Nicotine-like discriminative stimulus effects of bupropion in rats.

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine: however nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effect though a different mechanism that nicotine. Give bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of venlafaxine on the subjective, reinforcing, and cardiovascular effects of cocaine in opioid-dependent and non-opioid-dependent humans.

The effects of maintenance on venlafaxine, which blocks both norepinephrine and serotonin reuptake, on the response to smoked cocaine (0, 12, 25, or 50 mg) in 7 opioid-free and 7 methadone-maintained cocaine abusers was examined during a 42-day study. Participants received venlafaxine (225 mg daily) and placebo as part of a double-blind crossover design. Cocaine significantly increased heart rate, blood pressure, cocaine choice, cocaine ratings, and ratings of positive subjective effects (e.g., "I feel high") in both groups. Venlafaxine significantly decreased the subjective effects of cocaine by 10-20% without affecting cocaine choice or cardiovascular response in both groups. Although the reduction in cocaine's effects was small, further studies using a longer venlafaxine maintenance period or a larger venlafaxine dose are warranted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex differences in analgesic, reinforcing, discriminative, and motoric effects of opioids.

This review summarizes evidence for sex differences in behavioral effects of opioids, primarily in rats. Whereas mu agonists have been found to be more potent and in some cases more efficacious in producing analgesia and sedation in males than females, females are more sensitive than males to reinforcing and locomotor stimulant effects of opioids. Sex differences in motoric effects of opioids may contribute to sex differences in other behavioral effects of opioids; for example, sex differences in rats' ability to discriminate morphine from saline can be attributed entirely to greater morphine-induced sedation in males. Chronic estradiol blunts females' sensitivity to morphine's analgesic and sedative effects, but enhances females' sensitivity to the reinforcing and locomotor stimulant effects of mu opioids. The neurobiological basis for sex differences in and estradiol modulation of behavioral effects of opioids includes brain opioid receptor density (greater in males and under low-estradiol conditions in females) and dopaminergic function (greater in females and under high-estradiol conditions). Given the significant and growing use of opioids by women, both medicinally and recreationally, understanding how female biology influences analgesic and other effects of opioids is crucial. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of oral caffeine pretreatment on response to intravenous nicotine and cocaine.

Previous research suggests that under conditions of chronic daily caffeine administration, caffeine increases the effects of nicotine. Little is known about the effects of caffeine pretreatment on response to nicotine under infrequent caffeine administration conditions. The present study examined whether infrequent (not on consecutive days) acute oral caffeine administration alters subject-rated, physiological, and monetary value effects of intravenous nicotine in regular users of caffeine, tobacco, and cocaine. To determine the specificity of effects of caffeine on response to nicotine, the effects of caffeine administration on response to intravenous cocaine (another short-acting stimulant) were also studied. Fourteen (1 woman) volunteers participated in this 3–4 week, double-blind, inpatient study. Volunteers participated in 10 experimental conditions in pseudo-randomized order, in which oral caffeine (250 mg/70 kg) or placebo was administered 1 hr before an intravenous injection, consisting of nicotine (1 or 2 mg/70 kg), cocaine (15 or 30 mg/70 kg), or saline. Infrequent acute caffeine pretreatment attenuated the increase resulting from 2 mg/70 kg nicotine administration on ratings of “rush,” “good effects,” “liking,” “high,” and “drowsy/sleepy.” Caffeine had no significant effect on physiological response to nicotine. Caffeine had no significant effect on subject-rated and physiological response to cocaine, with the exception that caffeine significantly augmented blood pressure response to cocaine. In contrast to the previous research using chronic caffeine maintenance, these data suggest that infrequent acute caffeine administration may attenuate nicotine effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antagonism of cocaine's reinforcing and discriminative stimulus effects by !a-flupenthixol.

Examined the effects of the D?/D? dopamine receptor antagonist α-flupenthixol in animal models designed to assess abuse-related behavioral effects of cocaine. Rhesus monkeys self-administered cocaine (17 or 33 μg/kg/injection, iv) during 1-hr daily sessions; periods of food-maintained behavior preceded and followed cocaine access. α-Flupenthixol (0.003–0.03 mg/kg, iv) increased self-administration rates, indicating an antagonism of cocaine's reinforcing effects but decreased rates of food-maintained responding. α-Flupenthixol (0.03 mg/kg) blocked the discriminative stimulus effects of cocaine (0.3 mg/kg) in squirrel monkeys but did not do so in rats trained to discriminate 10 mg/kg cocaine from saline. On the basis of available animal data and preliminary clinical trials, α-flupenthixol may warrant further study as a cocaine abuse pharmacotherapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expectancy and pharmacology influence the subjective effects of nicotine in a balanced-placebo design.

The expectancy and pharmacological effects of nicotine (0.60 mg) on memory and the subjective effects of cigarettes were examined by using a balanced-placebo design (i.e., expect either nicotine or no nicotine and receive either nicotine or no nicotine). A total of 120 college students who smoke were assigned to 1 of the 4 experimental groups, then rated the cigarettes on a number of dimensions and completed questionnaires on smoking urges, tension, and energy. Participants also completed tests of memory as well as predictions of memory. Pharmacology played a stronger role than expectancy in most ratings of the cigarettes, but significant effects of expectancy did emerge for feelings of increased wakefulness, concentration, calming, cigarette satisfaction, and hunger reduction. The presence of nicotine significantly reduced smoking urges, but expectancy alone reduced tension after smoking. Neither variable produced significant effects on memory or memory predictions. These findings demonstrate that nonpharmacological factors can play an important role in the self-reported effects of nicotine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of nicotine dose, instructional set, and outcome expectancies on the subjective effects of smoking in the presence of a stressor.

The balanced placebo design (BPD) was used to evaluate the independent effects of nicotine dose and smoking-related expectancies on self-reported anxiety, urge to smoke, and withdrawal symptoms. After anxious mood was induced, participants smoked either a de-nicotinized cigarette or one with standard nicotine content. Nicotine dose was crossed with instructions that the cigarette was either de-nicotinized or standard. Nicotine cigarettes produced greater anxiety reduction than de-nicotinized cigarettes. Nicotine instructions attenuated anxiety only among those who held relevant expectancies. Nicotine dose and instructional set interacted such that either nicotine cigarettes or instructions that the cigarettes contained nicotine were sufficient to reduce urge to smoke. Implications of these findings and methodological issues regarding use of the BPD with cigarettes are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reinforcing effects of nicotine as a function of smoking status.

The authors compared acute nicotine self-administration among 4 groups varying in current or past dependence: dependent smokers, nondependent smokers, ex-smokers who had quit at least I year ago, and nonsmokers. Nicotine (0 vs. 12 μg/kg/8 sprays) available by nasal spray was self-administered with a choice procedure. Self-administration also was related to participant characteristics (sex, alcohol and caffeine intake, sensation-seeking score) and to subjective responses to initial nicotine spray exposure. Nicotine self-administration was similar between dependent and nondependent smokers but was greater in those groups than in ex-smokers and nonsmokers, who did not differ from each other. Self-administration was unrelated to most other participant characteristics. In nonsmokers, self-administration was related directly to pleasurable effects but inversely to aversive effects. Few effects were related to self-administration in the other groups. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcohol consumption, smoking urge, and the reinforcing effects of cigarettes: An ecological study.

Smokers (N=74) who volunteered for a smoking cessation study monitored their daily experiences for up to 6 weeks prior to the quit date. Self-reports from 7,707 diary records were used to examine the associations among alcohol consumption (present in 607 diary records), situational factors, smoking, urge to smoke, and subjective consequences of smoking. Alcohol use, smoking urge, and the subjective effects of smoking were context dependent. Momentary reports of smoking and alcohol consumption were associated with one another. Alcohol use predicted smoking even when contextual factors were covaried. Alcohol use was associated with more frequent reports of urge to smoke. Alcohol was also associated with more frequent reports that the last cigarette produced a rush/buzz, was good tasting, and reduced the urge. However, effects for rush/buzz and urge reduction were qualified by interactions between alcohol use and the latency since smoking. Rush/buzz tended to be associated with alcohol use, regardless of smoking recency. Alcohol was associated with urge reduction only when the cigarette being appraised was smoked more than 15 minutes prior to the diary entry. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interdose interval effects on the development of contextual tolerance to nicotine's analgesic effects in rats (Rattus norvegicus).

Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clubgoers and their trendy cocktails: Implications of mixing caffeine into alcohol on information processing and subjective reports of intoxication.

Alcoholic drink preferences in college students have made an interesting shift recently, with trends in consumption leaning toward caffeinated alcohol in various forms (e.g., Red Bull and vodka or caffeinated beers such as Anheuser-Busch's B-to-the-E). Despite the dramatic rise in popularity of these beverages, little research has examined the combined effects of alcohol and caffeine, which is problematic for adequately informing the public about the risk or lack thereof of these drinks. The purpose of this study was to directly investigate the acute effects of alcohol and caffeine, alone and in combination, on well-validated measures of cognitive performance and subjective intoxication in social drinkers. Participants (N = 12) performed a psychological refractory period task that measured dual-task interference as the prolonged reaction time to complete the 2nd of 2 tasks performed in close temporal sequence. Performance was tested under 2 active doses and 1 placebo dose of caffeine (0.0 mg/kg, 2.0 mg/kg, and 4.0 mg/kg) in combination with 1 active dose and 1 placebo dose of alcohol (0.0 g/kg and 0.65 g/kg). As expected, alcohol impaired task performance by increasing dual-task interference and increasing errors. The coadministration of caffeine counteracted the effects of alcohol on interference but had no effect on the degree to which alcohol increased errors. Subjective measures of intoxication showed that coadministration of caffeine with alcohol reduced participants' perceptions of alcohol intoxication compared with administration of alcohol alone. The results highlight the complexity of drug interactions between alcohol and caffeine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociative antagonistic effects of caffeine on alcohol-induced impairment of behavioral control.

The present study examined the separate and combined effects of alcohol and caffeine on behavioral control in a context in which preliminary cues signaled the likelihood that a response should be executed or inhibited. Social drinkers (N = 12) performed a cued go/no-go task that measured control as the quick execution of responses to go targets and sudden suppression of responses to no-go targets. Performance was tested under 3 doses of caffeine (0.0 mg/kg, 2.0 mg/kg, and 4.0 mgl/g) in combination with 2 doses of alcohol (0.0 g/kg and 0.65 g/kg). Alcohol impaired both inhibitory and activational aspects of behavioral control. Caffeine antagonized alcohol effects on response execution but had no effect on inhibitory control. The findings highlight potential differences in how activational and inhibitory aspects of behavioral control respond to drug interactions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The influence of nicotine dose and nicotine dose expectancy on the cognitive and subjective effects of cigarette smoking.

This study investigated the independent and interactive effects of nicotine dose and nicotine dose expectancy on smoking outcomes using a 2 (given nicotine vs. placebo) × 2 (told nicotine vs. placebo) Balanced Placebo Design (BPD). Smokers (N = 148) completed the Rapid Visual Information Processing Task (RVIP) and measures of smoking urge, mood, and cigarette ratings (e.g., satisfying) after smoking a nicotine or placebo cigarette crossed with instructions that the cigarette contained either nicotine or no nicotine. Nicotine cigarettes (0.6 mg nicotine) produced better sustained attention performance than placebos as indicated by RVIP reaction time, hits, and sensitivity (A′). Nicotine cigarettes also produced better mood and greater rewarding subjective effects of the cigarettes on 11 of 11 dimensions compared to placebos. Nicotine instructions resulted in fewer RVIP false alarms, better mood, and greater rewarding subjective effects of the cigarettes on 9 of 11 dimensions compared to placebo instructions. Nicotine dose by nicotine dose expectancy interactions were also observed for urge and tension-anxiety, such that the dose expectancy manipulation produced differential effects only among those who smoked placebo cigarettes. In contrast a significant interaction for self-reported vigor-activity demonstrated that the dose expectancy manipulation produced effects only among those who smoked nicotine cigarettes. This study provides additional evidence that nicotine improves cognitive performance, and provides initial evidence that denicotinized cigarettes smoked under the guise that they contain nicotine influence cognitive performance, albeit with less robust effects than nicotine. These data may inform the development of expectancy-based interventions for tobacco dependence. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

The Influence of Instructions and Nicotine Dose on the Subjective and Reinforcing Effects of Smoking.

Subjective and reinforcing effects of smoking a cigarette were examined within a 2 x 2 modified balanced-placebo design, which manipulated instructions about nicotine content (i.e., told regular nicotine vs. told low nicotine) and actual nicotine dose (given a regular nicotine brand vs. a denicotinized brand). Most ratings of the nicotine content and reward value of cigarettes were higher for those told regular nicotine versus told low nicotine, and for those given regular nicotine versus given low nicotine. Nicotine and instructions did not affect craving, withdrawal, or smoke-reinforced responding, but instructions affected the number of puffs earned for those given low nicotine (i.e., placebo effect). Thus, verbal information (instructions) can influence some responses to smoking consistent with the presence of placebo and antiplacebo effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of acute caffeine administration on adolescents.

Acute caffeine administration has physiological, behavioral, and subjective effects. Despite its widespread use, few studies have described the impact of caffeine consumption in children and adolescents. The purpose of this study was to investigate the effects of acute caffeine administration in adolescents. We measured cardiovascular responses and snack food intake after acute administration of 0 mg, 50 mg, 100 mg, and 200 mg of caffeine. We also compared usual food intake and subjective effects of caffeine between high- and low-caffeine consumers. Finally, we conducted a detailed analysis of caffeine sources and consumption levels. We found main effects of caffeine dose on heart rate (HR) and diastolic blood pressure (DBP), with HR decreasing and DBP increasing with increasing caffeine dose. There were significant interactions among gender, caffeine use, and time on DBP. High caffeine consumers (>50 mg/day) reported using caffeine to stay awake and drinking coffee, tea, soda, and energy drinks more than low consumers (     

Subjective effects of transdermal nicotine among nonsmokers.

The subjective experience of nicotine, which may be influenced by personality traits as well as environmental factors, may be important for understanding the factors associated with the initiation and maintenance of nicotine dependence. The present study examined the effects of 7 mg transdermal nicotine among a relatively large sample (n = 91; 44 women) of college-aged nonsmokers. Using a placebo controlled, double-blind, within-subjects design, nicotine’s effects were examined at rest and again after participants completed a sustained attention task. Sex and personality factors (Behavioral Inhibition and Behavioral Approach; BIS/BAS Scales; Carver & White, 1994) were examined as potential moderators. Overall, the effects of nicotine were generally modest and unpleasant. In the context of the cognitive task, nicotine increased nausea and negative affect but reduced fatigue, relative to placebo. In contrast, effects of nicotine during the initial 4 hr of patch administration, in which participants were in their natural environments, were moderated by individual differences in behavioral approach. Neither behavioral inhibition nor gender reliably moderated any subjective effects of nicotine. The present work suggests transdermal nicotine exerts only modest, mostly negative effects among nonsmokers. Future work should examine both contextual and personality moderators in large samples of participants who are exposed to nicotine through multiple routes of administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of success and failure on the discrimination learning of normal and retarded children.

30 normal and 30 retarded children learned a 3-choice size discrimination following exposure to experimental tasks under conditions of success, failure, or neutrality. Both normal and retarded children learned more quickly following success and failure than under the neutral condition. In a 2nd study, 32 normal and 32 retarded children learned the same criterion task under success or failure conditions. Here, both success and failure again facilitated the performance of both normal and retarded Ss. Also, social responsivity interacted with intelligence and exeprimental conditions in influencing the children's learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.