Chronic nicotine-induced improvement of spatial working memory and D2 dopamine effects in rats

Nicotine improves working memory function in a variety of different testing situations. In a series of studies, we have found that chronic nicotine infusion improves working memory performance of rats in the win-shift version of the radial-arm maze. In the current studies, we examined the interaction of chronic nicotine effects in the radial-arm maze with dopamine D₂ agonist and antagonist drugs, since we have previously found significant interactions of acute nicotinic agonist and antagonist effects with D₂ systems. Replicating our earlier results, significant nicotine-induced improvements in working memory performance were seen. Chronic co-infusion of raclopride, a D₂ antagonist, or quinpirole, D₂/D₃ agonist, were not found to significantly interact with the choice accuracy improvement caused by nicotine. Acute challenge with a range of quinpirole doses also did not affect the facilitating effect of chronic nicotine. This stands in contrast to the significant interactions of D₂ systems with acute nicotine effects. Acute and chronic nicotine administration have similar effects of facilitating memory performance in the radial-arm maze. However, these effects appear to have differential interactions with D₂ systems. Drug Dev. Res. 39:29–35. © 1997 Wiley-Liss, Inc.     

Bridged nicotine,isonicotine, and norisonicotine effects on working memory performance of rats in the radial‐arm maze

Nicotine and other nicotinic agonists have been found to improve performance in a variety of tasks, including the radial‐arm maze to improve memory. There has been an active effort to develop novel nicotinic agonists for the treatment of cognitive dysfunction such as is seen in Alzheimer's disease. These novel ligands can also serve as tools with which to increase our knowledge concerning the involvement of nicotinic systems with cognitive function. The current studies were conducted to assess the actions of three new nicotinic agonists, i.e., bridged nicotine, isonicotine, and norisonicotine, on choice accuracy in the radial‐arm maze. Rats were trained on a win‐shift working memory task in the eight‐arm radial maze. In Experiment 1, the rats were administered (subcutaneously) saline and three doses of bridged nicotine, isonicotine, and norisonicotine (0.5, 1.5, and 4.5 mg/kg). Bridged nicotine did not cause any significant effects on memory performance, although it did significantly increase latency and at the high dose caused severe slowing and nonperformance. Both isonicotine and norisonicotine caused a significant linear dose‐related improvement in choice accuracy, indicative of improved working memory function. In Experiment 2, another set of rats received the effective doses of 4.5 mg/kg of isonicotine and norisonicotine as well as higher doses of 13.5 mg/kg of each compound. These doses were administered alone or in combination with 5 mg/kg of the nicotinic antagonist mecamylamine to determine the nicotinic nature of the effects. As in Experiment 1 the 4.5 mg/kg of isonicotine caused a significant memory improvement. The 4.5 mg/kg dose of norisonicotine caused a more modest rise in performance, which was not significantly different from control in this experiment. When both experiments were considered together, the 4.5 mg/kg doses of both isonicotine and norisonicotine were the most effective in improving working memory performance. Significant improvements in working memory were seen with both drugs (P < 0.025). The higher doses of 13.5 mg/kg of both isonicotine and norisonicotine resulted in nearly control‐level performance. Thus, the typical inverted U‐shaped dose‐effect function was evident for both isonicotine and norisonicotine. Mecamylamine brought performance improved by the 4.5 mg/kg dose back to control levels, providing evidence for the nicotinic nature of the effect. Both isonicotine and norisonicotine show promise for development as memory‐improving nicotinic agonist drugs. Drug Dev. Res. 46:107–111, 1999. © 1999 Wiley‐Liss, Inc.     

Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats.

Nicotine has been shown in a variety of studies to improve memory performance. The cognitive effects of nicotine are particularly important with regard to schizophrenia. In the current studies nicotine interactions with three different antipsychotic drugs, haloperidol, clozapine and risperidone, were assessed with regard to memory function. Female Sprague-Dawley rats were trained on the radial-arm maze to asymptotic levels of choice accuracy. They were then administered nicotine alone or in combination with haloperidol, clozapine or risperidone. Acute haloperidol (0.04 mg/kg) did not by itself affect memory performance. Co-administration of haloperidol with nicotine, however, decreased memory performance compared with nicotine administration in isolation. Acute clozapine (1.25 and 2.5 mg/kg) caused a significant memory impairment, an effect reversed by acute nicotine co-treatment. Risperidone (0.05 mg/kg), like haloperidol, did not by itself affect memory performance. Risperidone co-administration with nicotine, however, did significantly attenuate the improvement caused by nicotine administration in isolation. The similar interaction of haloperidol and risperidone with nicotine may be due to their common action of blocking D(2) receptors, a mechanism of action not shared by clozapine. In contrast to the interaction of nicotine with haloperidol or risperidone, nicotine effectively reversed clozapine-induced memory impairment. These studies demonstrate interactions between nicotine and antipsychotic drugs in terms of memory, which may have important impacts on the treatment of schizophrenia.     

Effects of dopamine D1-like and D2-like agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect functions

Rationale: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D_1-like and D_2-like receptor mechanisms may be involved, recent studies suggest that D_1-like and D_2-like agonists have differing profiles of cocaine-related actions. Objective: To develop a procedure for rapid assessment of complete dose–effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D_1-like and D_2-like agonists on cocaine self-administration using this procedure. Methods: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D_1-like and D_2-like agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. Results: Complete inverted U-shaped dose–effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose– effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D_1-like agonists SKF 82958 (0.32–1.8 mg/kg) and R-6-Br-APB (0.1–1.0 mg/kg) produced downward shifts in the cocaine dose–effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D_2-like agonists quinelorane (0.001–0.01 mg/kg) and 7-OH-DPAT (0.01–0.10 mg/kg) shifted the cocaine dose–effect function to the left. D_2-like agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. Conclusions: The results suggest that D_1-like and D_2-like agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence. Received: 20 March 1999 / Final version: 10 August 1999     

Persistence of nicotinic agonist RJR 2403‐induced working memory improvement in rats

Nicotinic systems are involved in the neural basis of memory function and nicotinic agonists have shown promise for the treatment of cognitive dysfunction. Both acute and chronic nicotinic treatment has been shown to improve memory performance. There is some evidence for the persistence of nicotine‐induced memory improvements lasting longer than the pharmacokinetic presence of nicotine. Novel nicotinic agonists may produce the beneficial effects of nicotine on cognitive function with fewer side effects. RJR 2403 (metanicotine or (E)‐N‐methyl‐4‐(3‐pyridinyl)‐3‐butene‐1‐amine) a preferential α4β2 nicotinic agonist has been shown in previous studies to improve memory function. The present study examined the persistence of oral RJR 2403 on memory performance in young adult Sprague‐Dawley rats (3–5 months old) 30 min, 1 h, and 6 h post‐administration (PO). In the first experiment, the typical inverted U‐shaped dose response curve for cognitive enhancing drugs was seen with RJR 2403 30 min after administration. The lower dose of 1 mg/kg (3.6 μmol/kg), but not higher doses of 3 or 10 mg/kg (10.8 or 36 μmol/kg), of RJR 2403 significantly (P < 0.05) improved working memory on the radial‐arm maze relative to placebo‐treated controls. In the second experiment, young adult rats were administered RJR 2403 (0, 0.3, or 1.0 mg/kg) and tested 1 h or 6 h following administration in separate treatment groups. The 0.3 mg/kg RJR 2403 dose (1.08 μmol/kg) caused a significant (P < 0.05) memory improvement 1 h after oral administration. Interestingly, both the 0.3 and 1.0 mg/kg RJR 2403 doses (1.08 and 3.6 μmol/kg) significantly (P < 0.05) improved memory six hours after administration. These data demonstrate the efficacy of oral RJR 2403 in improving cognitive performance and the long duration of action of RJR 2403 in young adult rats. In contrast, no significant memory improvement was seen in aged rats aged (24–26 months old) after RJR 2403 administration. The inability of RJR 2403 to enhanced cognitive functions in aged rats might be related to the decrease in the number of α4β2 nicotinic receptors, which occurs with age. A similar decreased responsiveness in aged rats has been seen with nicotine. The persistence of action of RJR 2403 provides additional promise for its potential as a treatment for cognitive dysfunction. However, the decreased responsiveness in subjects in populations with decreased nicotinic receptor number may limit the effectiveness of nicotinic therapies. Drug Dev. Res. 55:97–103, 2002. © 2002 Wiley‐Liss, Inc.     

Chronic treatment with D1 and D2 dopamine receptor agonists: combined treatments interact to differentially affect brain levels of monoamines

Summary Recent evidence of functional interactions between D1 and D2 dopamine receptor subtypes has led to the concept that many of the behavioural effects of dopamine agonists occur only with activation of both receptor subtypes. Thus, combined treatment with dopamine agonists selective for each of the D1 and D2 receptors may be an effective therapy for Parkinson's disease, chiefly characterized by loss of central dopamine-containing neurons. In addition, recent hypotheses of the possible pathogenesis of this disorder have suggested that metabolism of dopamine by monoamine oxidase in the presynaptic terminal may contribute to the loss of dopaminergic cells, through the production of reactive by-products. Therefore, the effects of chronic (15 day) treatment of rats with different doses of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a D2 receptor agonist), SKF 38393 (a D1 receptor partial agonist) or combinations of both drugs on levels of brain monoamines and some of their acidic metabolites were investigated. Little or no effects of the drugs were observed on measures of dopamine or noradrenaline when given separately, while each selective agonist dose-dependently reduced serotonin levels. Combined treatment with the two agonists produced profound effects on the catecholamines, but with no effect on 3,4-dihydroxyphenylacetic acid, the metabolite of dopamine produced by monoamine oxidase. In addition, the effects of combined treatment on serotonin levels were opposite of those of the drugs given independently. Concomitant treatment of animals with both D1 and D2 receptor agonists can therefore increase tissue levels of dopamine without increasing the potentially harmful metabolism of dopamine by monoamine oxidase.     

Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol

Rationale Although chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans, there are few reports about an animal model that reflects METH-induced impairment of working memory. Objectives In this study, we investigated the effect of repeated METH treatment on spatial working memory in rats. Materials and methods Rats were repeatedly administered METH (2 mg/kg) once a day for 7 days, and their memory function was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Results METH-treated animals showed an impairment of performance in the test phase when the delay time was increased from 5 to 30 min or longer. The effect of METH persisted for at least 14 days after the drug withdrawal. METH-induced impairment of working memory was reversed by clozapine (3 and 10 mg/kg, for 7 days), but not haloperidol (1 and 2 mg/kg, for 7 days). The improving effect of clozapine diminished 7 days after the withdrawal. Phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) levels were significantly increased in the hippocampus of saline-treated control rats from 5 to 60 min after the training phase. In contrast, hyperphosphorylation of ERK1/2 was abolished in the hippocampus of rats treated with METH. Conclusions These findings suggest that repeated METH treatment induces impairment of working memory, which is associated with a dysfunctional ERK1/2 pathway in the hippocampus. Furthermore, clozapine may be effective for the treatment of METH-induced cognitive dysfunction. Taku Nagai and Kazuhiro Takuma contributed equally to the work.     

Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task

RATIONALE: Understanding the mechanistic basis of working memory, the capacity to hold representation "on line," is important for delineating the processes involved in higher cognitive functions and the pathophysiology of thought disorders. OBJECTIVES: We compared the contribution of glutamate and dopamine receptor subtypes to temporal aspects of working memory using a modified rodent spatial working memory task that incorporates important elements of clinical working memory tasks. METHODS: A discrete paired-trial variable-delay T-maze task was used. Initial characterization studies indicated that performance on this task is stable at seconds-long retention intervals, is sensitive to retention interval and proactive interference, and is dependent on the integrity of the medial prefrontal cortex. RESULTS: Consistent with clinical findings, low dose amphetamine (0.25 mg/kg) produced a delay-dependent improvement in performance, while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted dose- and delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/kainate antagonist had effects similar to the mGluR2/3 agonist. In contrast, NMDA receptor antagonist-induced impairment was memory load-insensitive, resulting in chance-level performance at all retention intervals. CONCLUSIONS: These findings suggest that activation of NMDA receptors is necessary for the formation of mnemonic encoding while modulatory components involving slow asynchronous release of glutamate and phasic release of dopamine contribute to the active maintenance of information during the delay period.     

Effects of subchronic exposure to toluene on working and reference memory in rats

Rats that had inhaled 600 ppm of toluene vapor 24 h a day for 50 days after weaning at 3 weeks of age were trained in a radial-arm maze with a 4-out-of-8 baiting procedure, and their performance based upon reference and/or working memory was compared with that of air-exposed control animals during the early stage of acquisition. Pharmacological challenge testing was also conducted after completing a total of 48 training sessions; the effects of scopolamine and methylscopolamine on the maze performance were measured after acute IP administration to determine the long-lasting effects of toluene exposure. During the acquisition stage, toluene-exposed rats made a significantly smaller number of reference memory errors (entries into “never-baited” arms) and total arm entries than the control rats. No significant effects of exposure were observed for working memory errors (reentries into “already-entered” arms). During the pharmacological challenge testing, only scopolamine increased both types of errors significantly. No significant differences due to toluene exposure were revealed.     

Mesocortical dopamine modulation of executive functions: beyond working memory

Rationale Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D₁ receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D₂ and D₄) is unclear.Objectives This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making.Results and conclusions Whereas PFC D₁ receptor activity is of primary importance in working memory, D₁ and D₂ receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the “inverted U-shaped” function of D₁ receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D₁, D₂, and D₄ receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.     

Chronic nicotine working and reference memory effects in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs

Chronic nicotine infusion has been found in a series of studies in our laboratory to significantly improve choice accuracy of rats in the eight-arm radial maze. The current study was designed to compare the effects of chronic nicotine infusion on working and reference memory in a 16-arm radial maze. Nicotine was administered to female Sprague-Dawley rats at approximately 5 mg/kg per day SC via osmotic minipumps. Controls received saline infusions. Chronic nicotine infusion significantly lowered the number of working memory errors compared to controls, whereas the number of reference memory erros was not significantly affected. The modest nicotine-induced reduction in working memory errors was seen as a main effect over the 4 weeks of infusion, but the clearest effect was seen in weeks 3–4 of nicotine administration. For the 2 weeks after withdrawal, the nicotine effect was no longer evident. Acute D₁ challenges were given with the D₁ agonist dihydrexidine (0, 0.25, 0.5 and 1 mg/kg) and the D₁ antagonist SCH 23390 (0, 0.005, 0.015 and 0.05 μg/kg) during weeks 3–4 of chronic nicotine administration and weeks 1–2 after withdrawal from nicotine. Dihydrexidine caused a modest dose-related increase in reference memory errors but not working memory errors in the nicotine-treated, but not the control rats. The D₁ antagonist SCH 23390 caused a modest though significant decrease in reference memory errors but not working memory errors in the control, but not the nicotine-treated rats. The behavioral specificity of chronic nicotine infusion was demonstrated with selective improvement in working memory function. Pharmacological interactions were seen with chronic nicotine treatment increasing responsivity to D₁ agonist and decreasing responsivity to a D₁ antagonist with regard to reference memory. The mechanisms of this interaction are still undiscovered.     

银杏叶提取物对东莨菪碱所致大鼠空间工作记忆障碍的影响

目的探讨银杏叶提取物对东莨菪碱所致大鼠空间工作记忆障碍的影响。方法大鼠随机分成3组:正常组、东莨菪碱组和银杏叶治疗组。水迷宫试验,东莨菪碱组按0.4mg/kg腹腔注射,以后每天注射等体积生理盐水,连用6d。正常对照组每天注射与东莨菪碱等体积的生理盐水连用6d;银杏叶治疗组按10mg/kg腹腔注射,1次/d,连用6d。1周后进行Morris水迷宫试验,观察3组大鼠平台逃避潜伏期,并与实验后第1天比较。结果两次逃避潜伏期在正常组呈非常显著性差异(46.4±17.7,13.4±8.2,P<0.01)东莨菪碱组无统计学差异(23.6±14.3,18.1±9.8,P>0.05),银杏叶组呈显著性差异(27.9±14.3,9.0±3.8,P<0.05)。结论M-型胆碱能受体阻滞剂东莨菪碱能损害大鼠空间工作记忆,银杏叶提取物能改善这种损害,说明银杏叶提取物是通过影响胆碱能系统来发挥其促智作用的。     

脱氢表雄酮对慢性轻度应激小鼠认知功能的影响

目的 :观察慢性轻度应激 (CMS)小鼠模型的自发活动与认知行为变化 ,中枢胆碱能毒蕈碱型(M)受体的改变及药物脱氢表雄酮 (DHEA)的干预作用。方法 :连续 3wk对小鼠采用 7种不可预知的应激原建立CMS模型 ,设DHEA低、高两个药物治疗组 ,用自发活动和水迷宫法测定行为改变 ,用放射性配基法测定皮层、海马、下丘脑和小脑的M受体改变。结果 :CMS组小鼠自发运动明显减少 ,寻找平台潜伏期明显延长 ,DHEA补充后可有效改善上述行为变化 ;CMS组小鼠大脑皮层、海马的M受体特异性结合与正常对照组比较显著减少 (P <0 .0 5)。使用DHEA后 ,恢复至正常水平。结论 :CMS可使动物的自发运动减少 ,并使其空间学习记忆功能减退 ,该变化与脑内胆碱能受体活性低下有关。补充DHEA可有效缓解上述变化 ,以低剂量效果好     

Gradient of dopamine responsiveness to dopamine receptor agonists in subregions of the rat nucleus accumbens

The present study sought to investigate the possibility that the degree of selectivity of dopamine D3/D2 receptor agonists such as quinelorane, 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), quinpirole and apomorphine on dopamine D3 over D2 receptor subtypes can be assessed by measuring dopamine transmission in the shell vs. core compartments of the nucleus accumbens by using microdialysis in freely moving rats. Significant reductions in dialysate dopamine levels compared to vehicle-treated animals were observed in the shell of the nucleus accumbens with 3, 10 and 30 microg/kg quinelorane, 100 microg/kg 7-OH DPAT, 25 and 100 microg/kg quinpirole, and 100 microg/kg apomorphine. In the core subregion, significant reductions in dopamine were seen at 10 and 30 microg/kg quinelorane, 25 and 100 microg/kg 7-OH-DPAT, 100 microg/kg quinpirole and 100 microg/kg apomorphine. However, a significant shell/core dichotomy could only be observed in response to the lowest dose of quinelorane (3 microg/kg) with the shell being hyper-responsive compared with the core. The present findings suggest that quinelorane is one of the most selective dopamine D3 receptor agonists based on its ability to target the shell subregion of the nucleus accumbens.     

Nω-硝基-L-精氨酸对大鼠八臂迷宫工作记忆的作用(英文)

目的:研究一氧化氮合成酶抑制剂N_ω-硝基-L-精氨酸(NNA)对大鼠空间工作记忆的作用.方法:采用八臂迷宫延迟插板的程序.结果:腹腔注射NNA 100 mg kg~(-1)对大鼠八臂迷宫选择的准确性没有显著影响,只能增加反应的潜伏期.东莨菪碱0.25 mg kg~(-1)使大鼠延迟后的错误选择显著增加.脑室内注射NNA(10,50,100 nmo1/1 μL)没有影响准确性.结论:急性NNA给予对大鼠空间工作记忆的形成和使用没有显著影响.     

Effects of dopamine antagonists in a two-way active avoidance procedure in rats: interactions with 8-OH-DPAT,ritanserin, and prazosin

Using a conditioned avoidance procedure in rats, the present study examined the ability of 8-OH-DPAT, ritanserin, and prazosin to alter the effects of the dopamine antagonists, raclopride and haloperidol, on avoidance- and on escape responding. The 5-HT_1A agonist 8-OH-DPAT (0.16 mg/kg) significantly enhanced the inhibitory effects of both raclopride and haloperidol on the conditioned avoidance response and produced a small enhancement of the effects of haloperidol on escape failures. The α₁-adrenoceptor antagonist prazosin (0.63 mg/kg) significantly enhanced the effects of raclopride on the conditioned avoidance response, but enhanced the effects of only a single dose of haloperidol; prazosin did not alter the effects of either dopamine antagonist on escape failures. The 5-HT₂ antagonist ritanserin (0.16 mg/kg) failed significantly to alter the effects of the dopamine antagonists examined here. These findings suggest that blockade of 5-HT₂ receptors may not enhance the antipsychotic efficacy of D₂-like antagonists. Further, they confirm previous findings with respect to interactions between 5-HT_1A agonists and neuroleptics, and support the hypothesis that combined 5-HT_1A agonist/D₂-like antagonist properties may be of clinical importance. Received: 19 April 1996/Final version: 1 July 1996     

Effects of stimulation of putative dopamine autoreceptors on electroencephalographic power spectrum in comparison with effects produced by blockade of postsynaptic dopamine receptors in rats

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D₂ blocker) or SCH 23390 (0.2 mg/kg i.p., D₁ blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D₁ or D₂ postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D₁ and D₂ receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.     

Effects of chlorisondamine on nicotinic receptor binding in whole brain and nicotine-induced changes in locomotor activity in rats

Chlorisondamine, a nicotinic cholinergic receptor antagonist, can block many of the in vivo effects of nicotine for weeks after a single icv injection. The time course of this effect was examined in a single group of rats by assessing the effects of nicotine on locomotor activity at 1, 3, and 6 weeks after the icv administration of 23 nmol of chlorisondamine. The effects of nicotine on locomotor activity were biphasic as has been previously reported, with decreases in activity early in the session and increases in activity later in the session. These effects of nicotine were blocked in chlorisondamine-treated rats at 1 or 3 weeks but not 6 weeks after administration of chlorisondamine. Nicotinic receptor binding in the brains of chlorisondamine-treated rats revealed no change in B_max but a significant increase in affinity (47–59% decrease in K_d) 1, 3, 6, or 7 weeks after treatment. In contrast to its effects on affinity when administered icv, chlorisondamine did not alter binding affinity when added directly to the incubation buffer in vitro. Thus, although chlorisondamine significantly alters neuronal nicotinic cholinergic receptor binding affinity, this effect of chlorisondamine on binding affinity does not appear to be a direct effect of chlorisondamine on the receptor or to match the time course of chlorisondamine blockade of nicotine-induced changes in locomotor activity. © 1994 Wiley-Liss, Inc.     

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D₂ autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D₁ receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D₁ class receptor agonist SKF 38393, the DA D₂ class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D₁ receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D₁ responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D₁ receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization. Received: 23 February 1998/Final version: 2 April 1998     

Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats

RATIONALE: Rolipram, a selective inhibitor of cyclic AMP-specific phosphodiesterase (PDE4), has been shown to enhance scopolamine-induced impairment of working memory. However, its effect on reference memory, which appears to be related to the level of cyclic AMP (cAMP), has not been investigated yet; in addition, the mechanism involved in its effects on memory remains to be elucidated. OBJECTIVES: To investigate the effects of rolipram on working and reference memories impaired by scopolamine and the involvement of cAMP. METHODS: By administration (IP) of rolipram and forskolin, an activator of adenylyl cyclase (AC), the effects of both drugs on the number of correct choices and errors in experiment 1 and, the frequency of both working memory errors and reference memory errors in experiment 2 were observed in two eight-arm radial maze tasks in rats. RESULTS: In experiment 1, rolipram (0.01-1.0 mg/kg) attenuated the scopolamine-induced (0.5 mg/kg) increase in the total number of errors in dose- and time-dependent manners. The minimum effective dose of rolipram was 0.05 mg/kg and the effects lasted nearly 60 min. By contrast, forskolin (1.0-10.0 mg/kg) failed significantly to affect any of the above indices altered by scopolamine. In experiment 2, rolipram (0.05 and 0.1 mg/kg) decreased the frequencies of both working and reference memory errors that were elevated by scopolamine. Forskolin did not alter either type of error at a dose that increased the exploration time. CONCLUSION: Rolipram may exert its effects of reversing both working and reference memory impairments via increased cyclic AMP concentrations in certain signal transduction pathways, rather than by a generalized increase in cAMP.