Intravenous cocaine discrimination in humans.

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20 mg/70 kg cocaine. During the first session, saline and cocaine injections were alternated twice, with each separated by 1 hr. The injections were identified by letter codes. During the next 3 sessions, 12 trials were conducted, with saline and cocaine administered 6 times each in pseudorandom order. Thirty minutes following each injection, participants were asked to identify the injection by letter code. Seven of the 10 learned the discrimination (at least 10 trials correct). To evaluate sensitivity, the investigators tested participants with different doses of cocaine in test sessions. In the next phase, methamphetamine (5 and 10 mg/70 kg) and pentobarbital (50 and 100 mg/70 kg) were given intravenously during test sessions to determine whether the discrimination exhibited pharmacological class selectivity. During the evaluation of sensitivity and selectivity, training sessions were interspersed. As dose of cocaine increased, the number of participants identifying the test dose as cocaine increased, demonstrating sensitivity. The higher doses of methamphetamine and pentobarbital substituted for cocaine. The physiological and subjective effects of cocaine and methamphetamine were stimulant-like and dose related. Pentobarbital produced no physiological changes but increased Visual Analog Scale ratings of Sedation, Good Drug Effect, and High. This failure to demonstrate pharmacological selectivity may be related to participants' learning a drug-vs.-no-drug discrimination, and thus it may be necessary to alter training procedures in future studies. (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)     

Effects of repeated-dose isradipine on the abuse liability of cocaine.

Despite preclinical studies suggesting that isradipine may antagonize the abuse liability of cocaine, pretreatment with sustained-release isradipine did not reduce euphoric mood in cocaine-using volunteers. This double-blind, within-subject, crossover laboratory study determined whether maximal dose-loading with isradipine could antagonize effects of cocaine in 12 cocaine-dependent research volunteers administered intravenous cocaine doses (0, 0.325, and 0.65 mg/kg) on different days after 5 days of treatment with isradipine or placebo. Isradipine dose was 30 mg sustained release nightly plus 15 mg immediate release 2 hr before cocaine infusion. Cocaine produced dose-related increases in cocaine's subjective effects and a behavioral measure of reinforcement. Isradipine enhanced, rather than antagonized, subjective effects, indicating that isradipine does not antagonize cocaine's abuse liability in dependent research volunteers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1–4 & Days 9–12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5–8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13–40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus-outcome interactions during instrumental discrimination learning by rats and humans.

The associative structure mediating goal-directed action was investigated using congruent and incongruent conditional discriminations. The stimulus was the same as the outcome in each component of the congruent discriminations, whereas the stimulus of one component of the incongruent discriminations was the same as the outcome of the other component. Humans, but not rats, learned the congruent discrimination more rapidly than the incongruent discrimination, a difference that the authors attribute to the fact that outcome-response associations caused response conflict in the incongruent discrimination. Moreover, responding was resistant to outcome devaluation following incongruent, but not congruent, training, suggesting that both humans and rats adopted a stimulus-response strategy to resolve the incongruent discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of methamphetanine on duration discrimination.

Experiments 1 and 2 address the controversy regarding the reliability of methamphetamine effects on interval timing. A temporal discrimination procedure was used, in which the rats were reinforced for pressing the left or the right levers after short and long signals, respectively. Methamphetamine (0.5 mg/kg sc) severely disrupted operant performance at 20-100 min after injection, which disabled the measurement of drug effects on temporal perception (Experiment 1). The same dose of methamphetamine shifted the psychometric function to the left at 100-180 min after injection, indicating an increase in subjective durations (Experiment 2). Although these results confirm the role of dopamine in interval timing, that a change in the speed of a neural clock mediates the methamphetamine-induced change in temporal perception is still a working hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

D-cycloserine--naloxone interactions in opioid-dependent humans under a novel-response naloxone discrimination procedure.

Six participants currently in opioid maintenance treatment were trained to distinguish between naloxone (0.15 mg/70 kg, intramuscularly [i.mj) and placebo under an instructed novel-response drug-discrimination procedure. Doses of the partial glycine agonist D-cyclostrine (0-500 mg/70 kg, per os [P.O.]) alone and combined with naloxone (0.15 mg/70 kg) were then tested. D-cycloserine alone produced minimal drug-appropriate responding, no significant changes in self-reported effects, and increases only in systolic blood pressure. When combined with the naloxone, D-cycloserine partially attenuated naloxone-appropriate responding. D-cycloserine attenuated naloxone-induced increases in visual analog scale ratings of "like naloxone" and scores on the Lysergic Acid Diethyl Amide subscale of the Addiction Research Center Inventory (D. R. Jasinski, 1977; W. R. Martin, J. W. Sloan, J. D. Sapiro, & D. R. Jasinski, 1971). Naloxone attenuated D-cycloserine-induced increases in systolic blood pressure. These results suggest that D-cycloserine at doses up to 500 mg/70 kg may have some limited usefulness in relieving symptoms of opioid withdrawal. (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)     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2–32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32–56 mg/kg/day, IV) on food- and cocaine-maintained (0.001–0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The brief abstinence test: Effects of continued incentive availability on cocaine abstinence.

This study compared the effects of 4 voucher incentive conditions of a brief abstinence test on continuous cocaine abstinence. In 3 conditions, cocaine-abusing methadone patients could earn $100 for 2 days of cocaine abstinence; 2 of these conditions offered, on either a continuous or interrupted schedule, an additional $300 for evidence of sustained abstinence over the next 9 days. In the 4th condition, no incentives were available. In incentive conditions, 70-80% of patients initiated abstinence, compared with 48% in the no-incentive condition. Both continuing reinforcement conditions produced higher rates of sustained abstinence than the single and no-voucher conditions. The study confirmed the utility of quantitative urine-testing methods combined with high valued incentives to promote cocaine abstinence initiation in methadone maintenance patients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned reinstatement of drug-seeking behavior with a discrete compound stimulus classically conditioned with intravenous cocaine.

The present study investigated the ability of a light and tone (LT) compound stimulus paired with cocaine infusions to reinstate cocaine-seeking behavior. Rats were trained to self-administer cocaine in the presence or absence of the LT during daily 3-hr sessions (maintenance). During Maintenance Days 5 and 10, rats underwent classical conditioning, whereby passive cocaine infusions were paired with either short-delayed, random, or no presentations of an LT. After extinction sessions, rats underwent test sessions in which the LT was presented in a noncontingent or response-contingent manner to measure conditioned cocaine-seeking behavior. The results demonstrated that response-contingent LT presentations significantly increased cocaine-seeking behavior and that the LT trained in a classical conditioning format transferred to an operant secondary reinforcer. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of psychopathology on visual discrimination.

"Perceptual and motor aspects of the Bender-Gestalt Test performance were compared for 4 groups of Ss: 10 student nurses, 10 acute schizophrenic patients, 10 chronic schizophrenic patients, and 10 patients hospitalized for neurological reasons… . After the Ss had obtained equal experiences with the Bender designs by reproducing them under memory and copy conditions, a perceptual multiple-choice test was administered under memory and matching conditions. Results indicate that there are marked differences in perceptual accuracy between the 4 groups: the control population was most accurate, with the acute schizophrenic, chronic schizophrenic, and neurological patients less proficient in that order." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Progesterone effects on cocaine use in male cocaine users maintained on methadone: A randomized, double-blind, pilot study.

Previously, the authors reported that progesterone treatment attenuated reports of cocaine-induced high in male and female cocaine users. In this pilot clinical trial, the authors tested the safety and efficacy of oral progesterone as a treatment for cocaine dependence in methadone-stabilized male cocaine users. This was a 10-week, randomized, double-blind, placebo-controlled trial. Forty-five male methadone-stabilized cocaine users were randomized to receive placebo (n=15) or progesterone (n=30) for 9 weeks. The progesterone dose was gradually increased from 100 mg to 300 mg twice daily by Week 4 and maintained through Week 10. Treatment retention for the clinical trial was 80%, without significant group differences (log rank=2.4, p=.12). Hierarchical linear modeling estimates of obtaining a cocaine positive urine result across 10 weeks showed a very slight reduction in cocaine use for the progesterone group (Z=-2.89, p     

Reinforcing effects of stimulants in humans: Sensitivity of progressive-ratio schedules.

Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of schedules of reinforcement, including progressive-ratio schedules. As the name implies, in a progressive-ratio schedule, the response requirement for each subsequent delivery of drug increases, and the primary outcome variable is often the break point (i.e., the last ratio completed to receive a drug delivery). These schedules have been used in a number of human laboratory studies evaluating the reinforcing effects of stimulants. The results of these studies have demonstrated that progressive-ratio schedules are sensitive to manipulation of a pharmacological variable, dose, and to nonpharmacological variables contributing to stimulant drug effects. In addition, findings with progressive-ratio schedules are largely concordant with clinical findings, suggesting that drug self-administration under these schedules has predictive validity in terms of drug abuse and dependence. Future research is necessary, however, to understand better how pharmacological factors like route of administration, onset of effects, and pretreatment influence the reinforcing effects of stimulants under progressive-ratio schedules. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of visual context on pattern discrimination by pigeons (Columba livia) and humans (Homo sapiens).

Three experiments examined the role of contextual information during line orientation and line position discriminations by pigeons (Columba livia) and humans (Homo sapiens). Experiment 1 tested pigeons' performance with these stimuli in a target localization task using texture displays. Experiments 2 and 3 tested pigeons and humans, respectively, with small and large variations of these stimuli in a same-different task. Humans showed a configural superiority effect when tested with displays constructed from large elements but not when tested with the smaller, more densely packed texture displays. The pigeons, in contrast, exhibited a configural inferiority effect when required to discriminate line orientation, regardless of stimulus size. These contrasting results suggest a species difference in the perception and use of features and contextual information in the discrimination of line information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of homework in cognitive-behavioral therapy for cocaine dependence.

This study examines the effect of homework compliance on treatment outcome in 123 participants receiving cognitive-behavioral therapy (CBT) for cocaine dependence. Regression analyses revealed a significant relationship between homework compliance and cocaine use that was moderated by readiness to change. Homework compliance predicted less cocaine use during treatment but only for participants higher in readiness to change. For those lower in readiness to change, homework compliance was not associated with cocaine use during treatment. Homework compliance early in therapy was associated with better retention in treatment. Homework compliance was not predicted by participants' level of education or readiness to change. These findings support the use of homework during CBT for substance use disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans

This study evaluated the effects of i.v. cocaine, hydromorphone and their combination, and assessed the ability of oral naltrexone, an opioid antagonist, to modulate these effects. Volunteers with cocaine and heroin abuse histories (n = 8) participated in this placebo-controlled, cross-over study while residing on a closed research unit. Daily treatment with capsules containing placebo or naltrexone in ascending doses (3.125, 12.5, 50 and 200 mg) were given for 7-day periods. In thrice weekly experimental sessions, cocaine, hydromorphone and their combination were given in random order. Drug doses were given in an ascending order 1 hr apart as follows: cocaine at 0,20 and 40 mg, hydromorphone at 0, 1.5 and 3.0 mg, and the combination of 0 and 0 mg, 20 mg cocaine and 1.5 mg hydromorphone and 40 mg cocaine and 3.0 mg hydromorphone. Hydromorphone and cocaine produced distinct pharmacodynamic profiles, and the combination produced effects similar to both drugs. In some cases, the magnitude of effects produced by the combination was greater than that produced by either drug alone. Naltrexone produced dose-related blockade of hydromorphone effects, but did not after any of the physiological or subjective effects of cocaine. All naltrexone doses partially attenuated the effects of the combination and this appeared to be attributable to selective opioid blockade. These data do not support the use of naltrexone as a treatment for cocaine abuse, but suggest it may be useful for treating patients with concurrent cocaine and heroin abuse.     

The effects of acute pretreatment with high-dose memantine on the cardiovascular and behavioral effects of cocaine in humans.

This study examined the acute effects of pretreatment with high-dose memantine, an N-methyl-D-aspartate antagonist, on the effects of cocaine in humans. Six African American men completed this laboratory study, in which, following pretreatment with memantine (0 or 60 mg), they had 5 opportunities to smoke cocaine base (0, 12, 25, or 50 mg) or receive an alternative reinforcer ($5.00 merchandise voucher). Cocaine alone produced the well-documented dose-dependent increases in cardiovascular activity and ratings of positive mood. Maximal systolic blood pressure was elevated during memantine pretreatment days. Peak ratings of "I feel stimulated" and "I feel anxious" were also higher with memantine pretreatment. However, memantine pretreatment did not alter the choice to self-administer cocaine. These data suggest that memantine pretreatment may not be helpful in the treatment of cocaine dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acquired equivalence in human discrimination learning: The role of propositional knowledge.

The current study investigated the role of propositional knowledge in human acquired equivalence effects. Across 5 experiments, human adults were trained to associate different visual stimuli. Subsequent procedures presented training that was either consistent or inconsistent with the previous associations. More accurate responding in the consistent versus inconsistent condition reflected an acquired equivalence effect. The results of Experiment 1 indicated that a previously reported divergence between verbal and associative processes was likely due to instructional control. Experiments 2-5 further examined the role of verbal processes and demonstrated that acquired equivalence may be produced with verbal instructions alone and critically through a combination of instructions and actual stimulus pairings. The current data not only challenge a purely associative account but actively support an interaction between verbal and associative processes in producing the acquired equivalence effect in humans. (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)