initially suggested to be 5-HT_1B receptor mediated. However, since the discovery of the 5-HT_1C receptor a number of compounds, considered to be 5-HT_1B selective, appear to bind more strongly to the 5-HT_1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP (0.22–2.2 mg/kg), TFMPP (0.46–1.0 mg/kg) and MK 212 (0.1–1.0 mg/kg). The 5-HT agonist DOI (0.022–0.22 mg/kg) did not induce PE in placebo-pretreated rats but in rats pretreated with various 5-HT₂ antagonists it did. These compounds have in common a strong affinity for the 5-HT_1C receptor. mCPP (0.46 mg/kg)-induced PE could be antagonized by the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin, ritanserin and ketanserin. Their ED₅₀s were 0.04, 0.4, 0.03, 0.06, 0.4 and 2 mg/kg, respectively. The potency of both the agonists to induce, and the antagonists to inhibit, PE was found to be dependent on their selectivity for the 5-HT_1C receptor versus the 5-HT₂ receptor. Spiperone (0.1–1.0 mg/kg) and GR 38032F (1–10 mg/kg) did not antagonise mCPP-induced PE. 8-OH-DPAT and 5MeODMT counteracted mCPP (0.46 mg/kg)-induced PE. Their ED₅₀s were 0.03 and 0.4 mg/kg, respectively. DOI counteracted mCPP induced PE only at doses above 1 mg/kg, whereas CGS 12066B (1.0–10 mg/kg) was inactive. The results suggest that PE are induced by activation of the 5-HT_1C receptor and are functionally inhibited by activation of 5-HT_1A or 5-HT₂ receptors.     

Evidence that 5-HT2C receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety

Four non-selective 5-HT_2C/5-HT_2A receptor antagonists, mianserin (2–8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5–1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT_2A receptor antagonists ketanserin (0.2–1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT_1A, 5-HT_1B and-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT_1D receptor partial agonist and ₂ adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H₁ receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT_2C/5-HT_2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT_2C/5-HT_2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT_2C receptor, although the possibility of 5-HT_2B receptor mediation is discussed.     

Neuropharmacological reassessment of the discriminative stimulus properties ofd-lysergic acid diethylamide (LSD)

The neuropharmacological mechanisms underlying the behavioral effects ofd-lysergic acid diethylamide (LSD) were assessed by comparing the discriminative stimulus properties of LSD with those of agonists and antagonists that act selectively at putative serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes (5-HT₁ and 5-HT₂). Male Sprague-Dawley rats (N=23) were trained to discriminate LSD (0.08 mg/kg) from saline and given substitution tests with the following agents: 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT; 0.02–0.64 mg/kg), Ru 24969 (0.2–3.2 mg/kg),m-chlorophenylpiperazine (MCPP; 0.1–1.6 mg/kg), 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.1–1.6 mg/kg), and quipazine (0.2–3.2 mg/kg). Only quipazine mimicked LSD. In combination tests, BC 105 (0.2–3.2 mg/kg), 2-bromolysergic acid diethylamide (BOL; 0.1–1.6 mg/kg), Ly 53857 (0.4–3.2 mg/kg), metergoline (0.05–0.8 mg/kg), ketanserin (0.2–3.2 mg/kg), and pipenperone (0.0025–0.08 mg/kg), all of which act as 5-HT₂ antagonists, blocked the LSD cue; only spiperone (0.02–0.32 mg/kg) was without effect. Although commonalities may exist among 5-HT agonists, the present results demonstrate that such agonists are not identical. Since putative 5-HT₁ agonists do not mimic LSD and the LSD cue is potently blocked by 5-HT₂ antagonists, it appears that 5-HT₂ neuronal systems are of greater importance than 5-HT₁ systems in mediating the discriminative stimulus and, perhaps, other effects of LSD.     

Implication of 5-HT<Subscript>2</Subscript> receptor subtypes in the mechanism of action of antidepressants in the four plates test

Rationale The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants.Methods The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT).Results Paroxetine administered intraperitoneally (IP) (0.5, 2–8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT_2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT_2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT_2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2–16 mg/kg. This effect was reversed by the 5-HT_2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT_2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT_2A and 5-HT_2B receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT_{2A, 2B, 2C} receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration.Conclusion These results indicate that the co-administration of 5-HT₂ receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

ACP-103, a 5-HT<Subscript>2A/2C</Subscript> inverse agonist,potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

Rational Atypical antipsychotic drugs (APDs) such as clozapine, olanzapine, quetiapine, risperidone, and ziprasidone are serotonin (5-HT)_2A antagonists and relatively weaker dopamine (DA) D₂ antagonists, with variable 5-HT_2C antagonist properties. The ability of atypical APDs to preferentially increase DA release in the cortex compared to the limbic system is believed to be due in part to their antagonism of 5-HT_2A and D₂ receptors and believed to contribute to their beneficial effects on cognition, negative, and psychotic symptoms. Previous studies from this laboratory using microdialysis have shown that pretreatment of the 5-HT_2A antagonist M100907 with the typical APD and D₂ antagonist haloperidol produced an increase in the medial prefrontal cortex (mPFC), but not in the nucleus accumbens (NAC), DA release. However, pretreatment with the 5-HT_2A/2C receptor antagonist SR46349-B with haloperidol increased both mPFC and NAC DA release, suggesting that both 5-HT_2A and 5-HT_2C properties may be important for atypical APD effects.Objective The purpose of this study was to examine the effects of a novel putative atypical APD ACP-103 on mPFC and NAC DA release using in vivo microdialysis in freely moving rats that are awake. ACP-103 is an inverse agonist at both 5-HT_2A and 5-HT_2C receptors and has intermediate affinities for 5-HT_2C receptors relative to their affinities for 5-HT_2A receptors compared to M100907 and SR46349-B. In addition, the effects of ACP-103 were compared to M100907 and SR46349-B, and ACP-103 was also coadministered with haloperidol.Results ACP-103 10.0 mg/kg, but not 3.0 mg/kg, increased DA release in the mPFC, while neither dose increased DA release in the NAC. Like M100907, ACP-103 (3.0 mg/kg) potentiated 0.1 mg/kg haloperidol-induced DA release in the mPFC while inhibiting that in the NAC. However, ACP-103 (3.0 mg/kg), similar to SR46349-B, potentiated a high dose of haloperidol (1.0 mg/kg)-induced DA release in both regions. The potent 5-HT_2C antagonist SB242084 1.0 mg/kg significantly potentiated 0.1 mg/kg haloperidol-induced DA release in both the mPFC and NAC. However, SB242084, at 0.2 mg/kg, significantly potentiated DA release only in the NAC. Moreover, SB242084 0.2 mg/kg potentiated DA release in the NAC produced by the combination treatment of 3 mg/kg ACP-103 and 0.1 mg/kg haloperidol.Conclusion These data suggest that the relative extent of 5-HT_2A and 5-HT_2C antagonism, as well as the extent of D₂ receptor blockade, has a critical influence on DA release in the mPFC and NAC and may be a determining factor in the action of this class of atypical APDs on these two potentially clinically relevant parameters.     

Effects of serotonin (5-HT)2 receptor ligands on depression-like behavior during nicotine withdrawal

A pronounced withdrawal syndrome including depressed mood prevents cigarette smoking cessation. We tested if blockade or activation of serotonin (5-HT)₂ receptors affected the time of immobility (as an indirect measure of depression-like behavior) in naïve animals and in those withdrawn from chronic nicotine in the forced swim test (FST). The antidepressant imipramine was used as a control. In the FST, the selective 5-HT_2A receptor antagonist M100,907 (1-2 mg/kg, but not 0.5 mg/kg), the selective 5-HT_2C receptor antagonist SB 242,084 (0.3-1 mg/kg, but not 0.1 mg/kg), the 5-HT_2C receptor agonists Ro 60-0175 (10 mg/kg, but not 3 mg/kg) and WAY 163,909 (1.5-10 mg/kg, but not 0.75 mg/kg) as well as imipramine (30 mg/kg, but not 15 mg/kg) decreased the immobility time while the non-selective 5-HT₂ receptor agonist DOI (0.1-1 mg/kg) was inactive in naïve rats. We found an increase in immobility time in rats that were withdrawn from nicotine exposure after 5 days of chronic nicotine treatment. This effect increased from day 1 until day 10 following withdrawal of nicotine, with maximal withdrawal effects on day 3. M100,907 (1 mg/kg), SB 242,084 (0.3 mg/kg), Ro 60-0175 (3 mg/kg), WAY 163,909 (0.75-1.5 mg/kg) and imipramine (15-30 mg/kg) shortened the immobility time in rats that had been removed from nicotine exposure for 3 days. Locomotor activity studies indicated that the effects of SB 242,084 might have been non-specific, as we noticed enhanced basal locomotion in naïve rats. This data set demonstrates that 5-HT_2A receptor antagonist and 5-HT_2C receptor agonists exhibited effects similar to antidepressant drugs and abolished the depression-like effects in nicotine-withdrawn rats. These drugs should be considered as adjuncts to smoking cessation therapy, to ameliorate abstinence-induced depressive symptoms.     

Lack of effects of 5HT3 receptor antagonists in the social interaction and elevated plus-maze tests of anxiety in the rat

The effects of three 5HT₃ receptor antagonists: BRL 43964 (0.1 and 1 mg/kg, oral), GR 38032F (0.1 and 1 mg/kg, oral), and zacopride (0.01, 0.1 and 1 mg/kg, IP) were examined in low light test conditions of the social interaction test. None of the three 5HT₃ receptor antagonists had a significant effect on social interaction. In contrast, in two experiments chlordiazepoxide (7.5 mg/kg) significantly increased social interaction and this effect was greatest in the unfamiliar test condition. In a third experiment, the effects of GR 38032F (0.1 and 1 mg/kg, oral) and zacopride (0.01, 0.1 and 1 mg/kg, oral) were investigated in the high light test conditions of the social interaction test; neither compound had a significant effect. In the elevated plus-maze, chlordiazepoxide (7.5 mg/kg oral or IP) significantly increased both the per cent number of entries made onto open arms and the per cent of time spent on the open arms, indicating an anxiolytic action. Zacopride (0.01, 0.1 and 1 mg/kg, oral or IP) had no significant effect in this test. The effect of the baseline rate of responding in the social interaction test on the effects of 5-HT₃ antagonists is discussed. The results from the present experiment and those from other animal tests of anxiety caution against the conclusion that 5HT₃ receptor antagonists are anxiolytic.     

Lithium decreases 5-HT1A and 5-HT2 receptor and α2-adrenoreceptor mediated function in mice

Lithium administration (LiCl, 10 mmol/kg, SC on day 1, followed by 3 mmol/kg twice daily subsequently) for 14 days to mice produced attenuation of the hypothermic response to injection of 8-hydroxy-2-(di-n-propyla-mino)tetralin (8-OH-DPAT, 0.5 mg/kg SC). Head twitch responses to the 5-HT-receptor agonist 5-methoxy-N,N-dimethyltryptamine (2.5 mg/kg IP) and to precursor loading with carbidopa (25 mg/kg, IP) and 5-hydroxytryptophan (100 mg/kg IP) were similarly attenuated. By contrast with this reduction of 5-hydroxytryptamine (5-HT) function mediated by the 5-HT_1A and 5-HT₂ receptor sub-types, repeated lithium administration had no effect on the motor response to a putative 5-HT_1B receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole (RU 24969, 3 mg/kg IP). Alpha₂ adrenoceptor function, assessed by the sedation response to clonidine (0.25 mg/kg, IP), was also attenuated by repeated lithium administration. It is proposed that these actions may explain the emergence of lithium as an adjunct to the treatment of refractory depressive illness.