Associative influences on tolerance to decreased fixed-interval responding by clonidine

Responding of rats was maintained under a 5-min fixed-interval schedule of food presentation. One group of animals (n = 5) received the alpha-2-agonist clonidine (0.1 mg/kg/day) before experimental sessions for 16 weeks. Additional animals (n = 5) also received 0.1 mg/kg/day for 16 weeks but experienced drug administration after sessions for 4 weeks, before sessions for 4 weeks, after sessions for 4 weeks, and then finally, before sessions for 4 weeks. Animals receiving clonidine before daily experimental sessions for the entire period developed tolerance to decreased responding within 3 weeks, and their responding remained near control levels except when clonidine was occasionally preceded by the alpha-2-antagonist yohimbine. Animals receiving clonidine after sessions did not develop tolerance, and responding was markedly suppressed during the first exposure to presession clonidine. When these animals subsequently received clonidine again after sessions, responding was disrupted (increased) in spite of continued drug administration as if animals were "dependent" on clonidine in specific circumstances. When these animals again received clonidine before sessions, responding was partially suppressed in spite of uninterrupted drug administration as if animals had "lost" tolerance in specific circumstances. Tolerance to the behavioral effects of clonidine on fixed-interval responding was not determined by the presence of drug alone, but by the associative influence of drug-related effects in the presence of specific environmental stimuli.     

Antidepressant-like actions of an AMPA receptor potentiator (LY392098)

LY392098 is a member of a novel class of biarylpropylsulfonamides that potentiates AMPA receptor-mediated responses both in vitro and in vivo. In this study, the effects of LY392098 were evaluated in two “behavioral despair” models (the forced swim and tail suspension tests) commonly used to identify clinically useful antidepressants. LY392098 reduced immobility in the forced swim test in both rats and mice, with a minimum effective dose of 0.5 mg/kg (i.p.) in both species. LY392098 (0.1–10 mg/kg, i.p.) did not affect motor activity of rats, indicating that the ability of this compound to reduce immobility in the forced swim test is unrelated to a motor stimulant action. LY392098 also reduced immobility in the tail suspension test in a dose-dependent manner, with a minimum effective dose of 5 mg/kg (i.p). A non-competitive AMPA antagonist (LY300168) blocked the activity of LY392098 in the forced swim test, but did not affect imipramine-induced reductions in immobility. Thus, AMPA receptor activation appears to be required for the antidepressant-like effect of LY392098, but not imipramine. These findings indicate that biarylpropylsulfonamides, exemplified by LY392098, may represent a novel class of antidepressants.     

Effects of fixed-ratio length on the development of tolerance to decreased responding by l-nantradol

Key pecking of pigeons was maintained under either a 100-response or a 300-response fixed-ratio schedule of food presentation, and animals received 0.03 mg/kg/day l-natradol prior to experimental sessions. Tolerance developed for initial rate decreases under fixed ratio 100 in 10–12 sessions, but tolerance did not develop under fixed ratio 300 for up to 30 sessions. When the fixed ratio was changed from 300 back to 100, tolerance developed in three to four sessions, and when the fixed ratio was changed from 100 back to 300, tolerance diminished in two to three sessions. The importance of fixed-ratio parameter for the observation of tolerance extends the generality of the influence of reinforcement processes on tolerance.     

Effects of fixed-ratio requirement on observed tolerance to decreased responding by clonidine

Responding of rats was maintained under either a 10- or a 40-response fixed-ratio schedule, and "local" rates of responding were 0.29-0.37 responses per sec for both schedules. Clonidine decreased responding for both schedules in a similar and dose-dependent manner, and the largest dose tested (0.3 mg/kg) completely suppressed behavior. When 0.1 mg/kg was administered immediately prior to 30 daily experimental sessions, FR10 responding recovered to control levels within 15 sessions, whereas FR40 responding recovered only to approximately 60% of control level at asymptote. These results continue to identify boundary conditions for the influence of reinforcer loss on tolerance development, and they emphasize the overriding influence of behavioral processes on observed tolerance to the behavioral effects of drugs.     

The development of pharmacological tolerance to the effect of nicotine on schedule-controlled responding in mice

The effects of nicotine in mice responding on a fixed-ratio schedule for a sweetened milk reinforcer were determined before, during, and after daily administration of the drug. Druing chronic treatment, responding was initially depressed in a group of mice given presession injections of nicotine and gradually returned to prechronic baseline levels. Responding to single doses of nicotine shifted to the right following chronic treatment for animals receiving either presession or postsession chronic injections of 1.2 mg/kg nicotine. Following termination of chronic treatment, both groups lost tolerance to the chronic dose at similar rates. These data indicate that animals given chronic pre- and postsession injections of nicotine develop tolerance to the pharmacological effects of the drug and that behavioral variables do not influence the development of tolerance to nicotine.     

Effects of shock intensity on observed tolerance to decreased avoidance responding by clonidine

Interruption of a photobeam by rats was maintained under a Sidman avoidance schedule, and moderate response rates were maintained at low frequencies of electrical stimulation. After acute injections of clonidine, responding decreased, and frequency of electric stimulation increased, in a dose-dependent manner. At a lower intensity of electric stimulation, response-suppressive effects of clonidine did not diminish for up to 40 sessions with daily administration of clonidine. At a higher stimulus intensity, however, response-suppressive effects of clonidine diminished within 15 sessions, and stimulus frequency was at control level after 40 sessions with daily administration of clonidine. Behavioral consequences altered the effects of chronic clonidine so that tolerance was observed at a higher, but not a lower, intensity of electric stimulation.     

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.     

The effects of new sigma (σ) receptor ligands,PB190 and PB212, in the models predictive of antidepressant activity

BackgroundA number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms (e.g. forced swim test, tail suspension test, olfactory bulbectomy model, conditioned fear stress). The objective of the present study was to find out whether PB190 and PB212, new σ₁ receptor ligands, show the effects in some models predictive of antidepressant activity.MethodsThe impact of PB190 and PB212 on the immobility time in the forced swim test (FST) and tail suspension test (TST) was assessed in C57BL/6J male mice. Extracellular bradykinin triggers a transient increase in intracellular calcium concentration by activating the phospholipase C/IP₃ pathway. The intracellular calcium concentration was estimated with the dual wavelength ratiometric probe Fura-2.ResultsIn the FST model, PB190 showed a moderate antidepressant-like effect (only in the dose of 3 mg/kg) which was enhanced by joint treatment with amantadine (AMA), 10 mg/kg (inactive per se). The decrease in the immobility time induced by the combined treatment with PB190 and AMA was counteracted by PB212 and by BD1047, a σ₁-receptor antagonist. The in vitro studies indicated that Ca²⁺-response was increased by 1 μM PB190, like by the σ₁-agonist (+)-pentazocine, while 1 μM PB212 behaved line σ₁-antagonist, BD1063. On the other hand, 100 μM PB190 negatively affected the Ca²⁺-response after bradykinin.ConclusionsThe obtained results: 1/indicated that in the in vivo conditions PB190 behaved as a σ₁-receptor agonist while PB212 counteracted its effect, confirming the in vitro data; 2/gave support to the hypothesis that σ₁-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity; 3/revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA.     

Effects of antidepressants and anticholinergics in a mouse "behavioral despair" test

A new "behavioral despair" test previously asserted to be selectively sensitive to antidepressant treatments was examined for specificity. The results of the present study demonstrate that, in addition to antidepressants, agents with anticholinergic properties such as scopolamine, danitracin, benactyzine, benztropin, clozapine and cyproheptadine also reduce immobility in this test. These results indicate that the swim test in mice cannot be considered selectively sensitive to antidepressants.     

Situational specificity of tolerance to decreased operant responding by cocaine

Responding of rats was maintained in three different environmental situations each day. Interruption of a photobeam was maintained under a shock avoidance schedule in the first session, lever pressing was maintained under a 5-min fixed-interval (FI) schedule of food presentation in a second session, and nose-key pressing was maintained under a 30-response fixed-ratio (FR) schedule of food presentation in a third session. After receiving once-weekly injections of cocaine (3-17 mg/kg) prior to each of the sessions, animals received daily administration of 13 mg/kg after responding in the third daily session for four weeks, before responding in the third session for four weeks, before responding in the second daily session for four weeks, and then before responding in the first daily session for four weeks. Tolerance that developed in the environment that was coincident with the pharmacological actions of cocaine did not extend to operants in other environmental situations. Instead, tolerance to the behavioral effects of cocaine was specific to particular stimulus conditions associated with drug administration, indicating that the expression of tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.     

Self-inhibiting action of nortriptyline's anti-immobility effect at high plasma and brain levels in mice

Animals were treated acutely with 0, 2.5, 5, 10, 20 and 40 mg/kg nortriptyline (NT) 30 min before the tail suspension test (TST). They were sacrificed after test for evaluation of plasma and brain levels of NT. The anti-immobility effect increased with increasing doses and concentrations of the drug, reaching statistical significance (P<0.01, Dunnett test) at a dose of 20 mg/kg, 865 ng/ml in plasma and 11 µg/g in brain tissue. The anti-immobility effect was, however, blocked with the highest, non-toxic, concentrations. Results seem to indicate a biphasic curvilinear relationship between plasma and brain levels of NT and behaviour in mice.     

Effects of local anesthetics on fixed-interval responding in rhesus monkeys

Several local anesthetics of both the ester and amide type were administered IM to rhesus monkeys trained to respond on a fixed-interval 5 min schedule of food delivery. With the exception of procainamide, all local anesthetics produced dose-related decreases in response rates. Effects on pattern of responding varied between local anesthetics. With some (cocaine, dimethocaine and lidocaine), rate-dependent effects were apparent. When control rates were low, these compounds increased rates; when control rates were high, they decreased rates. However, with others (procaine, chloroprocaine, tetracaine and propoxycaine) no rate-dependent effects were noted; i.e., these compounds had little or no effect on the pattern of responding, even at doses that substantially reduced response rates. Consistent with other experiments with these compounds, cocaine was the most potent of the group. In several instances, local anesthetics which had similar stimulus properties in other behavioral paradigms differed in terms of their effects on fixed-interval behavior.     

GL-21抗抑郁的药效初探

目的：初步评价GL-21的抗抑郁药效,并探讨其可能的优势。方法：采用小鼠悬尾试验模型和小鼠强迫游泳试验模型初步评价抗抑郁效果。小鼠自发活动实验评价其兴奋作用。小鼠育亨宾毒性增强实验探讨其可能的作用机制。大鼠阴茎勃起实验,考察其对性功能的改善作用。结果：GL-21（1、2、4、8 mg·kg-1）可显著减少悬尾和强迫游泳试验的不动时间（P<0.01或P<0.05）,且不显著增加小鼠自发活动的总路程。GL-21（2、4、8 mg·kg-1）显著增强育亨宾毒性,增加小鼠死亡。剂量低至1.25 mg·kg-1（sc）可显著诱导大鼠阴茎勃起。结论：GL-21可能具有抗抑郁作用且改善性功能障碍。     

Situational specificity of tolerance to decreased operant responding by morphine andl-nantradol

In one experiment, key pressing of rats was maintained under a fixed-ratio schedule of food presentation in a first daily session in one environmental situation, and interruption of a photobeam was maintained under a continuous shock avoidance schedule in a second daily session in another environmental situation. After receiving acute injections of the cannabinoidl-nantradol (0.01–0.3 mg/kg), rats received daily administration of a rate-decreasing dose of the drugafter the second session, thenbefore the second session, and thenbefore the first session. Tolerance that developed to decreased avoidance responding in the second daily session did not extend to decreased fixed-ratio responding in the first daily session, but was specific to circumstances coinciding with the pharmacological actions ofl-nantradol. In a second experiment, lever pressing of squirrel monkeys was maintained under an identical fixed-interval schedule of food delivery in two separate daily sessions in different experimental situations. After receiving once-weekly acute injections of morphine (0.3–3.0 mg/kg), monkeys received daily administration of a rate-decreasing dose of morphine in a counter-balanced orderbefore each session. Just as for experiment 1, tolerance that developed in the environment coinciding with the pharmacological actions of morphine did not immediately generalize to operants in the other environmental situation. Instead, tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.Animals used in this study were maintained in accordance with guidelines of the Animal Care Committee of the Worcester Foundation for Experimental Biology and of the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication Number (NIH)85-23, revised 1985     

Vigabatrin attenuates the development and expression of tolerance to morphine-induced antinociception in mice

The efficacy of opioids is limited in chronic pain treatment, as a result of development of opioid tolerance. Based on previous demonstration of the effect of anticonvulsant drugs on morphine antinociception, the present study investigated the effects of vigabatrin (VGB) on the development and expression of morphine tolerance in mice. 101 male NMRI mice weighing 20-25 g were used in these experiments. To evaluate the VGB effects on the development or expression of morphine tolerance, animals received VGB (5, 10 or 20 mg/kg; i.p.), 30 min before morphine (50 mg/kg; s.c.) during induction period once daily for 3 days; or 30 min before challenge dose of morphine (5 mg/kg) before and after morphine-induced tolerance, respectively. The analgesic effect of VGB was evaluated at 30-time intervals (30, 60, 90 and 120 min) by tail-flick analgesiometer. The results showed that VGB at the dose of 20 mg/kg significantly attenuated the development and expression of morphine tolerance. Additionally, VGB alone did not affect the tail-flick latency times. Therefore, while VGB alone has no antinociceptive effect, it can prevent the development of morphine tolerance in mice.     

丁螺环酮贴剂对小鼠抗焦虑作用的研究

目的:研究丁螺环酮贴剂对小鼠的抗焦虑作用.方法:应用小鼠应激性直肠升温、爬梯及悬尾试验,观察丁螺环酮贴剂抗焦虑的药效和维持作用时间.结果:与对照组比较,丁螺环酮贴剂B、C(30、60 mg/kg)组直肠温度均显著降低(P<0.05,P<0.01);丁螺环酮贴剂A(15 mg/kg)、C组后肢站立数与对照组比较,差异具有显著性统计学意义(P<0.05,P<0.01),丁螺环酮贴剂B、C组后肢站立时间与对照组比较,差异具有显著性统计学意义(P<0.05,P<0.01),丁螺环酮贴剂B组总爬梯数与对照组比较,差异具有非常显著性统计学意义(P<0.01);丁螺环酮贴剂B、C组静相累积时间与对照组比较,差异具有非常显著性统计学意义(P<0.01),丁螺环酮贴剂C组身体扭动次数与对照组比较,差异具有显著性统计学意义(P<0.05);丁螺环酮贴剂(100 mg/kg)维持作用时间可达120 min.结论:丁螺环酮贴剂对小鼠具有明确的抗焦虑作用,最佳剂量为60 mg/kg,维持作用时间为120 min.     

柴芪口服液抗抑郁作用实验研究

摘要目的：实验观察柴芪口服液的抗抑郁作用。方法：将动物随机分为空白对照组、阳性对照（氟西汀）组、柴芪口服液高、中、低剂量组,分别灌胃给予同等容积的相应药物,qd,连续给予14d,末次给药后40min,采用小鼠悬尾实验、强迫游泳实验及开场实验等方法观察柴芪口服液的抗抑郁作用。结果：在小鼠强迫游泳实验和小鼠悬尾实验中,柴芪口服液大剂量（生药6．4g·kg^-1）能明显缩短两种“行为绝望”模型小鼠的不动时间;在小鼠开场实验中,柴芪口服液6．4g·kg^-1使小鼠水平方向活动次数显著提高,与对照组比较有显著性差异（P＜0．05）。结论：柴芪口服液具有抗抑郁作用。     

Toluene has antidepressant-like actions in two animal models used for the screening of antidepressant drugs

Rationale  Many abused solvents share a profile of effects with classical antidepressants. For example, toluene, which is a representative and widely abused solvent, has been reported to increase both serotonin and noradrenaline levels in several brain areas after an acute exposure and to act as a noncompetitive antagonist of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptor subtype. Therefore, it is possible that toluene could possess antidepressant-like actions. Objective  To provide an initial screening of toluene’s antidepressant-like actions in the forced swimming test (FST) and the tail suspension test (TST) in mice and to analyze its possible mechanism of action. Materials and methods  Two series of experiments were performed. In the first one, male animals were exposed to toluene (0, 500, 1,000, 2,000, or 4,000 ppm) in a static exposure chamber for 30 min, and immediately after, evaluated for antidepressant-like effects. The results were compared with those obtained from mice treated with the serotonergic antidepressant clomipramine (CMI), the noradrenergic antidepressant desipramine (DMI), and the glutamatergic antidepressants, ketamine and MK-801. In the second part, we analyzed the effect of a combined administration of a subeffective concentration of toluene with a suboptimal dose of the various antidepressants acting at different neurotransmitter systems. Results  Toluene produced a concentration-dependent antidepressant-like action in the FST and TST and facilitated both MK-801 and ketamine antidepressant-like effects, but not those of DMI or CMI. Conclusions  Toluene has antidepressant-like effects that are synergized with NMDA receptor antagonists.     

Effects of amphetamine and methylphenidate on fixed-interval responding in the squirrel monkey.

The effects of oral doses of d-amphetamine and methylphenidate on a fixed-interval operant response were studied in four young male squirrel monkeys. A fixed-interval of 80 sec with a limited hold of 20 sec was used. Methylphenidate produced no observable changes in behavior, while d-amphetamine produced dose related changes in both the rate of responding and the temporal patterning of responses. Since dose levels used included, and exceeded, human clinical dosages, the present findings may have implications for future research involving the clinical use of these drugs.     

Effects of drugs on responding under concurrent fixed-interval schedules and concurrent fixed-ratio schedules

Pigeons were trained to respond under concurrent fixed-interval fixed-interval (concurrent FI FI) schedules with Fl values (in seconds) of 30/300, 60/240, 60/60, 240/60 and 300/30. A second group was trained to respond under concurrent fixed-ratio fixed-ratio (concurrent FR FR) with FR values of 10/40, 10/20, 20/20, 20/10 and 40/10. Under the concurrent Fl Fl schedules, pigeons responded much less often on the key with the higher reinforcement density than would be predicted basing on a perfect matching of the ratio of responses made to the ratio of reinforcers delivered, and the pigeons also showed a bias towards responding on the left key. Pentobarbital, methamphetamine, morphine and phencyclidine had little effect on bias, but high doses of methamphetamine, morphine and phencyclidine decreased undermatching. Under the concurrent FR FR schedules, pigeons responded almost entirely on the key with the higher reinforcement density. Only pentobarbital consistently disrupted this pattern of responding.