Anne Jackson

Is the discriminative stimulus produced by phencyclidine due to an interaction with N-methyl-D-aspartate receptors?

Rats were trained to discriminate phencyclidine (PCP) from saline at doses of 2 and 4 mg/kg, using a two-lever food reinforced operant technique. ±N-allylnormetazocine (±SKF 10047), +5-methyl-10,11-dihydro-5H-dibenzo[A,D]cyclohepten-5,10-imine (MK 801), 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and ifenprodil, which have been shown to antagonise the effects of N-methyl-d-aspartate (NMDA), were tested for their ability to give rise to PCP-appropriate responding. In rats trained at both doses of PCP, ±SKF 10047 (2–12 mg/kg) and MK 801 (0.0125–0.2 mg/kg) produced dose-related responding on the lever associated with PCP injection. The relative potency of these two compounds was the same in the two groups of animals, but their absolute potencies to produce a PCP-like discriminative stimulus were dependent on the training dose of PCP. In contrast, neither the competitive NMDA antagonist CPP (4–20 mg/kg) nor the non-competitive antagonist ifenprodil (2–12 mg/kg) produced PCP-appropriate responding and ifenprodil (4-mg/kg) neither potentiated nor antagonised PCP. These findings are discussed in the light of the hypothesis that the behavioural effects of PCP are mediated via a reduction of neurotransmission at the NMDA-subtype of glutamate receptors.

Acquisition and extinction of flavour preferences conditioned by caffeine in humans.

Previous research has shown that moderate caffeine users develop a liking for the flavour of a novel caffeinated drink only if they experience this drink in a caffeine-deprived state. This study tested how sensitive these conditioned-flavour preferences are to subsequent changes in deprivation state and the continued presence or absence of caffeine. Thirty-six moderate caffeine consumers were given 4 training days during which they evaluated a novel flavoured caffeinated drink consumed mid-morning after 12 h caffeine deprivation. Subjects were then divided into four groups depending on whether or not they remained caffeine-deprived and whether the test drink continued to contain caffeine. They then re-evaluated the novel drink over a further 4 test days. As expected, liking for the test drink increased across the 4 training days, and this increased liking was maintained across the 4 test days in the group who continued to receive the caffeinated version of the drink in a caffeine-deprived state. Liking decreased in the test phase in the caffeine-deprived group who no longer received caffeine (extinction). It is surprising that both groups who were tested in a non-deprived state showed a marked decrease in liking on all 4 test days relative to the last training day. This implies that conditioned-flavour preferences may not be expressed in the absence of the relevant motivational state (caffeine deprivation). Together, these data suggest that flavour preferences conditioned by caffeine are very sensitive to changes in the contingent relationship between deprivation state and caffeine content of the drink.

Behavioural effects of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-receptor antagonists and their relevance to substance abuse

This review presents some of the work that has been carried out to investigate the behavioural effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-receptor antagonists in animal models of substance abuse. Many of the studies have been conducted in light of current ideas that emphasise the analogous role of glutamatergic mechanisms in synaptic plasticity and long-term behavioural adaptation to drugs. Experiments on behavioural sensitisation indicate that whereas N-methyl-D-aspartate receptors are involved in induction, AMPA-receptors may mediate expression of the established response. In this regard, an important factor may be the degree of drug-environment conditioning. Thus, studies of the effects of AMPA-receptor antagonists on conditioned behaviours are reviewed here. Relatively few studies on the effects of AMPA-receptor antagonists on primary reinforcement from self-administered drugs and the subjective effects of drugs have been carried out, but a profile that contrasts with that of the N-methyl-D-aspartate antagonists appears to be emerging. Studies of withdrawal from opioids suggest that whilst AMPA-receptor antagonists may not be able to prevent tolerance or dependence from developing, they may ameliorate both the physical and emotional consequences of withdrawal. Overall, the AMPA-receptor antagonists may represent a promising new approach for treating the consequences of drug abuse. However, as results are often complicated by the use of the less-selective compounds, it will be important to use better tools in future studies.

Differential Involvement of Glutamatergic Mechanisms in the Cognitive and Subjective Effects of Smoking

There is growing preclinical evidence for the involvement of glutamate in the behavioral actions of nicotine. The aim of this study, was to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the cognitive and subjective effects of smoking in humans. Sixty regular smokers took part in this double-blind placebo controlled study, that investigated the effect of the NMDA-antagonist memantine (40 mg) and the nicotinic-receptor antagonist mecamylamine (10 mg) on smoking-induced improvement in performance of a task of sustained attention and on smoking-induced changes in subjective effects and craving. Increases in subjective ratings of ‘buzzed’ following smoking were reversed by memantine, but not by mecamylamine. In contrast, improvement on a Rapid Visual Information Processing task by smoking was opposed by mecamylamine, but not by memantine. Smoking reduced craving for cigarettes, but neither drug altered this effect. Our results suggest that glutamatergic mechanisms may have differential involvement in the subjective and cognitive actions of smoking. Further investigations using different ligands are warranted to fully characterize the role of glutamate underlying the consequences of smoking behavior.

Degree of dependence influences the effect of smoking on cognitive flexibility

Pre-frontal cortical (PFC) dysfunction has been put forward as the basis for development and maintenance of addiction. To explore this relationship, the present study investigated the effects of smoking on PFC-mediated cognitive flexibility and subjective states in low- (LD) and high-dependent (HD) smokers. Twenty-four LD and 24 HD smokers (Fagerström dependence scores ≤ 4 and ≥ 5, respectively) were randomly allocated to non-smoking or smoking condition (12 LD and 12 HD participants per condition). After abstaining from smoking for a minimum of two hours volunteers completed a battery of questionnaires [nicotine-specific Visual Analogue Scales (Nic-VAS), Questionnaire of Smoking Urges (QSU) and Profile of Mood States (POMS)] at baseline [T1] and again after smoking one cigarette or remaining abstinent [T2]. Cognitive flexibility was evaluated at T2 using the Intra-Extra Dimensional Set-Shift test. The Rapid Visual Information Processing test was performed as a control nicotine-sensitive task at several time points during the experiment. Compared to LD smokers, HD smokers had higher salivary cotinine and breath CO levels at baseline and reported more craving (QSU) and felt less stimulated (Nic-VAS), vigorous, friendly and elated (POMS) throughout the experiment. Smoking increased Nic-VAS ratings of ‘Buzzed’ and ‘Dizzy’ and decreased craving in all participants. Smoking selectively impaired cognitive flexibility in HD smokers since HD smokers allocated to the smoking condition made significantly more errors with the intra-dimensional set-shift than their counterparts in the abstinent condition. No effect of smoking on RVIP test was observed, most likely due to the practice effect which was significant in both groups of smokers. The practice effect, however, was more pronounced in LD smokers. This study demonstrates that PFC-mediated cognitive effects of smoking as well as subjective reports vary according to the degree of nicotine dependence.

Gender differences in response to lorazepam in a human drug discrimination study

Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes been reported, although we have previously found no differences in subjective or discriminative responses in human subjects acquiring an alcohol discrimination. The aim of the present work was to determine if there were gender differences in the effects of lorazepam, a benzodiazepine-receptor agonist which substituted for the alcohol stimulus in trained social drinkers. Volunteers who had already acquired an alcohol (0.2g/kg) placebo discrimination were administered (double-blind) either placebo (nine females, nine males) or lorazepam 2mg (six females, six males). They then sampled a series of five drinks and rated each one for likeness to the training stimulus (the generalization response). In addition they completed rating scales for subjective effects and the Digit Symbol Substitution Test (DSST). Lorazepam substituted for the alcohol stimulus equally in both sexes and increased associated scores for lightheadedness. Females however, showed a much greater DSST performance impairment following lorazepam, compared with males. This effect was independent of body weight differences and sedation. These results are discussed in the light of current knowledge of gender differences in response to drugs of abuse and suggest that the stimulus and cognitive effects of benzodiazepine-receptor agonists are modulated by different brain mechanisms.

Comparison of benzodiazepine (BZ) receptor agonists in two rodent activity tests

The effects of four BZ receptor ligands in an operant test were compared with a rotarod test. In the operant test, rats were trained to pull a chain on a schedule that regulates the probability of delivery of food pellets to maintain a steady chain-pulling rate across a 1 h test session. For the rotarod test, mice were trained to remain on a rotarod for 2 min. Diazepam (0.1-3.0 mg/kg, i.p.), FG 8205 (0.1-3.0 mg/kg, i.p.), quazepam (3.0-60.0 mg/kg, i.p.) and zolpidem (0.3-10.0 mg/kg, i.p.) each produced dose-related impairments of performance in both the chain- pulling test and the mouse rotarod test. Furthermore, the impairment in performance induced by FG 8205 (10.0 mg/kg, p.o.) was dose-dependently reversed by the BZ receptor antagonist, flumazenil (1.0-10.0 mg/kg, i.p.), indicating that the chain-pulling deficit was mediated via BZ receptor activation. Diazepam, FG 8205 and quazepam all had comparable potencies in both the rotarod assay and the chain-pulling test. However, zolpidem suppressed the chain-pulling rates at a dose 30-fold lower than that required to induce a significant deficit in the rotarod performance. As zolpidem is a preferentially sedative compound, this pattern of results is consistent with the hypothesis that the chain-pulling test is sensitive to sedation induced by BZ receptor agonists.

N-Methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate (AMPA) glutamate-receptor antagonists have different interactions with the discriminative stimuli of abused drugs

Abstract The effects of the AMPA-receptor antagonists NBQX and GYKI 52466 were compared with those of the NMDA-receptor channel blocker dizocilpine in two drug discrimination tests. In the first, rats were trained to discriminate morphine (2 mg/kg) from saline and in the second, to discriminate ketamine (7 mg/kg) from saline, using a two-lever food reinforced method. NBQX (1–6 mg/kg) did not substitute for either morphine or ketamine, even at a dose which reduced response rates (6 mg/kg). Likewise, the non-competitive antagonist GYKI 52466 (5 and 10 mg/kg) produced only saline lever responding in the ketamine trained rats. When tested in combination with the training drug, NBQX (4.5 mg/kg) did not alter the morphine generalisation gradient, and similarly, neither NBQX (3 mg/kg) nor GYKI 52466 (5 and 10 mg/kg) interacted with the ketamine cue. In contrast, dizocilpine (0.05 mg/kg) significantly disrupted discrimination of morphine and produced clear drug lever responding (0.0125–0.1 mg/kg) in ketamine trained rats. These results suggest that AMPA-receptor antagonists and non-competitive NMDA-antagonists have different stimulus properties.

Varenicline, the clinically effective smoking cessation agent, restores probabilistic response reversal performance during withdrawal from nicotine.

There is recognition that cognitive problems can contribute to renewed drug taking in former addicts. Our previous work has indicated that current smokers show reduced performance on a probabilistic reversal learning (PRL) task, relative to former smokers. To further explore PRL performance and its relevance to smoking, in addition to the role of nicotine, we developed a model of nicotine withdrawal‐induced deficits in rodents. A second goal was to test varenicline, an α4β2 partial agonist, for its ability to restore any cognitive impairment. Acute effects of nicotine and varenicline on PRL performance in non‐dependent animals were minimal and confined to speed of responding. When rats were made dependent on nicotine via osmotic minipumps implanted for 7 days (3.16 mg/kg/day), repeated tests at specified withdrawal time points revealed PRL disruption peaking at 12 and 24 hours following surgical removal of minipumps. Withdrawal was characterized by significant deficits in the number of reversals (P < 0.05), speed of responding (P < 0.01) and increases in omissions (P < 0.05). Nicotine (0.2 mg/kg SC) or varenicline (0.3 and 1.0 mg/kg SC) administered 10‐minute prior to PRL test sessions during withdrawal, relieved the performance deficits. At 24‐hour withdrawal, nicotine and varenicline (1 mg/kg) prevented decrements in reversals, in addition to ameliorating slower speed of responding. The high dose of varenicline only reduced omissions. These results confirm the role of nicotine in withdrawal‐induced disruption of PRL performance and suggest that the model may be useful for investigating efficacy of potential new treatments for smoking cessation.

Performance monitoring in nicotine dependence: Considering integration of recent reinforcement history

Introduction: Impaired monitoring of errors and conflict (performance monitoring; PM) is well documented in substance dependence (SD) including nicotine dependence and may contribute to continued drug use. Contemporary models of PM and complementary behavioural evidence suggest that PM works by integrating recent reinforcement history rather than evaluating individual behaviours. Despite this, studies of PM in SD have typically used indices derived from reaction to task error or conflict on individual trials. Consequently impaired integration of reinforcement history during action selection tasks requiring behavioural control in SD populations has been underexplored. Methods: A reinforcement learning task assessed the ability of abstinent, satiated, former and never smokers (N = 60) to integrate recent reinforcement history alongside a more typical behavioural index of PM reflecting the degree of reaction time slowing following an error (post‐punishment slowing; PPS). Results: On both indices there was a consistent pattern in PM data: Former smokers had the greatest and satiated smokers the poorest PM. Specifically satiated smokers had poorer reinforcement integration than former (p = 0.005) and never smokers (p = 0.041) and had less post‐punishment slowing than former (p < 0.001), never (p = 0.003) and abstinent smokers (p = 0.026). Conclusions: These are the first data examining the effects of smoking status on PM that use an integration of reinforcement history metric. The concordance of the reinforcement integration and PPS data suggest that this could be a promising method to interrogate PM in future studies. PM is influenced by smoking status. As PM is associated with adapting behaviour, poor PM in satiated smokers may contribute towards continued smoking despite negative consequences. Former smokers show elevated PM suggesting this may be a good relapse prevention target for individuals struggling to remain abstinent however prospective and intervention studies are needed. A better understanding of PM deficits in terms of reinforcement integration failure may stimulate development of novel treatment approaches. HIGHLIGHTSPerformance monitoring (PM) is often indexed by slowing following error.However, models of PM emphasise integration of reinforcement history.We find that smoking status affects PM on both slowing and integration indices.Reduced PM was found in satiated smokers and this may contribute to continued use.Elevated PM in former smokers suggests that PM may be a cessation target.