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Risky decision-making is characteristic of drug users, but little is known about the effects of circumstances, such as abstinence, on risky choice behavior in human drug users. We hypothesized that cocaine users would make more risky choices for cocaine (defined as taking a chance to receive a large number of cocaine doses as opposed to choosing to receive a fixed amount of cocaine) after 3 or 7 days of cocaine abstinence, compared to 1 day of cocaine abstinence. Six male nontreatment-seeking current cocaine smokers were enrolled in a 21-day inpatient within-subject study. Participants repeatedly smoked six 25 mg doses of cocaine during a training session and were instructed that they would be making decisions about smoking this dose throughout the study. After 1, 3 and 7 days of cocaine abstinence, participants completed a computerized task in which they repeatedly decided between receiving a guaranteed number of cocaine doses (between 1 and 5; fixed option) or receiving a chance (0.13 to 0.75) to smoke a larger number of cocaine doses (probabilistic option). After completing the computerized task, one of the participants' choices was randomly implemented and they smoked either the fixed number of cocaine doses or had the specified chance to smoke the greater number of doses. Contrary to our hypothesis, 5 of the 6 participants made fewer risky choices after 3 and 7 days of cocaine abstinence compared to one day of abstinence suggesting greater risk-aversion. Thus, even during cocaine abstinence cocaine users make rational decisions related to their drug use.

Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how ‘free’ doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25 mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose–response function for cocaine self-administration (10 choices of 0.0125–0.1 mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large ‘free’ self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

Rationale Previously, we reported that acute marijuana intoxication minimally affected complex cognitive performance of daily marijuana smokers. It is possible that the cognitive tests used were insensitive to marijuana-related cognitive effects. Objectives In the current study, electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana. Methods Research volunteers (N = 24), who reported smoking ∼ 24 marijuana cigarettes/week, completed this study. Participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% ∆ 9 -THC w/w), and completed additional cognitive tasks; sessions were separated by at least 72-hours. Cardiovascular and subjective effects were also assessed throughout sessions. Results Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling “new” words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task. Heart rate and “positive” subjective-effect ratings were increased in a ∆ 9 -THC concentration-dependent manner. Conclusions Relative to previous findings with infrequent marijuana users, the frequent users in the current study exhibited similar neurophysiological effects but more subtle performance effects. These data emphasize the importance of taking into account the drug-use histories of research participants and examining multiple measures when investigating marijuana-related effects on cognitive functioning.

In a limited number of studies modafinil has been shown to decrease food intake by laboratory animals and humans. The present study represents a secondary data analysis, in which the effects of modafinil on several measures of food intake were determined in humans living in a residential laboratory during simulated shift work. During this 23-day study, a wide selection of food items and beverages were freely available. During this double-blind, within-participant study, volunteers (N = 11) received oral modafinil dose (0, 200, or 400 mg) 1 h after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an "off" day. Modafinil (200, 400 mg) dose-dependently decreased total caloric intake by approximately 18% and approximately 38%, respectively, regardless of shift condition, without selectively altering the proportion of total calories derived from carbohydrate, fat and protein. Ratings of "Hungry" were also significantly decreased by both active doses, but only immediately before the lunch break period. In addition, tolerance to the anorexic effects of modafinil was not apparent, as these effects remained stable across the three days of modafinil dosing. These findings show that modafinil produced clear reductions in food intake and suggest that future prospective studies should examine the drug in obese participants.

Numerous studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Given that female rhesus monkeys have menstrual cycles that are remarkably similar to those of humans, they provide an ideal laboratory animal model for assessing the effects of cocaine across the menstrual cycle. The present study assessed the effects of 4 injections of intravenous (i.v.) cocaine (0.00, 0.25 or 0.50 mg/kg), spaced 15 min apart, in 4 female rhesus monkeys. Each monkey was tested with each dose during 4 phases of the menstrual cycle: menses, midfollicular, periovulatory and midluteal. Estradiol and progesterone levels were measured each session before cocaine administration to verify phase of the menstrual cycle. Cocaine and cocaine metabolite levels were measured 5 min after each cocaine dose and 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Similarly, levels of luteinizing hormone (LH) and prolactin levels were measured before, 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Cocaine and metabolite levels increased as a function of dose, but there were minimal differences across the menstrual cycle following repeated injections of cocaine. With a few exceptions, LH levels decreased as a function of time within the session, with no differences as a function of cocaine dose. Cocaine produced transient increases in LH levels during the luteal phase, with maximal levels occurring after the second cocaine injection. Lastly, cocaine substantially decreased prolactin levels across all menstrual cycle phases. Taken together, these data indicate that any behavioral differences observed either across the menstrual cycle or between males and females, are probably not related to alterations in the pharmacokinetics of cocaine across the menstrual cycle.

This study examined how the GABA(b) agonist baclofen (0.5-5.6 mg/kg, p.o.), reported to increase food intake in rodents, affected the appetitive and consummatory aspects of feeding of non-human primates. Baboons had access to food 24 h each day, but they had to complete a two-phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Responding during the appetitive phase resulted in presentations of food-related stimuli only. Baclofen increased the latency to the first meal and decreased both appetitive and consummatory behavior. At the largest dose, baclofen induced emesis, indicating that the effects were due to malaise rather than a specific motivational action. In contrast, the positive control diazepam (GABA(a) agonist, 1.0-2.0 mg/kg, i.m.) decreased the latency to the first meal and increased both appetitive (P0.07) and consummatory behavior. Although the baclofen-induced decrease in appetitive behavior replicates data obtained in rodents, the baclofen-induced decreases in consummatory behavior do not. The findings suggest that the effects of large doses of baclofen in non-human primates may, in part, be due to non-specific behavioral disruptions.

Although recent research has focused on "crack" cocaine, the majority of the cocaine users in the United States insufflate ("snort") cocaine rather than smoke it. Furthermore, the intranasal route of administration is often the first way that many cocaine-dependent individuals used cocaine. Numerous studies have reported on the effects of repeated doses of smoked or intravenous cocaine, the relationship between cocaine plasma level and cocaine's effects, and the development of acute tolerance to smoked or intravenous cocaine. Significantly less information is available about similar effects of intranasal cocaine. The purpose of this study was to determine the dose-dependent effects of repeated intranasal cocaine in humans. Ten experienced male cocaine users were admitted to the hospital on two separate occasions for four days each, with a minimal two-week interval between admissions. During each admission, an intranasal cocaine (0.06, 0.34, 0.69, and 1.37 mg/kg) dose-response curve was determined during four laboratory sessions: Two administrations of the same cocaine dose occurred each session at 40-min intervals. Intranasal cocaine produced dose-related increases in ratings of "positive" drug effects, heart rate, and blood pressure. Plasma cocaine levels peaked following the second cocaine insufflation of each session, while metabolite levels increased during each session. Although the plasma cocaine level approximately doubled following the second cocaine administration, the ratings of positive drug effects, heart rate, and blood pressure did not increase after the second cocaine administration. These data demonstrate that, as observed with smoked and intravenous cocaine, acute within-session tolerance develops during repeated intranasal cocaine administration.

The purpose of the present study was to evaluate the reinforcing effects of smoked heroin in nonopioid-dependent nonhuman primates when an alternative reinforcer, sweetened fluid, was made available. Four adult male rhesus monkeys lived in three chambers, with heroin self-administration (0, 0.3, and 0.6 mg/kg) specific to one end of the chamber, oral sweetened fluid self-administration specific to the other end chamber, and no commodity available in the middle chamber. The length of time monkeys spent in the drug-associated chamber provided one measure of drug seeking (i.e., location preference). During self-administration sessions, a second-order schedule of reinforcement was used, with responding during the first component maintained by a brief presentation of the stimuli associated with reinforcement. Responding during the second component was maintained by a delivery of the reinforcer, and the associated stimuli. Responding during the first component provided a second measure of drug seeking. Monkeys also had choice trials each day, when they could choose to work for either commodity. Choice behavior provided a third measure of drug seeking. Each experimental day consisted of a smoking session (four smoking trials), a sweetened fluid session (four fluid trials), and a choice session (four choice trials). Monkeys typically completed all four smoking trials each day when either of the active heroin doses was available. They chose both heroin doses over fluid on 3.5 of the four choice trials, and they had a location preference for the heroin chamber. Under baseline conditions, the number of acquisition responses and the number of consumption responses (inhalations) were greater for the high dose of heroin compared to the low dose of heroin. Further, it took longer to extinguish the responding for the high dose of heroin compared to the low dose of heroin when a vehicle was substituted. During heroin extinction, acquisition responding for fluid increased, the number of fluid choices increased, and location preference shifted to the fluid chamber. These data suggest that in nondependent rhesus monkeys, measures of heroin seeking decreased when heroin was not available and seeking behavior shifted to the available alternative commodity.

The first purpose of this study was to compare the effects of D-amphetamine (AMPH) on operant responding reinforced under fixed ratio (FR) or progressive ratio (PR) schedules of reinforcement, testing the hypothesis that responding reinforced under a PR operant schedule would be disrupted by lower doses of AMPH than responding reinforced under a FR operant schedule. The second purpose of this study was to test the generalizability of the first hypothesis by comparing the effects of AMPH on responding reinforced by two different reinforcers under both FR and PR operant schedules. Rhesus monkeys had five to six candy and five to six fruit drink sessions per day, and could receive two reinforcers per session. Responding was initially reinforced under a PR procedure, such that the ratio size increased with each subsequent session. The parameters of the PR schedule were individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day. The effects of oral AMPH (0.5, 0.75, 1.0 mg/kg) on responding were assessed. Responding was then stabilized using a FR schedule with parameters individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day, and the effects of oral AMPH were again assessed. The PR breakpoint was significantly greater for candy than fruit-drink. AMPH produced dose-related decreases in both candy and fruit-drink intake, but each AMPH dose decreased the number of fruit-drink deliveries to a greater extent than the number of candy deliveries. The results failed to support the hypothesis that responding under PR schedules of reinforcement would be disrupted by lower doses of AMPH.

Using a laboratory animal procedure designed to measure two aspects of reinforcement (self-administration and location preference), five adult rhesus monkeys each lived in three chambers: oral cocaine self-administration (0.26 mg/kg/delivery cocaine hydrochloride in a sweet fluid) was specific to one end chamber, food self-administration was specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day monkeys experienced multiple food, cocaine, and choice (food vs. sweet cocaine fluid), sessions. Oral d -amphetamine (AMPH; 0.5–1.5 mg/kg) or placebo was administered before the sessions to determine if this anorectic drug would differentially alter food and sweet cocaine fluid self-administration. Further, the effects of AMPH on the length of time a monkey spent in each chamber, when the stimulus cues indicating commodity availability were not present (location preference) were determined. AMPH produced dose-dependent decreases in both food and cocaine self-administration without affecting choice behavior. AMPH also increased the length of time monkeys spent in the food chamber, even when no stimuli indicating food availability were present. These results indicate that the relationship between self-administration and location preference measures of reinforcement is not completely concordant. The current procedure may prove useful in studying these two measures of reinforcement.

The effects of time of day and social context on daily patterns of marijuana self-administration were examined in two groups of three adult male marijuana smokers during a 12-day residential study. Days were divided into 6.5-h work and social-access periods. Order of occurrence (i.e., work before social access or social access before work) was counterbalanced between groups and reversed for both groups on day 8. Up to eight marijuana cigarettes (0.0% or 2.3% delta 9-THC) could be smoked each day. Stable patterns of marijuana smoking were observed across days for each subject. Three subjects smoked more marijuana during the social-access period, regardless of when it occurred. The other three smoked more marijuana during the first period, regardless of whether it was a work or social-access period. The number of marijuana cigarettes smoked was unrelated to THC content. In contrast, subjective reports of "High," "Liking," "Potency" and "Drug" on visual-analog scales were increased on active marijuana days. Subjective reports of drug effects were not predictive of drug self-administration.

Eight adult male research volunteers received cocaine and marijuana, alone and in combination during experimental sessions. Following the determination of baseline cardiovascular indexes, a one-gram marijuana cigarette (0-2.9% delta 9-THC w/w) was smoked, and cocaine hydrochloride (4-96 mg) was inhaled five minutes after completion of marijuana smoking. Subjects performed a learning task 25 and 70 minutes after initiating marijuana smoking. Cocaine increased heart rate, which averaged 68 bpm under resting baseline conditions, by up to 15 bpm, marijuana increased heart rate by up to 27 bpm, and task performance increased heart rate by 5 bpm. The combination of cocaine and marijuana produced increases in heart rate that were similar to those seen with marijuana alone. During task performance in combination with cocaine and marijuana administration, however, heart rate was elevated by 37 bpm. Although more variable, the largest increases in blood pressure were observed following combinations of cocaine, marijuana, and task performance. These findings suggest that the self-administration of cocaine and marijuana under nonresting conditions has greater cardiovascular effects than the self-administration of these drugs under resting conditions.

Nine male research volunteers, in three groups of three subjects each, resided in a residential laboratory for up to 25 days. All contact with the experimenter was through a networked computer system and subjects' behaviors including food intake were continuously recorded. Subjects brought their own activities such as model-making, and these in combination with those provided by the laboratory resulted in rich behavior repertoires. During the first part of the day, subjects remained in their private rooms doing planned work activities, and during the remainder of the day, they were allowed to socialize. Cigarettes containing active marijuana (1.84% THC) or placebo were smoked prior to the private work period and during the social access period. A single active marijuana cigarette prior to the private work period had no effect on food intake. The administration of two or three active marijuana cigarettes during the social access period increased average daily caloric intake. The increased intake was due to an augmentation of calories consumed as between-meal snack items rather than an increase in meal size per se.

Food intake of four adult male baboons (Papio c. anubis) was monitored during daily experimental sessions lasting 22 hours. Food was available under a two-component operant schedule. Following completion of the first "procurement component" response requirement, access to food, i.e., a meal, became available under the second "consumption component" during which each response produced a one-g food pellet. After a 10-minute interval in which no response occurred, the consumption component was terminated. The effects of oral d-amphetamine (AMPH: 0.03-1.0 mg/kg) and fenfluramine (FEN: 0.25-2.0 mg/kg) were determined by having the baboons drink a dose on Tuesdays and Fridays 45 to 60 min before the daily session. Dose-dependent decreases in food intake were observed with AMPH being four times as potent as FEN. Although both drugs were equally efficacious in decreasing food intake, they had dissimilar effects on the topography of feeding behavior. AMPH decreased food intake by increasing the latency to the first meal, decreasing the size of the first meal, and decreasing the number of meals within a session. FEN, in contrast, had no significant effect on latency to the first meal or size of the first meal, but decreased the number of meals within a session. In addition, the drugs had different effects on the patterning of responding within the first meal. Finally, at the doses tested, there was no evidence of nonspecific motor deficits disrupting food intake. Although there are some differences between these results and the previously reported effects of these drugs, it is clear that AMPH and FEN influence feeding behavior in different ways.

Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to nine research volunteers during daily experimental sessions. Following the determination of baseline cardiovascular indexes, an ETOH cocktail (0, 19.4, 38.7, or 58.1 g of ETOH in lemonade) was consumed over a ten-minute period. Cocaine hydrochloride (4, 48, 96 mg) was inhaled 25 minutes after the start of ETOH drinking. Breath samples were collected 50 minutes after the start of ETOH drinking to estimate blood alcohol level (BAL). The effect of these doses, alone and in combination, on heart rate (HR) and blood pressure (BP), while resting and while performing a serial acquisition task, were determined. COC and ETOH alone significantly increased HR up to 6 bpm without affecting BP. Combining the two highest doses of COC with the highest BAL increased HR by 20 bpm. During task performance, in the absence of drug, HR was increased up to 5 bpm, and BP was unchanged. Combining the highest COC dose and BAL with task performance increased HR by 40 bpm. Small increases in BP were also observed under these conditions. These results indicate that combinations of ETOH, COC and task performance produce greater increases in HR than BP, and, in addition, this increase in HR is greater than that observed following COC, ETOH, or task performance alone.

Eleven adult male subjects with histories of cocaine use participated in daily experimental sessions consisting of resting cardiovascular (heart rate, blood pressure) baseline measures followed by intranasal cocaine (4, 48 or 96 mg) administration and further cardiovascular monitoring. Subjects in Group I performed a learning task before and after cocaine administration, while subjects in Group II rested. Cocaine administration alone significantly increased heart rate up to 10 beats per minute (bpm) and mean arterial pressure (MAP) up to 15 mm/Hg. Task performance alone increased heart rate up to 8 bpm and MAP up to 10 mm/Hg. In combination, increases in heart rate up to 19 bpm and MAP up to 18 mm/Hg were observed. Thus, combinations of cocaine administration and task performance increased heart rate and blood pressure above levels observed following the occurrence of either activity alone. These results indicate the importance of understanding the effects of drugs within the environmental context in which they are taken.

Seven adult male volunteers residing on a research ward received intravenous cocaine and smoked marijuana, alone and in combination, during daily experimental sessions. Following the determination of baseline cardiovascular indexes, a one gram marijuana cigarette (0-2.7% delta 9-THC w/w) was smoked. Cocaine hydrochloride (0-32 mg) was administered intravenously 13 minutes after the start of marijuana smoking. Cocaine alone produced dose-dependent increases in heart rate, while both low and high THC blood levels produced a similar increase in heart rate. Both doses of cocaine increased mean arterial pressure (MAP) similarly, while THC alone produced blood level dependent increases in MAP. Combinations of cocaine and marijuana increased heart rate above levels seen with either drug alone, with increases plateauing at nearly 50 bpm for all dose-blood level combinations. Increases in mean arterial pressure following combinations of cocaine and marijuana were equivalent to those produced by cocaine alone.

Specific lesions of the central dopaminergic system produced by intraventricular injections of 6-hydroxydopamine with pargyline and desmethylimipramine pretreatment significantly attenuated conditioned taste aversions to a sweetened-condensed milk solution induced by methylamphetamine. Identically treated rats formed an aversion to the milk solution when lithium chloride was utilized. These results suggest that the methylamphetamine-induced aversion is dependent upon intact dopaminergic neurons.

Food intake of rhesus monkeys was limited to a single daily 2 hr session of banana flavored pellet availability, seven days a week. Following stabilization of intake, the effects of intragastric bromazepam, diazepam and pentobarbital, when given alone, were determined by delivering a dose twice weekly, 60 min before the session. Dose-dependent increases in food intake were observed with the following descending order of potencies: bromazepam, diazepam and pentobarbital. RO 15-1788 (O.5–1.0 mg/kg, IM), when given alone, five min before the session had no effect on food intake. When given in combination with bromazepam and diazepam, RO 15-1788 completely blocked the increases in food intake observed when the benzodiazepines were given alone. The specificity of this antagonism was shown by the failure of RO 15-1788 to alter the food intake increases induced by pentobarbital. These results confirm and extend previous reports of the specific antagonism of benzodiazepine behavioral effects by RO 15-1788 to an additional species and another behavioral effect of benzodiazepines.

When the presentation of a novel food to a rat is followed by the injection of a certain compounds, including many psychomotor stimulants, the animal consumes less of that food on subsequent presentations compared to an animal injected with saline. This phenomenon has been termed gustatory avoidance conditioning. The effect of dl-cathinone, a psychomotor stimulant drug structurally similar to amphetamine, was determined in this paradigm. Fluid intake was limited to a single 15 min presentation, seven days a week. Following the determination of baseline water intake, sweetened milk was presented for five consecutive sessions. There were six groups of rats with each group receiving a different dose of cathinone (0--16.0 mg/kg) five min after the session each day. Following these five days of milk-cathinone pairings, milk intake was significantly decreased only in the rats receiving 16 mg/kg. These results indicate that cathinone which is nearly as potent as amphetamine in many other behavioral measures, is less potent in inducing gustatory avoidance responses.

The effects of intraperitoneal (2.0-32 mg/kg) and intragastric (8.0-96 mg/kg) methylphenidate on milk intake were determined in two groups of rats. Experimental sessions consisted of 15 min access to a sweetened milk solution each day, seven days a week. Following the determination of baseline intake, a dose of methylphenidate was administered prior to the session once every four days with all rats in each group receiving all doses. Although methylphenidate was equally effective in decreasing milk intake using either route of administration, intraperitoneal methylphenidate was four times as potent as intragastric methylphenidate.