Time-dependent changes in the effects of cholinesterase inhibitors on shuttle-box avoidance

Physostigmine and neostigmine were compared for their effects on shuttle-box avoidance acquisition and retention. Physostigmine impaired acquisition at doses lower than neostigmine. Avoidance performance 1, 7, or 14 days after acquisition was impaired by the administration of 0.4 mg/kg physostigmine or an equimolar dose of neostigmine. The effects of lower doses of physostigmine, but not of neostigmine, were dependent upon the time of original training relative to drug administration and retesting. The results suggest that the peripheral effects of higher doses of cholinesterase inhibitors impair avoidance performance. The effects of lower doses of physostigmine on acquisition and the time-dependent effects on subsequent performance are probably due to the central actions of this drug.     

Residual effects of prolonged cannabis administration on exploration and DRL performance in rats

Chronic oral administration of cannabis extract to rats (daily ⁹ dose 20 mg/kg) was examined for its residual effect on open field activity and DRL (differential reinforcement of low-rate responding) performance, following a 2–3-month drug-free period. Locomotor activity during the latter part of an open field test was markedly increased in rats previously treated for either 6 months or 3 months with the drug. The same treatments also produced a significant impairment on a DRL-20 task relative to control subjects' performance. These and other findings (impaired maze learning and facilitated two-way shuttle box avoidance) might mean that cannabis produces long-lasting hippocampal, dysfunction in rats.     

Improvement of shuttle-box avoidance by combinations of orotic acid and central stimulants

The effect of orotic acid and central stimulants on retention of shuttle-box avoidance was investigated in rats. Orotic acid (100 mg/kg) was injected 30 min before training; caffeine (20 mg/kg), strychnine (1 mg/kg), or methylphenidate (10 mg/kg) were injected immediately after training. When given alone, these drugs improved avoidance retention when tested 24h after training. However, improvement of retention was much more evident when orotic acid was given in combination with a stimulant. The data are discussed in relation to the role of macromolecule synthesis and arousal in memory formation.     

Residual effects of chronic cannabis treatment on behavior in mature rats

Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.     

Learning impairment in the radial-arm maze following prolonged cannabis treatment in rats

Chronic oral administration of cannabis extract to rats (daily ⁹tetrahydrocannabinol dose 20 mg/kg) was examined in three experiments for its residual effect on radialarm maze learning following a 1-month drug-free period. Learning a simple eight-arm maze was significantly impaired in rats treated for either 6 months (Experiment I) or 3 months (Experiment II) with the drug. In Experiment III, animals that received the extract for 3 months exhibited significant learning deficits on a much more difficult 12-arm radial maze. The results demonstrate that the deleterious effects of cannabis on radial-arm maze learning are probably due to a tendency toward increased vigilance and perseveration, possibly combined with an impaired utilization of spatial cues.     

Etorphine and shuttle-box self-stimulation in the rat

Rats were trained to turn rewarding electrical brain stimulation on and off by crossing back and forth in a shuttle-box. Moderate doses of the narcotic analgesic, etorphine, increased mean ON times while having little effect on OFF times. Tolerance did not develop to the reward enhancement action over five consecutive days of injections. This paradigm seems valuable for exploration of the reinforcing properties of narcotic drugs.     

Dose-response effects of d-amphetamine on passive avoidance learning in the rat

Trials and errors to learning a passive avoidance response were assessed in 63 albino rats injected subcutaneously with d-amphetamine, in amounts ranging from 0–7 mg/kg body weight. Both measures indicated dose-response effects on responding; animals under either low or high doses of d-amphetamine made significantly less errors and took significantly fewer trials to learn the response than did middle dosage animals. The scores of the lower and higher dosage animals did not differ from the nondrug control group. Results are discussed in terms of amphetamine stereotypy.     

The mechanism of action of α2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box

The precise mechanism of action of α₂ adrenoceptor blockers is not known, although in principle they have two main effects: (i) they stimulate the norepinephrinergic system by inhibiting the negative feed back of norepinephrine release (presynaptic effect) and (ii) they inhibit the effects of norepinephrine on postsynaptic α₂ adrenoceptors. We postulate that if the presynaptic actions of the antagonists prevail, the enhanced norepinephrine release leads to an activation of postsynaptic α₁ or β adrenoceptors. In this case the effects of α₂ adrenoceptor blockers can be reversed by antagonists acting on the latter two adrenoceptors, since postsynaptic α₂ adrenoceptors are also blocked. If the postsynaptic blockade of α₂ adrenoceptors is the main cause of effects, than the blockade of α₁ or β adrenoceptors should not reverse the action of α₂ blockers. The α₂ blocker idazoxan (dose 0.5–5 mg/kg) increased locomotor activity in an open field, an effect that was abolished by both α₁ and β receptor blockers (prazosin and propranolol, respectively). Escape responses in a shuttle box were strongly suppressed by idazoxan (0.5–2 mg/kg). However, this effect was not changed by concomitant α₁ or β receptor blockade. These results suggest that the mechanism of action of α₂ adrenoceptor blockers depends on which effects are studied. Exploration seems to be affected by a presynaptic mechanism as neurons bearing postsynaptic α₁ or β adrenoceptors are involved in the control of this behavior, while escape reactions appear to be affected by the postsynaptic blockade of α₂ adrenoceptors (i.e. neurons bearing postsynaptic α₂ adrenoceptors are involved in its control). Thus, there is no generalized mechanism of action for α₂ adrenoceptor blockers; their precise mode of action should be investigated in each particular case. Received: 15 November 1996 /Final version: 5 June 1997     

Facilitation of avoidance acquisition in rats produced by P-chlorophenylalanine or P-chloroamphetamine.

The effects of reducing brain serotonin using p-chlorophenylalanine (PCPA) were examined as a follow up to our previous report that reducing serotonin with p-chloroamphetamine (PCA) facilitated Y-maze avoidance acquisition and reduced open field activity. In the current work, PCPA was also found to facilitate Y-maze avoidance acquisition, while open field activity, although reduced, was not reduced significantly. In a second experiment, we re-examined PCA, except that the apparatus was changed in order to test the generality of the effect of PCA on avoidance performance in a task other than the Y-maze. Testing was also run at varying shock intensities to determine if this was a significant determinant of the effect. PCA reliably facilitated shuttle-box avoidance acquisition and did so at all shock intensities tested. Finally, in a third experiment, the time course of the onset of the PCA-induced avoidance facilitation was examined and found to develop 8--10 hours following drug treatment and not at a shorter drug to test interval of 4 hours. The present data, in conjunction with our previous data support the concept that lowered brain serotonin content facilitates avoidance acquisition regardless of the specific method used to reduce serotonin or to assess avoidance acquisition.     

Biomarkers for the effects of cannabis and THC in healthy volunteers

An increasing number of novel therapeutic agents are targeted at cannabinoid receptors. Drug development programmes of new cannabinoid drugs may be facilitated by the identification of useful biomarkers. This systemic literature review aims to assess the usefulness of direct biomarkers for the effects of cannabis and tetrahydrocannabinol (THC) in healthy volunteers. One hundred and sixty-five useful articles were found that investigated the acute effects of cannabis or THC on the central nervous system (CNS) and heart rate in healthy volunteers. Three hundred and eighteen tests (or test variants) were grouped in test clusters and functional domains, to allow their evaluation as a useful biomarker and to study their dose–response effects. Cannabis/THC affected a wide range of CNS domains. In addition to heart rate, subjective effects were the most reliable biomarkers, showing significant responses to cannabis in almost all studies. Some CNS domains showed indications of depression at lower and stimulation at higher doses. Subjective effects and heart rate are currently the most reliable biomarkers to study the effect of cannabis. Cannabis affects most CNS domains, but too many different CNS tests are used to quantify the drug–response relationships reliably. Test standardization, particularly in motor and memory domains, may reveal additional biomarkers.     

The effect of medical cannabis laws on juvenile cannabis use

BackgroundA number of states in the United States legally allow the use of cannabis as a medical therapy to treat an illness or to alleviate symptoms. Concern persists as to whether these types of laws are increasing juvenile recreational cannabis use. It is also plausible that medical cannabis laws engender an escalation of illicit non-cannabis drug use among juveniles because cannabis is frequently considered to be a gateway drug.MethodsThis study uses longitudinal data drawn from the National Survey on Drug Use and Health for the 50 U.S. states and a cross-sectional pooled-time series research design to investigate the effect of medical cannabis laws on juvenile cannabis use and on juvenile non-cannabis illicit drug use. Our study period encompasses five measurement periods calibrated in two-year intervals (2002–2003 to 2010–2011). This research design is advantageous in that it affords us the ability not only to assess the effect of the implementation of medical cannabis laws on juvenile drug use, but also to consider other state-specific factors that may explain variation in drug use that cannot be accounted for using a single time series.ResultsFindings show that medical cannabis laws amplify recreational juvenile cannabis use. Other salient predictors of juvenile cannabis use at the state-level of analysis include perceived availability of cannabis, percent of juveniles skipping school, severity of perceived punishment for cannabis possession, alcohol consumption, percent of respondents with a father residing in household, and percent of families in the state receiving public assistance. There is little empirical evidence to support the view that medical cannabis laws affect juveniles’ use of illicit non-cannabis drugs.ConclusionBased on our findings, it seems reasonable to speculate that medical cannabis laws amplify juveniles’ use of cannabis by allaying the social stigma associated with recreational cannabis use and by placating the fear that cannabis use could potentially result in a negative health outcome.     

The effects of oral cadmium exposure on passive avoidance performance in the adult rat

Step-down passive avoidance acquisition and 24 h retention performance were examined in adult rats given daily doses of either 0, 1, or 5 mg/kg cadmium (Cd) (as CdCl2) via the diet. Results indicated that subjects exposed to the 5 mg/kg Cd diet were less likely to step off a safe platform onto an electrified grid floor than controls. The 1 mg/kg subjects did not differ from controls on this acquisition task. None of the groups showed differential performances on a retention test administered 24 h after acquisition training. These results are discussed in terms of recent claims that Cd exposure enhances emotional reactivity in animals.     

Comparative effects of physostigmine and neostigmine on acquisition and performance of a conditioned avoidance behavior in the rat

The actions of physostigmine (0.10 and 0.15 mg/kg) and neostigmine (0.12 mg/kg) given s.c. on acquisition and performance of conditioned pole jumping were studied in rats receiving either 0.9% saline, (?) hyoscyamine or atropine methylnitrate. As estimated by inhibition of acetylcholinesterase (AChE) activity, physostigmine but not neostigmine entered the rat brain. Even though neostigmine did not significantly alter brain AChE activity in equimolar doses to physostigmine, it depressed both the acquisition and performance of a behavioral task, suggesting a predominant peripheral action. Although physostigmine depressed behavior mainly via a central action, its peripheral actions also play a role in its behavioral effects.     

对钙调神经磷酸酶有激活作用的火麻仁提取物改善化学药品诱发的小鼠学习记忆功能障碍

目的:观察对钙调神经磷酸酶有激活作用的火麻仁提取物对化学药品诱发的小鼠学习记忆功能障碍的改善作用。方法:以对硝基苯酚磷酸盐为底物,测定了火麻仁提取物对钙调神经磷酸酶的作用,利用东莨菪碱、亚硝酸钠、乙醇和戊巴比妥钠造成小鼠学习记忆障碍,学习记忆功能检测采用小鼠跳台法和水迷宫法。结果:以牛脑中提取的钙调神经磷酸酶的比活力为100％,火麻仁提取物的浓度在10g/L时,对牛酶的最大激活达到35％±5％。化学药品如东莨菪碱、亚硝酸钠、45％乙醇和戊巴比妥钠均引起小鼠学习记忆功能障碍,主要表现为在跳台作业中潜伏期短,累计错误次数增多;在水迷宫中也同样出现了小鼠空间学习记忆障碍,用对钙调神经磷酸酶有激活作用的火麻仁提取物(0.2,0.4,0.8g/kg)连续给予(ig) 7 d,分别对上述改变有不同程度的改善作用。结论:对钙调神经磷酸酶有激活作用的火麻仁提取物能够改善化学药品诱发的小鼠学习记忆功能障碍。     

The influence of cannabis use expectancies on cannabis use and psychotic symptoms in psychosis

Introduction and Aims. Little is known about motives or expectancies for cannabis use in psychotic populations, despite these cognitive factors being a central focus of the treatment for substance misuse in psychosis. This study examined the relationship between cannabis use expectancies, cannabis use and psychotic symptoms among cannabis using psychotic inpatients. A secondary aim was to determine if there were significant differences in the cannabis use expectancies of psychotic patients with and without Diagnostic and Statistical Manual version IV (DSM‐IV) cannabis dependence. Design and Methods. Participants consisted of 101 in‐patients with psychosis who had used cannabis more than five times in the past year. Expectancies were assessed using the Cannabis Expectancy Questionnaire (CEQ). The frequency of cannabis use, severity of cannabis dependence, presence of DSM‐IV cannabis dependence and severity of psychotic symptoms were also assessed using standardised measures. Results and Conclusions. Results suggested that cannabis use expectancies were associated with cannabis use but not symptom variables. Expectances for cannabis use predicted recent cannabis use and the presence and severity of cannabis dependence. Psychotic patients with DSM‐IV cannabis dependence had significantly higher expectancies for negative effects from cannabis use. Prospective research examining the influence of motives and expectancies for cannabis use on cannabis use and psychotic symptoms is required to obtain a greater understanding of substance use in psychosis and assist with the development of innovative treatment interventions.[Hides L, Kavanagh DJ, Dawe S, Young RMcD. The influence of cannabis use expectancies on cannabis use and psychotic symptoms in psychosis. Drug Alcohol Rev 2009;28:250–256]     

Facilitating effects of chlordiazepoxide on the performance of mice in an inhibitory avoidance task

Inhibitory avoidance behaviour of mice was studied by using an automated procedure. Animals were subjected to five 15-min sessions. Facilitation of the inhibitory avoidance behaviour was observed following the administration of chlordiazepoxide at doses which did not produce significant effects on spontaneous locomotor activity.     

Further analysis of the effects of cholecystokinin octapeptides on avoidance behaviour in rats

Experiments were performed to examine the acute effects of cholecystokinin octapeptides and fragments on the active and passive avoidance behaviour of rats following peripheral and central administration. Both the sulphated (CCK-8-SE) and non-sulphated cholecystokinin octapeptide (CCK-8-NS) and also the COOH-terminal tetra-, penta-, hexa- and heptapeptides of cholecystokinin octapeptide facilitated the extinction of active avoidance behaviour and retention of passive avoidance behaviour. This latter effect of cholecystokinin octapeptides was reversed by anxiolytic chlordiazepoxide pretreatment, showing that in these test situations cholecystokinin octapeptides are able to modify fear-motivation or arousal of the animals; their effect is at least partly similar to that of the neuroleptic substance haloperidol. Subcutaneous treatment with CCK-8-SE or CCK-8-NS appeared to be 3-10 times more effective than intraperitoneal treatment. Following intracerebroventricular administration, 100-300 times lower doses were needed to cause a behavioural effect similar to that after subcutaneous injection. Microinjection of CCK-8-SE or CCK-8-NS in the fmol dose range into the nucleus accumbens facilitated the extinction of active avoidance behaviour and attenuated the retention of passive avoidance behaviour, while microinjection of these peptides into the central amygdaloid nucleus caused opposite effects on these behavioural tests. It seems that the neuroleptic-like effects of cholecystokinin octapeptides are mediated through the nucleus accumbens, and the opposite action (non neuroleptic-like) through the central amygdaloid nucleus.     

Increased disrupting effects of haloperidol on a conditioned avoidance response after 6-hydroxydopamine treatment.

The influence of prior catecholamine depletion was studied on the behavioral depressant effects of haloperidol using a conditioned avoidance response. The butyrophenone disrupting effects on the avoidance behavior were significantly increased by 6-hydroxydopamine pretreatment.