Scopolamine prevents tolerance to the effects of caffeine on rotational behavior in 6-hydroxydopamine-denervated rats

Continuous administration of caffeine has been shown to induce tolerance to its psychostimulant effects. In this study, using unilateral 6-hydroxydopamine nigrostriatal denervated rats, we tested the hypothesis that the muscarinic receptor antagonist, scopolamine, would prevent the tolerance to caffeine-induced contralateral rotational behavior. For that purpose we administered either caffeine (40 mg/kg) plus saline or scopolamine (5, 10 and 20 mg/kg) plus saline, as well as caffeine in combination with the various doses of scopolamine for 7 consecutive days, and measured ipsilateral and contralateral rotational behavior. The results showed that acute injections of scopolamine plus saline produced similar levels of both ipsilateral and contralateral turning, while caffeine produced more contralateral than ipsilateral turning. Tolerance to caffeine-induced contralateral turning was observed as of the second administration, while scopolamine plus saline injections did not produce significant changes in rotational behavior with repeated treatment. Scopolamine co-administered with caffeine significantly attenuated the increased contralateral turning produced by acute injections of caffeine plus saline, but significantly prevented the tolerance effects with repeated administration. These findings strongly suggest that muscarinic cholinergic processes may be involved in tolerance to caffeine-induced contralateral turning. The results are interpreted in terms of the possible interactions between dopamine, adenosine and acetylcholine neurotransmitter systems within the basal ganglia circuitry involved in motor behavior.     

Scopolamine prevents augmentation of stereotypy induced by chronic methamphetamine treatment

Cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. We have previously shown that blockade of muscarinic cholinergic receptors prevents the development of locomotor sensitization to methamphetamine. The present study was conducted to examine whether scopolamine, a muscarinic cholinergic antagonist, would also block augmentation of stereotypy induced by chronic methamphetamine (MA) treatment. Rats treated with MA (2.5 mg/kg, SC) for 10 days indicated significantly enhanced stereotyped behavior when tested with MA (2.5 mg/kg) after a 7-to 8- day withdrawal. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the augmentation of stereotypy. Rats treated with scopolamine alone showed no difference in MA-induced stereotypy compared to those treated with saline. Scopolamine methylbromide, a derivative of scopolamine that does not easily cross the blood-brain barrier, had no effect on the augmentation of stereotypy. These results suggest that stimulation of central muscarinic cholinergic receptors plays a role in the development of sensitization to the stereotypy stimulating effect of methamphetamine.     

The M₁/M₄ preferring agonist xanomeline reverses amphetamine-, MK801- and scopolamine-induced abnormalities of latent inhibition: putative efficacy against positive, negative and cognitive symptoms in schizophrenia

A major challenge in developing schizophrenia pharmacotherapy is treating the different symptoms of this disorder, typically divided into positive, negative and cognitive symptoms. M?/M? muscarinic acetylcholine receptor (mAChR) agonists have emerged as a promising therapeutic target, particularly for positive and cognitive symptoms. Here, we examined the activity of the M?/M? mAChR-preferring agonist xanomeline in four pharmacological latent inhibition (LI) models. LI is the poorer conditioning to a stimulus previously experienced as irrelevant during repeated non-reinforced pre-exposure to that stimulus. No-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak, but not strong, conditioning (2 vs. 5 tone-shock pairings). Amphetamine (1 mg/kg)- or scopolamine (0.15 mg/kg)-treated rats failed to show LI with weak conditioning, whereas MK801 (0.05 mg/kg)- or scopolamine (1.5 mg/kg)-treated rats persisted in displaying LI with strong conditioning. Xanomeline (5 mg/kg, 15 mg/kg) reversed amphetamine- and scopolamine-induced LI disruption, effects considered predictive of activity against positive symptoms of schizophrenia. In addition, xanomeline alleviated MK801-induced abnormally persistent LI. Activity of xanomeline on NMDA antagonist-induced behaviour was demonstrated here for the first time and suggests that the drug is effective against negative/cognitive symptoms. Finally, xanomeline alleviated abnormally persistent LI induced by scopolamine, which was suggested to model antipsychotic drug-resistant cognitive impairments, providing further evidence for the cognition-enhancing capacity of xanomeline. Although the use of xanomeline in schizophrenia was discontinued due to cholinergic-related side-effects, our findings suggest that M?/M? mAChR agonism should be an important target in drug development in schizophrenia, potentially beneficial for treatment of positive, negative and cognitive symptoms.     

Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset.

The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT) selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment induced by the muscarinic receptor antagonist, scopolamine. For this purpose, marmosets were trained in an object discrimination task utilizing the Wisconsin General Test Apparatus. Administration of scopolamine (0.01-0.04 mg/kg, SC) caused a dose-dependent impairment in the acquisition of the object discrimination task in that marmosets required more trials to reach criterion, made more errors, and took longer to choose the objects. Administration of arecoline (0.06-0.1 mg/kg, SC) or 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol- 1-yl)methyl]-4H-carbazol-4-one,HCl.2H2O (ondansetron) (0.1-1 micrograms/kg, SC) prevented the scopolamine-induced impairment in task acquisition in that the performance of marmosets was indistinguishable from that of saline-treated animals and was significantly better than that following scopolamine/saline. From these studies, we conclude that ondansetron prevents impairment in the cognitive performance of marmosets induced by administration of scopolamine.     

Relation between behaviorally augmented tolerance and upregulation of muscarinic receptors in the CNS: Effects of chronic administration of scopolamine

The present experiment was planned to provide information about relations between behaviorally augmented tolerance and accompanying upregulation of muscarinic receptors (mAChR) (physiological tolerance) in the CNS during chronic administration of the cholinergic antagonist scopolamine. Analyses of the data on mAChR binding established significant upregulation (B_max) had occurred in the cortex, hippocampus, and striatum of animals treated with scopolamine, but not of those in the saline or methylscopolamine groups. There were no treatment effects in affinity (K_D). The effect of scopolamine administered before a behavioral test session was to cause an acute decrease in FR₅ responding to water reinforcement, and hence in resulting water consumption. Animals immediately compensated for this decrement by higher response rates during a free drinking (FDR) period which followed. When scopolamine was injected between the FR₅ and FDR periods, FR₅ responding increased to compensate for the drug's effect on the FDR. There was evidence that physiological tolerance also occurred as indicated by a more slowly developing trend toward recovery of levels of behavioral responding related to mAChR upregulation, although full recovery to pretreatment baselines did not occur within the 25 days of chronic treatments. The results as a whole are consistent with a multifactorial model of tolerance development, to which both behavioral and neurochemical processes contribute.     

Increased bioavailability of clomipramine after sublingual administration in rats

This study examined the absorption and disposition of clomipramine in rats after sublingual (5 and 50 mg/kg), oral (50 mg/kg), and iv (5 mg/kg) administration. The mean oral bioavailability of clomipramine was 24.8% and 29.7%, respectively, in conscious rats and in rats anesthetized with ketamine/xylazine (30/3 mg/kg). When given sublingually in isotonic saline at a dose of 50 mg/kg, clomipramine was rapidly absorbed, and the mean absolute bioavailability (36.2%) was increased over oral dosing. The mean AUC values of clomipramine were 2258 +/- 1762 ng.h/mL and 1891 +/- 867 ng.h/mL after oral administration to conscious and anesthetized rats, respectively, and 3303 +/- 1576 ng.h/mL after sublingual administration to anesthetized rats. Sublingual administration (5 mg/kg doses) of clomipramine formulated with a permeation enhancer, 2-hydroxypropyl beta-cyclodextrin, further increased the sublingual bioavailability to 57.1%. The sublingual route may be an alternative route of administration of clomipramine, providing enhanced bioavailability.     

Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task

In this work we aimed to re-examine the 5-HT6 receptor role, by testing the selective antagonists SB-357134 (1-30 mg/kg p.o.) and SB-399885 (1-30 mg/kg p.o.) during memory consolidation of conditioned responses (CR%), in an autoshaping Pavlovian/instrumental learning task. Bioavailability, half-life and minimum effective dose to induce inappetence for SB-357134 were 65%, 3.4 h, and 30 mg/kg p.o., and for SB-399885 were 52%, 2.2 h, and 50 mg/kg p.o., respectively. Oral acute and chronic administration of either SB-357134 or SB-399885 improved memory consolidation compared to control groups. Acute administration of SB-357134, at 1, 3, 10 and 30 mg/kg, produced a CR% inverted-U curve, eliciting the latter dose a 7-fold increase relative to saline group. Acute injection of SB-399885 produced significant CR% increments, being 1 mg/kg the most effective dose. Repeated administration (7 days) of either SB-357134 (10 mg/kg) or SB-399885 (1 mg/kg) elicited the most significant CR% increments. Moreover, modeling the potential therapeutic benefits of 5-HT6 receptor blockade, acute or repeated administration of SB-399885, at 10 mg/kg reversed memory deficits produced by scopolamine or dizocilpine, and SB-357134 (3 and 10 mg/kg) prevented amnesia and even improved performance. These data support the notion that endogenously 5-HT acting, via 5-HT6 receptor, improves memory consolidation.     

The interactive effects of nicotinic and muscarinic cholinergic receptor inhibition on fear conditioning in young and aged C57BL/6 mice

Both normal aging and age-related disease, such as Alzheimer's disease, have diverse effects on forebrain-dependent cognitive tasks as well as the underlying neurobiological substrates. The purpose of the current study was to investigate if age-related alterations in the function of the cholinergic system are associated with memory impairments in auditory-cued and contextual fear conditioning. Young (2-3 months) and aged (19-20 months) C57BL/6 mice were administered scopolamine (0.1, 0.3, 0.5, or 1.0 mg/kg), a muscarinic cholinergic receptor antagonist, mecamylamine (1.0 and 2.0 mg/kg), a nicotinic cholinergic receptor antagonist, both scopolamine and mecamylamine (0.1 and 1.0 mg/kg, respectively), or saline prior to training. Training consisted of two white-noise CS (85 dB, 30 s)-footshock US (0.57 mA, 2 s) presentations. Testing occurred 48 h post-training. Scopolamine administration impaired contextual and cued fear conditioning in young and aged mice, although the aged mice were less sensitive to disruption by scopolamine. Mecamylamine did not disrupt conditioned fear in the young or aged mice. Scopolamine and mecamylamine co-administration, at doses sub-threshold for disrupting fear conditioning with separate administration, disrupted contextual and auditory-cued fear conditioning in the young mice, indicating that in the young mice the muscarinic and nicotinic cholinergic processes interact in the formation and maintenance of long-term memories for conditioned fear. Co-administration of both antagonists did not disrupt fear conditioning in the aged mice, indicating that age-related alterations in the cholinergic receptor subtypes may occur.     

Chronic clomipramine alters presynaptic 5-HT(1B) and postsynaptic 5-HT(1A) receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for the serotonin (5-HT) uptake site or transporter. Electrophysiological experiments have provided evidence that repeated administration of clomipramine induces an increase in the sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10mg/kg/day for 28 days by osmotic minipumps, on presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors in the hypothalamus, and on postsynaptic 5-HT(1A) receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT(1A) receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynaptic 5-HT(1A) autoreceptors, as measured by the effect of a subcutaneous (s.c.) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2mg/kg or 50 microg/kg) to reduce 5-HT levels, did not change, there was a reduction in sensitivity of presynaptic 5-HT(1B) receptors, as measured by the effect of an injection of the 5-HT(1B/1D) antagonist GR 127935 (5mg/kg, s.c.) to increase 5-HT levels. This effect probably accounted for the increase in basal 5-HT levels observed in the hypothalamus after chronic clomipramine administration. Postsynaptic 5-HT(1A) receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10mg/kg clomipramine for 28 days did not show a change in postsynaptic 5-HT(1A) receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 microg/kg, s.c.) to stimulate secretion of corticosterone. Taken together with the results of previous experiments involving the cerebral cortex, these in vivo results show that chronic clomipramine exerts effects on both pre- and postsynaptic serotonin receptors, but that these effects are highly region-specific.     

Reversal of morphine-induced memory impairment in mice by withdrawal in Morris water maze: possible involvement of cholinergic system

The effects of morphine and morphine withdrawal on memory performance were examined in mice by using Morris water maze task. Morphine-induced memory impairment at the doses of 5 and 10 mg/kg recovered after repeated administration. Oxotremorine, a muscarinic receptor agonist, at the dose of 0.1 mg/kg ip, and physostigmine, a cholinesterase inhibitor, at the dose of 0.1 mg/kg ip, significantly antagonized morphine (10 mg/kg sc)-induced memory impairment in mice. Furthermore, repeated naloxone (0.5 mg/kg ip) attenuated scopolamine (0.2 mg/kg ip)-induced memory impairment. By using escalating doses of morphine for 13 days, morphine-induced memory impairment was continuously maintained. When withdrawal was precipitated by naloxone (5 mg/kg ip), or administration of oxotremorine (0.1 and 0.2 mg/kg ip) or physostigmine (0.05 and 0.1 mg/kg ip), the impairment was completely reversed. These results suggest that morphine-induced memory impairment could be partially due to the inhibition of the central cholinergic activity.     

Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain,and reduces behavioral sensitivity to scopolamine in mice

To study the effects of repeated ketamine administration on central muscarinic acetylcholine receptors (mAchRs), ddY male mice were administered subcutaneous doses of 25 mg/kg ketamine every 3 days for a total of five times. Receptor binding assays of mAchR were carried out in the forebrain (FB), cerebellum (CB) and brainstem (BS), using [³H]quinuclidinyl benzilate ([³H]QNB) as a ligand. In addition, we examined whether repeated ketamine (12.5, 25 and 50 mg/kg) or saline (five times) could modify the hyperlocomotion induced by scopolamine (0.5 mg/kg, SC) (a muscarinic antagonist), using a behavior-pharmacological technique. Repeating the ketamine administration resulted in a significant increase in the receptor density value (B_max) for [³H]QNB only in FB, dependent on the numbers of administrations (1270 ± 33 fmol/mg protein for a single dose, 1620 ± 59 for four treatments, 1738 ± 70 for five treatments without any change in apparent affinity (defined as the reciprocal of the dissociation constant) (Kd). A competitive inhibition study of repeated (5 times) administration of ketamine failed to detect any subtype-specific changes in mAchRs. Repeated ketamine administration reduced the scopolamine-induced hyperlocomotion in a doserelated way, and the changes were significant at 50 mg/kg. Our results suggest that repeated ketamine administration produces an up-regulation of mAchRs, and this change may be associated with altered Ach transmission in the central nervous system.     

Functional reactivity of different central opioid receptor systems following clomipramine treatments

Intracerebroventricular administration of the enkephalinase inhibitor, phosphoramidon (PHA, 3.7 X 10(-7) moles, i.c.v.) induced distinct wet-dog-shakes (WDS) behaviour. Naltrexone (NX) given in a low dose (0.25 mg/kg, i.p.) did not antagonize the WDS induced by PHA. A higher dose of NX (2.5 mg/kg i.p.) decreased WDS behaviour. Morphine (25 mg/kg, i.p.) induced marked catalepsy. Ketocyclazocine (0.01-1.0 mg/kg, i.p.) induced a dose related decrease in spontaneous locomotor activity. Chronic (20 mg/kg, i.p. daily for 10 days and withdrawn, 24 h prior, C.CLO) and acute (20 mg/kg, i.p., 60 min prior, A.CLO) clomipramine treatments decreased PHA-induced WDS compared to saline pretreatments. However, C.CLO treatments antagonized the morphine-induced catalepsy and ketocyclazocine-induced sedation whereas A.CLO did not alter the opiate-induced cataleptic/sedative behaviours. It is suggested that chronic clomipramine treatment induced a functional deficiency of central mu and kappa opioid receptor systems without altering the delta opioid mechanisms.     

Regulatory role of 5-HT and muscarinic receptor antagonists on the migrating myoelectric complex in rats

The 5-HT(3) and 5-HT(4) receptor antagonists alosetron and piboserod, and the muscarinic receptor antagonists PNU-171990A (2-(diisopropylamino)ethyl 1-phenylcyclopentanecarboxylate, hydrochloride) and PNU-174708A (2-(diisopropylamino)ethyl 1-phenylcyclohexanecarboxylate) were studied by electromyography, defining the migrating myoelectric complex (MMC) after i.v. administration in conscious rats. Alosetron prolonged the MMC cycle length from 16.6 to maximally 30.4 min at the dose 0.5 mg kg(-1). Piboserod promptly abolished MMC pattern and prolonged cycle length from 16.5 to >60 min at 0.5 mg kg(-1). PNU-171990A and PNU-174708A had no effect on basal cycle length up to a dose of 20 mg kg(-1). In controls, saline did not change the MMC pattern, while L-hyoscyamine at the same dose, 20 mg kg(-1), prolonged cycle length from 17.6 to 29.0 min. None of the drugs affected duration or propagation velocity of phase III of MMC. Blockade of 5-HT(4) receptors seems to exert a powerful inhibitory effect on motility, 5-HT(3) receptor blockade is less efficient and muscarinic receptor blockade has low efficacy.     

盐酸戊乙奎醚作为冠心病患者术前用药的安全性评价

目的对比评价盐酸戊乙奎醚与东莨菪碱作为冠心病患者术前用药的安全性。方法ASAⅡ~Ⅲ级全麻下行非体外循环冠状动脉搭桥术的冠心病患者40例,随机分为两组,每组20例,P组:术前静注盐酸戊乙奎醚0.01mg/kg,S组:术前静注东莨菪碱0.01mg/kg。分别记录给药前(T0),给药后5min(T1)、10min(T2)、30min(T3)的口干VAS评分;T0、T1、T2、T3、60min(T4)、90min(T5)的唾液分泌量和HR、SBP、DBP、SpO2、RPP。结果口干程度的VAS评分两组在各时点差异无统计学意义(P>0.05)。两组在T1、T2、T3的唾液分泌量与T0比明显减少,与S组相比,P组在T4、T5的唾液分泌量仍显著减少(P<0.05)。P组给药后各时点与给药前比较,HR无显著变化(P>0.05),与P组比较,S组在给药后的HR、RPP显著增加(P<0.05)。结论盐酸戊乙奎醚作为冠心病患者术前用药优于东莨菪碱,对心率影响小,效果确切、安全。     

Methylscopolamine and conditioned location avoidance

On alternate days, rats were confined to one side of a shuttlebox following IP administration of saline and to the other following the peripherally-acting muscarinic antagonist, methylscopolamine (1.2 mg/kg). They later avoided the side associated with the drug effect. By duplicating an earlier finding with centrally- and peripherally-acting scopolamine, this result identified aversive peripheral actions of the two drugs as mainly responsible for the effects observed.     

东莨菪碱对吗啡诱发条件位置性偏爱重现大鼠杏仁核p-CREB及c-Fos表达的影响

目的：探讨东莨菪碱对吗啡诱发条件位置性偏爱（conditioned place preference,CPP）重现大鼠杏仁核（amygdala nucleus,Amy）cAMP反应元件结合蛋白（phospho-cAMP response element binding protein,p-CREB）和c-Fos表达的变化。方法：以剂量递增法建立大鼠CPP模型,生理盐水替代吗啡训练大鼠,使形成的CPP逐渐消退,小剂量吗啡激活已消退的CPP。采用免疫组化技术测定不同剂量东莨菪碱对吗啡诱发CPP重现时大鼠杏仁核p-CREB和c-Fos的变化。结果：东莨菪碱可抑制吗啡点燃诱发大鼠CPP重现行为;并可减少吗啡诱发的CPP重现时大鼠杏仁核p-CREB和c-Fos的表达。结论：东莨菪碱对小剂量吗啡诱发吗啡依赖大鼠CPP重现行为的抑制作用可能与其抑制大鼠杏仁核p-CREB和c-Fos蛋白表达有关。     

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT_2C/5-HT_2B receptors was assessed using a putative in vivo model of 5-HT_2C/5-HT_2B receptor function, mCPP-induced hypolocomotion. mCPP (2,4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily × 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily × 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o.daily × 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT_2C/5-HT/_2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.     

Effects of acute or chronic administration of substituted benzamides in experimental models of depression in rats

The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose–response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose–response relationship suggests that these drugs in small doses act on presynaptic dopamine D₂ receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.     

The effects of increased serotonergic and decreased cholinergic activities on spatial navigation performance in rats

In the present set of experiments the effects of a serotonin (5-HT) reuptake blocker, alaproclate (alap) and of a muscarinic antagonist, scopolamine (scop) on place navigation (hidden platform) and cued navigation (visible platform) water maze tasks were investigated. In hidden platform experiments it was observed that scopolamine (0.8 mg/kg) impaired performance (increased escape distance). Alaproclate 7.5 mg/kg and 20 mg/kg, but not 2.5 mg/kg produced a significant impairment. The combination of the highest dose of alaproclate (20 mg/kg) and of scopolamine (0.8 mg/kg) produced a far greater place navigation deficit than scopolamine (0.8 mg/kg) alone. Pilocarpine (pilo) (6.0 mg/kg) reversed the impairment induced by scopolamine (0.8 mg/kg) alone, but the impairment induced by a combination of scopolamine (0.8 mg/kg) and alaproclate (20 mg/kg) was only partially reversed. In visible platform experiment the administration of scopolamine (0.8 mg/kg) did not impair performance, but alaproclate (20 mg/kg) impaired acquisition. Scopolamine (0.8 mg/kg) did not augment alaproclate-induced deficit in visible platform version of the task. In conclusion, we suggest that pharmacological modulation of serotonergic and cholinergic systems affects spatial navigation by modulating different mechanisms underlying different navigation strategies.     

Desipramine induces yawning behaviour in rats

Yawning behaviour in rats injected subcutaneously with antidepressant drugs was studied by direct observation. Desipramine (0.1-30 mg/kg) elicited yawning that began 15-20 min after injection and lasted for 60 min, and the dose-response curve showed a bell-shaped form. Desipramine (10 mg/kg) elicited the maximal effect (mean number of yawns 13.6). Haloperidol (0.02 mg/kg), spiperone (0.2 mg/kg), pimozide (4 mg/kg), reserpine (7.5 mg/kg), alpha-methyl-p-tyrosine (250 mg/kg) and scopolamine (0.5 mg/kg) markedly reduced yawning induced by desipramine, whereas prazosin (1 mg/kg) and phenoxybenzamine (5 mg/kg) were without effect. These findings indicate that desipramine induces yawning by a dopaminergic mechanism, and that endogenous dopamine (DA) is necessary for its occurrence. Yawning was observed also after administration of imipramine, clomipramine, trazodone, its metabolite m-chlorophenylpiperazine and (+/-)sulpiride. These drugs given in a similar dose-range to desipramine produced a weaker effect than desipramine. Selective and potent inhibitors of the uptake of noradrenaline (NA) or 5-hydroxytryptamine (5-HT), (+)oxaprotiline and citalopram, did not elicit yawning. A possibility is considered that certain antidepressant drugs induced yawning through an influence on dopaminergic system.