Showing papers in "Psychopharmacology in 1999"

Varieties of impulsivity.

Abstract: The concept of impulsivity covers a wide range of ”actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes”. As such it plays an important role in normal behaviour, as well as, in a pathological form, in many kinds of mental illness such as mania, personality disorders, substance abuse disorders and attention deficit/hyperactivity disorder. Although evidence from psychological studies of human personality suggests that impulsivity may be made up of several independent factors, this has not made a major impact on biological studies of impulsivity. This may be because there is little unanimity as to which these factors are. The present review summarises evidence for varieties of impulsivity from several different areas of research: human psychology, psychiatry and animal behaviour. Recently, a series of psychopharmacological studies has been carried out by the present author and colleagues using methods proposed to measure selectively different aspects of impulsivity. The results of these studies suggest that several neurochemical mechanisms can influence impulsivity, and that impulsive behaviour has no unique neurobiological basis. Consideration of impulsivity as the result of several different, independent factors which interact to modulate behaviour may provide better insight into the pathology than current hypotheses based on serotonergic underactivity.

Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli.

Abstract: Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.

Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers.

Abstract: Rationale: Impulsivity is implicated in drug dependence. Recent studies show problems with alcohol and opioid dependence are associated with rapid discounting of the value of delayed outcomes. Furthermore, discounting may be particularly steep for the drug of dependence. Objectives: We determined if these findings could be extended to the behavior of cigarette smokers. In particular, we compared the discounting of hypothetical monetary outcomes by current, never, and ex-smokers of cigarettes. We also examined discounting of delayed hypothetical cigarettes by current smokers. Methods: Current cigarette smokers (n=23), never-smokers (n=22) and ex-smokers (n=21) indicated preference for immediate versus delayed money in a titration procedure that determined indifference points at various delays. The titration procedure was repeated with cigarettes for smokers. The degree to which the delayed outcomes were discounted was estimated with two non-linear decay models: an exponential model and a hyperbolic model. Results: Current smokers discounted the value of delayed money more than did the comparison groups. Never- and ex-smokers did not differ in their discounting of money. For current smokers, delayed cigarettes lost subjective value more rapidly than delayed money. The hyperbolic equation provided better fits to the data than did the exponential equation for 74 out of 89 comparisons. Conclusions: Cigarette smoking, like other forms of drug dependence, is characterized by rapid loss of subjective value for delayed outcomes, particularly for the drug of dependence. Never- and ex-smokers could discount similarly because cigarette smoking is associated with a reversible increase in discounting or due to selection bias.

Measures of impulsivity in cigarette smokers and non-smokers

Abstract: Rationale: Drug users are thought to be more ”impulsive” than non-users. Objectives: This study examined whether regular smokers are more impulsive than never smokers using personality and behavioral measures of impulsivity. Methods: Twenty regular smokers (≥15 cigarettes/day) and 20 never smokers were recruited. Participants completed five personality questionnaires to assess impulsivity: Adjective Checklist, Barratt’s Impulsivity Scale, the Tridimensional Personality Questionnaire, Eysenck’s Personality Questionnaire, and the Sensation-Seeking Scale. Participants also performed three behavioral choice tasks designed to assess impulsivity. In the delay task, participants chose between small, immediate and large, delayed monetary rewards. Impulsivity was defined as a relative preference for the small, immediate alternative. In the probability task, participants chose between small, certain and large, uncertain monetary rewards. Impulsivity was defined as a relative preference for the large but more risky alternative. In the work task, participants chose between small monetary rewards obtained by performing a negligible amount of work and a larger amount of money requiring more work. Impulsivity was defined as a relative preference for the smaller, easier alternative. Results: On the personality questionnaires, smokers had statistically higher impulsivity scores on most scales. On the behavioral choice tasks, smokers chose small, immediate money over large, delayed money more frequently, signifying greater levels of impulsivity. There were no differences between the groups’ choices on the other tasks. Correlations between questionnaire and task data were small, as were correlations between data from each task. Conclusions: Together, these results indicate that the smokers were more impulsive than never smokers.

Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors

Abstract: Rationale: Central cannabinoid systems have been implicated in appetite regulation by the respective hyperphagic actions of exogenous cannabinoids, such as Δ9-THC, and hypophagic effects of selective cannabinoid receptor antagonists. Objective: This study examined whether an endogenous cannabinoid, anandamide, could induce overeating, via a specific action at central (CB1) cannabinoid receptors. Methods: Pre-satiated male rats (n=18), received subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h, nocturnal food in- take tests. In a second series of intake tests ( n=8), anand- amide injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC). Results: All doses of anandamide induced significant overeating, with 1.0 mg/kg being most potent. Additionally, hyperphagia induced by 1.0 mg/kg anand- amide was dose-dependently attenuated by SR141716 pretreatment. Conclusion: This first demonstration of an- andamide-induced, CB1-mediated, overeating provides important evidence for the involvement of a central can- nabinoid system in the normal control of eating.

Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats.

Abstract: Rationale: Despite numerous reports that male and female animals differ in behavioral responses to drugs, few studies have investigated sex differences in drug-reinforced behavior. Objectives: Acquisition of IV cocaine and heroin self-administration was compared in 20 female and 22 male Wistar rats. Methods: An autoshaping procedure was used to train rats to press a lever that resulted in either a 0.2 mg/kg infusion of cocaine or a 0.015 mg/kg infusion of heroin under a fixed-ratio 1 (FR 1) schedule. Daily sessions consisted of six 1-h autoshaping components followed by a 6-h self-administration component. During each autoshaping component, a retractable lever briefly (15 s) extended into the test chamber on a random interval schedule with a mean of either 90 s (cocaine groups) or 480 s (heroin groups) and either ten (cocaine groups) or five (heroin groups) computer-automated infusions were delivered each hour. During each 6-h self-administration component, the lever remained extended and each response on the lever resulted in an infusion of either cocaine (0.2 mg/kg) or heroin (0.015 mg/kg). The criterion for acquisition of cocaine self-administration was a mean of at least 100 infusions and the criterion for heroin self-administration was a mean of at least 20 infusions during the self-administration component over five consecutive sessions. Results: Female rats acquired both cocaine and heroin self-administration more rapidly than males. Acquisition of cocaine self-administration occurred in a greater percentage of female rats compared to males. Female rats self-administered more cocaine than males after acquisition criteria had been met. Conclusions: These findings indicate that female rats were more vulnerable than males to the acquisition of cocaine and heroin self-administration under the conditions of the present experiment.

Stress-induced craving and stress response in cocaine dependent individuals.

Abstract: Two laboratory studies were conducted to examine the effects of acute psychological stress on craving and stress reactivity in cocaine abusers. In the first preliminary study, we examined the effects of a speech stressor task and a personalized stress imagery task on self-reported craving and emotional state in ten cocaine abusers. Both stressors led to significant decreases in neutral and joy states, and significant increases in fear ratings as compared to baseline ratings. In addition, the stress imagery condition led to significant increases in cocaine craving and sadness and anger ratings, as compared to baseline. Thus, the personalized stress imagery task appeared to be more effective than the speech stress task in inducing craving in the laboratory. The second study examined the effects of stress imagery as compared to neutral imagery on cocaine craving, subjective anxiety and physiological responses in a second group of ten cocaine abusers. The stress imagery task once again produced significant increases in cocaine craving along with increases in heart rate, salivary cortisol and subjective anxiety ratings. These data are the first to document that acute psychological stress consistently increases craving for cocaine in cocaine abusers. The studies also provide a promising method for examining the association between stress and drug craving in the laboratory.

Specific attentional dysfunction in adults following early start of cannabis use.

Abstract: Rationale and objective: The present study tested the hypothesis that chronic interference by cann- abis with endogenous cannabinoid systems during peri- pubertal development causes specific and persistent brain alterations in humans. As an index of cannabi- noid action, visual scanning, along with other atten- tional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. Methods: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physi- cal examination, analysis of routine laboratory para- meters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. Results : Of the potential pre- dictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclu- sively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not di⁄er from controls (n = 49). Conclusions: These data suggest that beginning cannabis use during early adolescence may lead to enduring e⁄ects on specific attentional func- tions in adulthood. Apparently, vulnerable periods dur- ing brain development exist that are subject to persistent alterations by interfering exogenous cannabi- noids.

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test

Abstract: Rationale: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. Objectives: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Methods: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Results: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Conclusions: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems.

Abstinence symptoms following smoked marijuana in humans.

Abstract: Symptoms of withdrawal after oral delta9-tetrahydrocannabinol (THC) administration have been reported, yet little is known about the development of dependence on smoked marijuana in humans In a 21-day residential study, marijuana smokers (n = 12) worked on five psychomotor tasks during the day (0915-1700 hours), and in the evening engaged in recreational activities (1700-2330 hours); subjective-effects measures were completed 10 times/day Food and beverages were available ad libitum from 0830 to 2330 hours Marijuana cigarettes (00, 18, 31% THC) were smoked at 1000, 1400, 1800, and 2200 hours Placebo marijuana was administered on days 1-4 One of the active marijuana doses was administered on days 5-8, followed by 4 days of placebo marijuana (days 9-12) The other concentration of active marijuana cigarettes was administered on days 13-16, followed by 4 days of placebo marijuana (days 17-20); the order in which the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between groups Both active doses of marijuana increased ratings of "High," and "Good Drug Effect," and increased food intake, while decreasing verbal interaction compared to the placebo baseline (days 1-4) Abstinence from active marijuana increased ratings such as "Anxious," "Irritable," and "Stomach pain," and significantly decreased food intake compared to baseline This empirical demonstration of withdrawal from smoked marijuana may suggest that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms

Beyond discounting: possible experimental models of impulse control

Abstract: Animal studies of impulsivity have typically used one of three models: a delay of reward procedure, a differential reinforcement for low rate responding (DRL) procedure, or an autoshaping procedure. In each of these paradigms, we argue, measurement of impulsivity is implicitly or explicitly equated with the effect delay has on the value of reward. The steepness by which delay diminishes value (the temporal discount function) is treated as an index of impulsivity. In order to provide a better analog of human impulsivity, this model needs to be expanded to include the converse of impulsivity - self-control. Through mechanisms such as committing to long range interests before the onset of temptation, or through bundling individual choices into classes of choices that are made at once, human decision-making can often look far less myopic than single trial experiments predict. For people, impulsive behavior may be more often the result of the breakdown of self-control mechanisms than of steep discount functions. Existing animal models of self-control are discussed, and future directions are suggested for psychopharmacological research.

Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice.

Abstract: Rationale: d-Fenfluramine stimulates the release of serotonin (5-HT) and is a potent inhibitor of the re-uptake of 5-HT into nerve terminals. Administration of d-fenfluramine suppresses food intake in both animals and humans. Objective: We have investigated the role of the 5-HT2C receptor in mediating the effect of d-fenfluramine on mouse food intake and the behavioural satiety sequence. Methods: Mutant mice lacking serotonin 5-HT2C receptors and wild-type animals were habituated to a daily presentation of wet mash. Animals were non-deprived and received d-fenfluramine (3–30 mg/kg) 30 min prior to being assessed for the presence of stereotypy and presented with wet mash. The behaviour of animals was observed for the subsequent 40 min and food intake was recorded. Results: d-Fenfluramine dose-dependently inhibited the consumption of a palatable wet mash by the mice. d-Fenfluramine (3 mg/kg) significantly reduced the amount of wet mash consumed by wild-type mice and induced a temporal advance in the behavioural satiety sequence consistent with an enhancement of satiety. Mutant mice were less sensitive to the satiating effects of 3 mg/kg d-fenfluramine. Hence, this dose of d-fenfluramine had a reduced effect on both food consumption and the behavioural satiety sequence in the 5-HT2C mutant mice. In contrast, mutant mice showed an increased sensitivity to the stereotypy induced by high doses of d-fenfluramine (10, 30 mg/kg) compared to that of wild-type littermates. Conclusion: These data demonstrate a role for the 5-HT2C receptor in mediating d-fenfluramine-induced satiety.

Memory deficits associated with recreational use of “ecstasy” (MDMA)

Abstract: Evidence from both animal, and human, studies suggests that repeated administration of 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”) produces lasting decreases in serotonergic activity. Serotonin is believed to play a modulatory role in a variety of psychological processes, including learning and memory. There are recent reports that polydrug users, who have used ecstasy recreationally, exhibit selective impairments in memory. However, these studies did not compare ecstasy users with polydrug users who had not taken ecstasy, leaving open the possibility that the memory deficits may be associated with a history of use of other illicit drugs. The present study used the Rivermead Behavioural Memory test to investigate immediate and delayed recall in: 25 polydrug-users who had taken more than 20 tablets of ecstasy (MDMA group), 22 participants (polydrug controls) who had never taken ecstasy, but, otherwise has personal characteristics (e.g. age, gender, education, height, weight), and illicit drug use histories, that were generally not significantly different from those of the MDMA group, and 19 participants who had not used illicit drugs but who also had similar personal characteristics (non-drug controls). Participants in the MDMA group recalled significantly fewer ideas (approximately 75% of the number of ideas recalled by participants in either of the other two groups), in both immediate and delayed recall conditions. The two illicit drug-using groups did differ in their estimated IQ scores and their duration of use of LSD, but only the latter proved to be a statistically significant covariate, and the difference in recall performance between the MDMA and polydrug controls groups remained statistically significant when this variable was treated as a covariate. The present findings provide the first evidence that deficits in memory performance in recreational ecstasy users are primarily associated with past exposure to ecstasy, rather than with the other legal and illicit drugs consumed by these individuals, and are consistent with reduced serotonergic modulation of mnemonic function as a result of long-term neurotoxic effects of MDMA in humans.

Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour.

Abstract: Rationale: Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-taking. However, little research has addressed the specific cognitive consequences of changed monoaminergic function that might contribute to the production of impulsive behaviour. Objectives and methods: We compared the effects of rapid plasma tryptophan depletion, acute doses of the mixed indirect catecholamine agonist, methylphenidate (40 mg), and acute doses of the α1/α2 agonist, clonidine (1.5 µg/kg), on aspects of visual discrimination learning involving either acquisition of altered stimulus-reward associations (i.e. updating the affective valence of exteroceptive stimuli) or the control of attention towards relevant as opposed to irrelevant stimulus dimensions. Results: Relative to subjects who received placebo, subjects with reduced tryptophan exhibited a deficit in the ability to learn changed stimulus-reward associations, but were still able to shift an acquired attentional set away from a now-irrelevant stimulus dimension towards a newly relevant dimension. By contrast, subjects who received methylphenidate were able to learn effectively about changing stimulus-reward associations, but showed an enhanced ability to shift an attentional bias, in combination with slowed response times. Subjects who received clonidine showed neither of these changes. Conclusions: These results suggest that reduction in central serotonin leads to altered neuromodulation of the cortical and subcortical regions (e.g. orbitofrontal cortex, striatum and anterior temporal structures) that mediate important aspects of associative learning whereby exteroceptive stimuli acquire altered incentive motivational value. On the other hand, facilitation of catecholamine neurotransmitters may disrupt the allocation of attention between relevant and irrelevant features of the environment, perhaps through altered modulation of the dorsolateral prefrontal cortex. The implications of these results for understanding the differential neuromodulation of cognitive functions are discussed.

Long-lasting increase in the set point for cocaine self-administration after escalation in rats.

Abstract: Rationale: When access time to a continuous schedule of drug self-administration is restricted, animals tend to limit intake to a certain level over time and across doses. This observation suggests an endogenous constraint or set point that determines the individual’s preferred level of pharmacological effects. Objectives: To assess whether the transition to increased levels of drug intake is associated with a change in set point. Methods: Two groups of rats were trained on a 1-h continuous schedule of cocaine self-administration (250 µg/injection), after which access to cocaine was increased to 6 h in one group (Long Access or LgA rats) or kept to 1 h in the other group (Short Access or ShA rats). After 22 sessions on this regimen, different doses of cocaine were tested (31.25, 62.5, 125, and 250 µg/injection). For each dose, the post-response time-out period was reduced to 4 s to reduce any temporal limitations on self-injections and subjects were tested several times. Results: In LgA rats, the first hour intake escalated over time and eventually reached a level 200% greater than that of ShA rats. Though all rats maintained relatively constant intake across doses, LgA rats took nearly two times as much cocaine than ShA rats. When access to cocaine for LgA rats was reduced to 1 h, intake returned very slowly toward pre-escalation levels but was still elevated even after 2 months of reduced availability. Conclusions: These data suggest that the transition to escalated levels of intake is associated with a long-lasting change in cocaine set point.

Cognitive performance in (+/-) 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") users: a controlled study

Abstract: Rationale: (±) 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is an amphetamine analog and drug of abuse. In animals, MDMA damages brain serotonin (5-HT) neurons at doses that overlap with those used recreationally by some humans. To date, few functional sequelae of MDMA-induced 5-HT damage have been identified. Objective: Since serotonin is thought to be involved in cognitive processes, and since previous studies have reported verbal and visual memory deficits in MDMA users, the present study sought to determine whether other cognitive processes are influenced by previous exposure to MDMA. Methods: Twenty-two MDMA users who had not used MDMA for at least 3 weeks and 23 control subjects were tested repeatedly with a computerized cognitive performance assessment battery while participating in a 5-day controlled inpatient study. Cerebrospinal fluid (CSF) measures of monoamine metabolites were also collected as an index of brain monoaminergic function. Results:MDMA users and controls were found to perform similarly on several cognitive tasks. However, MDMA subjects had significant performance deficits on a sustained attention task requiring arithmetic calculations, a task requiring complex attention and incidental learning, a task requiring short term memory and a task of semantic recognition and verbal reasoning. MDMA users also had significant selective decreases in CSF 5-HIAA. Conclusions: The present CSF data provide further evidence that MDMA is neurotoxic to brain 5-HT neurons in humans, and the behavioral data suggest that brain 5-HT injury is associated with subtle, but significant, cognitive deficits.

Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation.

Abstract: Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain.

Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease

Abstract: Rationale: Acute nicotine injections have been found to improve attentional performance in patients with Alzheimer’s disease (AD), but little is known about chronic nicotine effects. Objective: The present study was undertaken to evaluate the clinical and neuropsychological effects of chronic transdermal nicotine in Alzheimer’s disease subjects over a 4-week period. Methods: The double-blind, placebo controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period. Patients wore the nicotine patch (Nicotrol®) for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during weeks 2 and 3 and 5 mg/day during week 4. The eight subjects had mild to moderate AD and were otherwise healthy. Results: Nicotine significantly improved attentional performance as measured by the Conners’ continuous performance test (CPT). There was a significant reduction in errors of omission on the CPT which continued throughout the period of chronic nicotine administration. The variability of hit reaction time (reaction time for correct responses) on the CPT was also significantly reduced by chronic nicotine. Nicotine did not improve performance on other tests measuring motor and memory function. Conclusions: The sustained improvement in attention found in this study with nicotine dermal patches is encouraging. However, the lack of detected effects of nicotine treatment on other cognitive and behavioral domains in this study leaves questions concerning the clinical impact of nicotinic treatment in Alzheimer’s disease. The modest size of this study limited statistical power which may have been needed to detect more subtle but clinically significant cognitive effects. Higher doses of nicotine, other nicotinic ligands or combination treatment of nicotine with other therapies may be efficacious for producing broader therapeutic effects.

The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers.

Abstract: Rationale: Corticosteroids are elevated in certain neuropsychiatric disorders and this may contribute to the neuropsychological impairments reported in these disorders. Objective: To examine the effects of hydrocortisone on learning, memory and executive function. Methods: Hydrocortisone 20 mg was administered twice daily for 10 days to normal male volunteers in a randomized, placebo control, crossover, within-subject design. Learning, memory and executive function were measured using selected subtests from the Cambridge Neuropsychological Test Automated Battery. Results: Hydrocortisone caused impairments of visuo-spatial memory. These included increased within search errors and impaired use of strategies on the spatial working memory subtest. In addition, administration of hydrocortisone was associated with more errors in the paired associate learning subtest, although no effect was found on the Tower of London. Hydrocortisone speeded response latencies in certain tests (pattern and spatial recognition memory). Conclusion: These results indicate that chronic administration of hydrocortisone leads to deficits in certain tests of cognitive function sensitive to frontal lobe dysfunction and may contribute to the cognitive impairment reported in certain neuropsychiatric disorders.

Smoking behaviour and compensation: a review of the literature.

Abstract: Rationale: Compensation or compensatory smoking, accurately defined, deals with the question of whether switching to cigarette brands with different smoke yields is associated with a change in smoke uptake proportional to the change in machine-derived yields. The issue of compensation is important because it bears on whether switching to ”lighter” brands means lower overall smoke intake or not. Objectives: The present review investigated whether and to what extend low yield cigarettes are smoked more intensively. In addition, published data on whether nicotine, ”tar”, or any other smoke constituent or property influence compensational smoking are summarized. Methods: The studies on compensation were classified as follows: (1) studies on smoking behaviour in relation to cigarette yields (with and without brand switching); (2) studies on compensation for nicotine (switching between cigarettes which differ ”only” in their nicotine yield, nicotine supplementation, manipulation of renal nicotine excretion, administration of nicotine agonists or antagonists); (3) studies on compensation for other factors (influence of tar, taste, irritation, draw resistance). In order to quantify the degree of compensation, an index is defined and applied to selected brand switching studies. This compensation index determines, in relative units, the degree to which a smoker responds to a change in smoke yields with a change in smoke uptake measured by suitable biomarkers. The role of vent blocking is also briefly discussed. Results: Most of the studies which compare the smoking behaviour when smoking cigarettes with different smoke yields supply evidence for ”partial” compensation, suggesting that cigarettes with lower yields are smoked more intensively than those with higher yields. These studies also show that a change in the daily number of cigarettes is not a common mechanism of compensation. Effective vent blocking during smoking is a rare event and can therefore also be regarded as an uncommon mechanism of compensation. Evaluation of a suitable subset of brand-switching studies revealed an average compensation of 50–60% of the nicotine yield. Compensation tended to be more complete when changing to cigarettes with higher yields than when changing to cigarettes with lower yields. In general, brand-switching studies do not supply information on the underlying causal factors responsible for compensatory smoking. Results of the nicotine supplementation studies are not conclusive: some report evidence of nicotine titration, others do not. A general problem with this type of investigation is that continuous nicotine application does not mimic the spike-wise application with cigarette smoking, and may lead to nicotine tolerance. There is limited evidence that cigarettes were smoked more intensively when the urinary clearance of nicotine was increased. A small number of studies provide some evidence that smoking intensity increased after smokers were administered a nicotine antagonist. Several reports indicate that tar, taste and sensory properties of the smoke as well as the draw resistance of the cigarette may play a role in compensatory smoking. Low-yield cigarettes usually have reduced pressure drops which smoke researchers have suggested leads to increased puff volume. This effect seems to be independent of the smoke yield of the cigarette. There is also some evidence that some smokers maintain a consistent pattern of smoking which works independent of any changes in nicotine or tar yields, taste or design features of the cigarette (”functional autonomy”). Conclusions: The available data suggest that smokers partially compensate for a different smoke yield. While the factors and their interaction responsible for compensational smoking are not fully understood, there are data suggesting that a subgroup of smokers may partially compensate for nicotine. Even in this subgroup of smokers, however, the relative importance of the pharmacological versus the sensory effects of nicotine in smoke remains to be determined.

Serotonin and tolerance to delay of reward in rats.

Abstract: Rationale: Tolerance to delay of gratification, taken to reflect impulsiveness, has been proposed to be under the preferential control of central serotonin (5-HT) processes. Objective: The present study further examined the effects of drugs which directly or indirectly alter 5-HT transmission, on behaviour controlled by a delayed positive reinforcer. Methods: Rats were given the choice in a T-maze between two magnitudes of reward: small (two food pellets) and immediate versus large (ten pellets) but delayed. When a 15-s waiting period was imposed in the arm leading to the large reward, rats selected this arm on 65–70% of the trials. This frequency was reduced to less than 40% when the large reward was delayed by 25 s. Results: In rats whose ascending 5-HT pathways had been lesioned by infusion of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal raphe, the introduction of the 15-s delay contingency resulted in a transient larger reduction of the frequency of choice of the now-delayed reward, compared to sham operated controls. In contrast, choice behaviour of rats given 5,7-DHT into the substantia nigra did not differ from controls. para-Chlorophenylalanine (pCPA, 150 mg/kg IP, daily for 3 days), a 5-HT synthesis inhibitor, bretazenil (0.5-8 mg/kg IP), a benzodiazepine (BZD) receptor partial agonist, and muscimol (0.25-1 mg/kg IP), a GABAA receptor agonist, induced a shift toward immediate reward. In contrast to the other BZDs, alprazolam (1–2 mg/kg IP) enhanced the frequency of choice of the large-but-25 s-delayed reward. Similar increased preference for the large-but-delayed reward was induced by the selective 5-HT reuptake inhibitors, fluoxetine (4–8 mg/kg IP) and fluvoxamine (4 mg/kg IP). The full 5-HT1A receptor agonist, 8-OH-DPAT (0.015–0.5 mg/kg IP) enhanced the frequency of choice of the large reward delayed by 25 s, whereas the partial agonists, buspirone (1–4 mg/kg IP), ipsapirone (0.5–1 mg/kg IP) and MDL 73005EF (1–2 mg/kg SC), and the antagonist, WAY 100635 (4 mg/kg SC), reduced the number of choices of the large reward delayed by 15 s. Unexpectedly, WAY 100635 (2 mg/kg), which had no effect on choice whatever the delay, did not counteract the increased tolerance to delay induced by 8-OH-DPAT (0.06 mg/kg) and further reduced the frequency of choice of the large-but- 15 s-delayed reward induced by ipsapirone (0.5 mg/kg). Conclusions: These effects on tolerance to delay may be accounted for by a subtle balance between the opposing functional consequences of pre- versus post-synaptic 5-HT1A receptor activation or blockade. Overall, the present results provide further support to the idea that 5-HT processes participate in the control of impulsive-related behaviour, as assessed from tolerance to delay of reward in this particular T-maze procedure.

Interactive effects of subanesthetic ketamine and haloperidol in healthy humans.

Abstract: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with prominent psychoactive effects in humans. This study evaluated whether the oral administration of haloperidol 5 mg would block the effects of an intravenous ketamine infusion (bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour). Twenty healthy subjects completed 4 test days involving the oral administration of haloperidol or matched placebo 2 h prior to the intravenous infusion of ketamine or saline. Ketamine produced cognitive, behavioral, neuroendocrine, and physiologic effects in the healthy subjects that were similar to previous reports. Haloperidol pretreatment reduced impairments in executive cognitive functions produced by ketamine as measured by proverb interpretations and the Wisconsin Card Sorting Test. However, it failed to block the capacity of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria in healthy subjects. These data outline an important, but functionally delineated modulation of ketamine effects by dopamine2 receptors and other sites of haloperidol action.

Abstinence symptoms following oral THC administration to humans.

Abstract: Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use.

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP

Abstract: Rationale: Current treatment of Parkinson’s disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. Objectives: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro-1H-purine-2,6-dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson’s disease. Methods: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5’-N-ethylcarboxamidoadenosine (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. Results: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and l-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. Conclusions: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson’s disease, and may offer a new therapeutic approach to the treatment of Parkinson’s disease.

Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson's disease.

Abstract: Rationale: The mesotelencephalic dopamine system has been implicated in cognitive processes dependent on an intact prefrontal cortex. Most previous research in humans has focused on dopaminergic agonists and their effects on tasks of working memory. Objectives: The present study was designed to investigate the cognitive and subjective effects of two doses (200 mg and 400 mg) of the dopaminergic D2 receptor antagonist, sulpiride on a broad range of well-validated neuropsychological tasks in a group of 34 young healthy male volunteers. Methods: Cognitive tasks were administered to subjects after ingestion of either drug or placebo within a double-blind, placebo-controlled, cross-over design. The cognitive tests included tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and were designed to assess visuospatial recognition memory, planning ability, working memory, strategy learning, sustained attention and attentional set-shifting. In addition, the National Adult Reading Test (NART) was used to assess verbal IQ, and visual analogue scales to assess subjective effects of the drug. Results: Subjects on sulpiride were impaired on the tasks of spatial recognition, spatial working memory (sequence generation), planning (one-touch Tower of London) and attentional set-shifting. Only the spatial working memory task demonstrated a dose dependent effect. The impairments were not due to generalised sedative or motoric influences of sulpiride. Conclusions: All of the tasks impaired following sulpiride are known to be sensitive to frontal lobe damage and the precise pattern of deficits seen is consistent with the anatomical distribution of central dopamine receptors. The results are discussed with particular reference to their close simulation of the impairments seen in idiopathic Parkinson’s disease.

Theory and method in the quantitative analysis of ”impulsive choice” behaviour: implications for psychopharmacology

Abstract: Impulsive choice refers to the selection of small immediate gains in preference to larger delayed gains, or the selection of large delayed penalties in preference to smaller immediate penalties. Current theoretical interpretations of impulsive choice are reviewed, and a synthesis of these ideas, the ”multiplicative hyperbolic model of choice”, is presented. The model assumes that the value of a positive reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its delay and the odds against its occurrence. Each hyperbolic function contains a single discounting parameter which quantifies the organism’s sensitivity to the variable in question. The hyperbolic discounting functions combine multiplicatively to determine the overall value of the reinforcer. Equivalent functions are postulated to govern the (negative) value of aversive events, the net value of an outcome reflecting the algebraic sum of the positive and negative values. The model gives rise to a quantitative methodology for studying impulsive choice, based on a family of linear indifference (null) equations, which describe performance under conditions of indifference, when the values of the reinforcers are assumed to be equal. This methodology may be used to identify individual differences in sensitivity to the magnitude, delay and probability of reinforcement. The methodology is also suitable for the quantitative evaluation of the effects of some pharmacological interventions on discounting parameters. Recent psychopharmacological studies of impulsive choice are reviewed, and the utility of indifference equations for extending this work, and developing a quantitative psychopharmacology of impulsive choice is discussed.

Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration.

Abstract: Rationale: The neurobiological mechanisms underlying the persistence of drug craving in detoxified addicts are still poorly understood. Objective: The present study was designed to evaluate dopaminergic mechanisms in drug-seeking behaviour following long-term (>3 weeks) extinction of IV drug self-administration in rats. Methods: To that end, we studied the effects of direct and indirect dopamine (DA) agonists on reinstatement of previously extinguished responding for heroin (50 μg/kg per injection; 14–15 daily 3-h sessions) and cocaine (500 μg/kg per injection; 10–11 daily 2-h sessions). Results: In animals with a cocaine history, priming with cocaine, the selective DA reuptake inhibitor GBR-12909 and the DA D2 receptor agonist quinpirole resulted in robust and selective reinstatement of non-reinforced nose poking behaviour in the previously drug-paired hole. In contrast, the D1 agonist SKF-82958 failed to reinstate responding and the non-selective DA agonist apomorphine even suppressed responding in these animals. In heroin-trained rats, heroin and GBR-12909 strongly reinstated responding, whereas all direct DA agonists were ineffective. Again, the two highest doses of apomorphine decreased responding in these animals. In a parallel study, the ability of DA ligands to express behavioural sensitization in animals pretreated with amphetamine or morphine was evaluated. Interestingly, all agonists that reinstated responding in the present study caused expression of locomotor sensitization and vice versa. Conclusions: The differences between direct and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour long after detoxification. Moreover, the results show an important role of D2 receptor activation in the persistence of cocaine- but not heroin-seeking behaviour. Finally, the results from both studies suggest a relationship between drug-induced reinstatement and drug hyperresponsiveness in long-term abstinent rats.

Effects of methamphetamine on the adjusting amount procedure, a model of impulsive behavior in rats.

Abstract: Rationale: Moderate doses of d-amphetamine (given both acutely and chronically) have been shown to decrease impulsivity in children with attention deficit hyperactivity disorder (ADHD) and to improve attention and learning in normal adults. In contrast, chronic doses of methamphetamine (METH) in drug abusers have been associated with increased impulsivity, and impairments in learning and attention. Objectives: We report the effects of METH on an animal model of impulsive behavior. Methods: Rats were tested using the adjusting amount (AdjAmt) procedure in which the animals choose between a delayed fixed (large) amount of water and an immediate adjusting (small) amount of water. In the acute METH study, rats were given a single dose of 0.5, 1.0, 2.0, and 4.0 mg/kg METH or saline 30 min before testing. In the chronic METH study, we determined the effects of the 4.0 mg/kg dose of METH injected chronically 1 h after behavioral testing for 14 days. Thus the rats were tested using the AdjAmt procedure 22 h after injections of METH or saline. Results: After 0.5, 1.0 and 2.0 mg/kg METH, the rats valued the delayed large rewards more than after saline, indicating that the METH decreased impulsiveness. At the 4.0 mg/kg dose, the rats failed to respond. Rats treated repeatedly with the post-session large behaviorally disruptive dose of METH valued the delayed large rewards less than the saline-treated rats, indicating that this dosing regimen of METH increased impulsiveness. Conclusions: In these experiments, the rats became less impulsive after acute non-disruptive doses of pre-session METH, whereas they became more impulsive after receiving repeated post-session injections of a dose that was behaviorally disruptive when administered acutely.

Antidepressant effects of nicotine in an animal model of depression.

Abstract: Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg s.c.) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the alpha4beta2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the alpha7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

Working memory, executive processes and the effects of alcohol on Go/No-Go learning: testing a model of behavioral regulation and impulsivity

Abstract: Rationale: Impulsivity is associated with increased risk for alcoholism. Alcohol also may increase impulsive behavior, although little is known about the processes underlying this effect. Objectives: This study tested a model proposing that the executive processes of working memory (WM) and conditional associative learning (CAL) modulate behavioral inhibition. Subjects had either a positive (FHP) or a negative (FHN) family history of alcoholism. Hypotheses were that alcohol would increase Go/No-Go impulsive responding but only in subjects with low working memory capacity (low-WM), low-CAL ability, or FHP for alcoholism. The model also predicted that WM and CAL modulate inhibitory responses to contingency reversal on a Go/No-Go task. Methods: A Go/No-Go learning task with a midway contingency reversal was administered to 71 FHP and 78 FHN subjects when sober and after drinking one of two moderate doses of alcohol. WM (digits backward) and CAL (conditional spatial association task) were also assessed when sober. Results: Alcohol resulted in more false alarms but only in low-WM subjects. Both WM and CAL modulated learning to inhibit behavior after contingency reversal, suggesting separate modulation mechanisms for WM and CAL. Subjects with low- capacity WM and subjects with low-capacity CAL ability had more difficulty learning response inhibition after contingency reversal. FHPs and FHNs did not differ in their response to alcohol. Conclusions: The results support our model of the modulatory role of WM and CAL in the ongoing regulation of behavioral inhibitory systems. The results also suggest that individuals with low capacity WM are more susceptible to alcohol’s effect of increasing impulsive behavior, suggesting that alcohol reduces the capacity of working memory to modulate response inhibition.