Individual differences and social influences on the neurobehavioral pharmacology of abused drugs.

The interaction of drugs with biologic targets is a critical area of research, particularly for the development of medications to treat substance use disorders. In addition to understanding these drug-target interactions, however, there is a need to understand more fully the psychosocial influences that moderate these interactions. The first section of this review introduces some examples from human behavioral pharmacology that illustrate the clinical importance of this research. The second section covers preclinical evidence to characterize some of the key individual differences that alter drug sensitivity and abuse vulnerability, related primarily to differences in response to novelty and impulsivity. Evidence is presented to indicate that critical neuropharmacological mechanisms associated with these individual differences involve integrated neurocircuits underlying stress, reward, and behavioral inhibitory processes. The third section covers social influences on drug abuse vulnerability, including effects experienced during infancy, adolescence, and young adulthood, such as maternal separation, housing conditions, and social interactions (defeat, play, and social rank). Some of the same neurocircuits involved in individual differences also are altered by social influences, although the precise neurochemical and cellular mechanisms involved remain to be elucidated fully. Finally, some speculation is offered about the implications of this research for the prevention and treatment of substance abuse.

Acute behavioral and physiological effects of modafinil in drug abusers.

Modafinil, a novel stimulant, is effective in the treatment of excessive daytime sleepiness associated with narcolepsy. It is biochemically and pharmacologically distinct from prototypical stimulants such as D-amphetamine, cocaine, and methylphenidate. The present experiment was designed to assess the acute behavioral effects of oral modafinil, cocaine, and placebo in participants (n=9) with recent histories of cocaine use (i.e. positive urine for cocaine or benzoylecgonine during the initial screening interview). Drug effects were assessed with a battery of self-reported drug-effect questionnaires, performance measures, and physiological indices. Cocaine, but not modafinil, produced stimulant-like self-reported drug effects (e.g. increased ratings of High and Stimulated). Modafinil and cocaine dose-dependently increased heart rate and blood pressure. The results of the present study suggest that modafinil has minimal abuse potential, but should be viewed cautiously because of the relatively small sample size. Future studies should further characterize the abuse potential of modafinil using other behavioral arrangements, such as drug discrimination or drug self-administration. A full characterization of the abuse potential of modafinil will become important as the use of this drug increases.

Retrograde facilitation of memory by triazolam: effects on automatic processes.

RATIONALE: Retrieval processes have been implicated as a potential mechanism by which benzodiazepines can produce retrograde memory facilitation. OBJECTIVES: This study tested the degree to which benzodiazepine-induced retrograde facilitation of memory was due to an enhancement of automatic retrieval processes. METHODS: Forty healthy adults were randomly assigned to one of three dose conditions (double-blind), under which they received 0.0 mg (placebo), 0.125 mg, or 0.25 mg of the short-acting benzodiazepine triazolam (Halcion). Subjects studied a list of words just prior to dose administration. One hour after dose administration, subjects performed a word-stem completion task which tested their retrieval of the studied words. A process-dissociation procedure was used to estimate the degree to which retrieval was under the influence of memory processes that were automatic (i.e., unintentional) versus controlled (i.e., intentional). RESULTS: Subjects who received active doses of triazolam displayed a greater probability of using studied words as stem completions. Estimates of memory processes showed a greater influence of automatic influences during memory retrieval under triazolam doses. CONCLUSIONS: The findings indicate that retrograde memory facilitation following benzodiazepine administration does not necessarily reflect an improved ability to intentionally retrieve information but could instead reflect increased responsiveness to cues that automatically elicit retrieval of pre-drug information.

Triazolam impairs inhibitory control of behavior in humans.

This study tested the effects of the sedative-hypnotic drug triazolam (Halcion) on the ability to inhibit behavior in humans. Thirty adults practiced a stop-signal task that measured their ability to inhibit and activate behavioral responses on a choice reaction time task. Equal numbers of participants (i.e., n = 10) then received either 0.25 mg, 0.125 mg, or 0 mg (placebo) of triazolam under double-blind conditions and performed the task intermittently over a 3-hr period. In accord with the hypothesis, triazolam reduced response inhibitions and increased the time required to inhibit a response. The drug also slowed the activation of responses. The findings contribute to the understanding of the basic behavioral mechanisms by which sedative-hypnotic drugs can produce states of behavioral disinhibition in some individuals.

Exposure to novel environmental stimuli decreases amphetamine self-administration in rats.

Researchers examined whether exposure to novel environmental stimuli reduces drug self-administration. Rats were trained to self-administer amphetamine on a fixed ratio (FR) 5 schedule of reinforcement and then were exposed to novel stimuli during the session. Responding was significantly decreased with exposure to novelty but returned to baseline levels on intervening nonexposure sessions. In 2 subsequent experiments, rats were exposed to novel plastic objects prior to the session. Immediately following exposure, rats were allowed to self-administer amphetamine on an FR 1 schedule, which was increased gradually to an FR 5 either using predetermined increments or on the basis of performance criteria. Exposure to the novel objects significantly decreased acquisition of amphetamine self-administration in both situations. Results suggest that exposure to novel environmental stimuli may be effective at reducing drug self-administration.

Effects of d-amphetamine on task performance and social behavior of humans in a residential laboratory.

Six healthy adult male volunteers lived for 11 days in a residential laboratory. Acute effects of d-amphetamine (0, 5, or 10 mg/70 kg) on performance of tasks, social interaction, and self-reports of drug effects were measured. Each day, participants engaged in a 6.5-hr work period and a 6.5-hr recreation period. Beverages containing d-amphetamine or placebo were consumed daily before the work period and before the recreation period. d-Amphetamine increased response rate without affecting accuracy on some tasks. d-Amphetamine increased the proportion of time spent engaging in verbal interaction during the first but not the second week of study. No changes in self-reported drug effects were observed. Thus, d-amphetamine improved performance in the absence of stimulant-like subjective effects. This differentiation between performance and subjective effects confirms the importance of determining the effects of drugs on a range of behaviors.

Are choice and self-administration of marijuana related to delta 9-THC content?

The effects of delta 9-tetrahydrocannabinol (THC) content on choice marijuana, number of marijuana cigarettes smoked, and ratings of marijuana's effects were examined in 6 adult male marijuana smokers during a residential study consisting of four 3-day blocks of 2 sample days and 1 choice day. Days were divided into 6.5-hr work and social-access periods, beginning at 1000 and 1700. On sample days, marijuana cigarettes containing different THC concentrations (0.0% vs. 3.5% and 2.0% vs. 3.5% THC) were smoked at least once during each period. On choice days, independent choices between previously sampled marijuana cigarettes were made during each period. A maximum of 8 cigarettes could be smoked per day, and drug ratings were obtained after each period. Only choice behavior was sensitive to changes in THC content, whereas only the number of smoked marijuana cigarettes was related to context (i.e., work and social-access period).

Behavioral effects of alprazolam in humans.

The purpose of this study was to examine, in healthy volunteers without histories of extensive sedative use, the acute behavioral effects of doses of alprazolam used in clinical applications. Subjects participated in daily sessions over 12 study days. They consumed a standard breakfast, received an oral drug dose (0, 0.25, 0.5, 1 mg) and completed performance tasks for 3 hours after dosing. Tasks included a digit-symbol substitution task, a repeated-acquisition of response sequences task, a differential reinforcement of low response rate task designed to monitor time estimation, a number recognition task, and a second-order repeated-acquisition of response sequences task. Each active dose was administered prior to two sessions, according to a randomized block design, and placebo sessions separated successive active-dose sessions. With the exception of the second-order repeated acquisition of response sequences task, dose-related changes in performance were observed during all tasks, but effects were significant only following the 1 mg dose. No drug-related changes were observed on visual-analog scale ratings of drug effect. The data indicate that the risk of adverse performance effects following use of alprazolam is related to dose, with risks increasing at doses at or above 0.5 mg.

Discriminative stimulus effects of alcohol in humans.

The discriminative stimulus effects of alcohol were examined in 11 healthy moderate alcohol users. Study days occurred 5 days per week for 12-25 total days. Each day, participants completed visual-analog reports of drug effect and drug-discrimination tasks at 30-min intervals for 2.5 h following oral alcohol administration. Participants completed three phases. During the training phase, which occurred on the first 4 study days, participants were trained to discriminate color-coded placebo and alcohol doses (0 vs. 0.45 g per liter of body water (g/lbw)). Participants then completed a control phase, during which accurate drug-discrimination performance was verified. Finally, participants completed a testing phase, during which both training and intermediate doses (0.15 and 0.30 g/lbw) were administered. During the testing phase, 25 and 100% of responses occurred on the alcohol key at the 0- and 0.45-g/lbw doses, respectively, indicating that discrimination responding remained intact. At the low dose (0.15 g/lbw), 25% of the subjects responded on the alcohol key, whereas 75% of the subjects responded on the alcohol key at the moderate dose (0.30 g/lbw), indicating dose-related generalization to the training doses. These results confirm cross-species generality in the discriminative stimulus effects of alcohol, and further establishes the utility of human laboratory drug-discrimination procedures for analysis of the functional effects of alcohol.

Effect of amphetamine on human macronutrient intake.

Six male subjects participated in a 15-day residential study examining the effects of amphetamine on macronutrient intake. During the first 11 days, carbohydrate intake was manipulated by providing lunch meals high (155 g) or low (25 g) in carbohydrate. Subjects received oral d-amphetamine (5, 10 mg/70 kg, BID) or placebo. Total daily caloric intake was similar under both lunch conditions (approximately 3400/Kcal), but carbohydrate contributed more energy under the high-carbohydrate condition. Both doses of amphetamine decreased total caloric intake to approximately 2600 Kcal, by decreasing the number of eating bouts, without affecting macronutrient selection. During the last four days subjects received a higher daily dose of amphetamine (30 mg/70 kg in four doses) or placebo, and were allowed to self-select lunch. Although 30 mg amphetamine decreased intake of all macronutrients, the relative contribution of carbohydrate to total caloric intake was increased from 54% to 62%, while the contribution of fat was decreased from 32% to 26% and the contribution of protein was decreased from 14% to 12%. Thus, at a high dose, amphetamine altered the relative contribution of specific macronutrients to total caloric intake.

Effects of delta 9-tetrahydrocannabinol and social context on marijuana self-administration by humans.

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.

Effect of meal macronutrient and energy content on human performance.

The effects of planned meals, varying in carbohydrate (CHO), fat and caloric content, on psychomotor performance by male subjects with unrestricted access to commercially-available foods was investigated in two residential studies. In the first study, two groups of three subjects (n = 6) completed psychomotor tasks before and after consuming a lunch consisting of 431 or 844 kcal, with caloric differences produced through covert changes in either fat or CHO content. The effects of each of four lunch conditions (low-fat, high-fat, low-CHO, high-CHO) were determined for three consecutive days. In the second study, two groups of three subjects (n = 6) received breakfast, lunch and an afternoon snack and completed psychomotor tasks after breakfast and lunch. Cumulative caloric content of the three eating occasions was approximately 700, 1200 or 1700 kcal (low, medium or high), again with differences resulting from covert changes primarily in either fat or CHO content. The effects of each of six food conditions were determined for two consecutive days. While changes in some aspects of performance were altered after meals, the effects were not related to the CHO, fat or caloric content of the meal. When subjects have unrestricted access to commercially-available foods, neither calories nor the relative fat or CHO content of normal meals influence human psychomotor task performance.

Effects of delta 9-THC on marijuana smoking, dose choice, and verbal report of drug liking.

The effects of delta 9-tetrahydrocannabinol content of marijuana on cigarette smoking, dose choice, and verbal report of drug "liking" by adult males living in a residential laboratory were investigated. Marijuana cigarettes were available during programmed intervals while subjects were engaged in recreational activities. The tetrahydrocannabinol content of the cigarettes remained constant each day, but was changed across days. Subjects provided written ratings of drug liking at the end of each day. In the first study, placebo or active (2.3% delta 9-tetrahydrocannabinol) marijuana cigarettes were available for 1-, 2-, or 3-day intervals at varying times of day. The number of cigarettes smoked was unrelated to tetrahydrocannabinol content, although verbal reports of drug liking were consistently higher when marijuana cigarettes containing tetrahydrocannabinol were smoked. In a second study, a choice procedure, consisting of four 3-day blocks of 2 sample days and 1 choice day, was used. On sampling days, subjects smoked cigarettes varying in tetrahydrocannabinol content (0.0, 2.0, and 3.5%, w/w); on choice days they were allowed to choose between the two previously sampled doses. The number of cigarettes was not consistently related to tetrahydrocannabinol content. Ratings of drug liking were increased when marijuana cigarettes contained tetrahydrocannabinol, but ratings of marijuana containing 2.0% and 3.5% of the compound were similar. In contrast, subjects consistently chose the 3.5% dose over either the 0.0% or 2.0% dose. Dose choice was more sensitive to tetrahydrocannabinol content than either reports of drug liking or numbers of cigarettes smoked.

Performance-based testing for drugs of abuse: dose and time profiles of marijuana, amphetamine, alcohol, and diazepam.

The time courses of the effects of acute doses of amphetamine (5 and 10 mg/70 kg), alcohol (0.3 and 0.6 g/kg), diazepam (5 and 10 mg/70 kg), and marijuana (2.0% and 3.5% delta 9-THC) on performance engendered by each of four computerized behavioral tasks were evaluated in six human subjects. These performance-based tasks have potential commercial utility for drug-use detection in the workplace. Alcohol and marijuana effects were reliably detected for up to three hours following dose administration with most procedures. Amphetamine and diazepam effects were also detected, but the dose effects and time courses were variable. The profile of behavioral effects varied across drugs, suggesting that performance-based testing procedures might be useful in discriminating which drug was administered and the time course of the drug's effects. Results indicate that repeated measurement with performance-based drug detection procedures can provide immediate indications of performance impairment in a cost-effective and noninvasive manner and, as such, would be a useful supplement to biological sample testing for drug-use detection.

The effects of alcohol on free-operant aggressive behavior.

Although strong correlations between alcohol use and the frequency and intensity of social aggression have been observed in many populations, the relationship between these two events remains complex. Aggressive behavior is not always associated with alcohol or drug use, and substantial amounts of alcohol are consumed in social settings without the occurrence of violent or aggressive behavior. The relationship between alcohol and human aggressive behavior has been investigated using a free-operant procedure developed from the experimental tradition of behavioral pharmacology. The reliability of the free-operant procedure is evidenced by the similarity in experimental outcomes across laboratories using similar experimental procedures. Evidence for the validity of the procedure comes from recent studies with populations varying in histories of violent behavior, as well as from similarities in the outcome of studies using different experimental paradigms. Recent studies indicate clearly that both antecedent and consequent variables, such as the schedule of provocation and the response requirement for both aggressive and nonaggressive behavior, as well as the social context in which provocation occurs, influence the relationship between alcohol and aggressive behavior. The implications of the role of contextual factors for social policy regarding violence and alcohol use are discussed.

Behavioral effects of cocaine alone and in combination with ethanol or marijuana in humans.

Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to one group of seven research volunteers during daily experimental sessions. Following the determination of baseline subjective and performance measures, an ETOH cocktail (0, 19.4, 38.7 or 58.1 g of ETOH in lemonade) was consumed over a 10-min period. COC hydrochloride (4, 48, 96 mg) was inhaled 35-min after the start of ETOH drinking. In a separate experiment, seven research volunteers received intravenous cocaine and smoked marijuana (MJ), alone and in combination during daily experimental sessions. Following the determination of baseline measures, a 1-g MJ cigarette (0-2.7% delta 9-THC, w/w) was smoked and 13 min after the start of MJ smoking COC hydrochloride (0, 16, 32 mg) was given intravenously. ETOH increased simple-reaction time and decreased DSST trials. COC decreased DSST trials, increased incorrect responses on a list-learning task and attenuated the effect of ETOH on DSST performance. Only combinations of the high COC dose and the high MJ dose increased errors on a repeated acquisition task. Intranasal COC increased ratings of 'Stimulated,' and 'High' and LSD scores on the ARCI which were unaffected by ETOH. Increased ratings of 'Sedated' following ETOH alone were attenuated by intranasal (i.n.) COC. Intravenous COC and smoked MJ alone both increased ratings of 'Stimulated' and 'High.' There was a trend for combinations of i.v. COC and MJ to prolong these elevations. The results suggest that the interactive effects of COC in combination with ETOH or MJ, after acute administration, are subtle and in need of further analyses to better understand polydrug abuse.

Ethanol as an energy source in humans: comparison with dextrose-containing beverages.

Six subjects participated in a residential study assessing the effects of consuming beverages containing energy derived from ethanol or dextrose on total energy and macronutrient intake. On certain days, subjects had to consume four beverages containing a total of approximately 2400 or 4600 kJ, equivalent to 22% and 42% of energy intake under conditions in which no-beverages were required. Each of four conditions (2400 kJ ethanol, dextrose; 4600 kJ ethanol, dextrose), and a no-beverage control condition was examined for 2 days. Subjects compensated for approximately 37% of the energy contained in the beverages such that total intake increased by 13% under the 2400 kJ conditions and 27% under the 4600 kJ conditions. There was no differential effect of ethanol content on energy intake. Cumulative intake curves indicated that caloric compensation was minimal following the consumption of beverages in the evening. While all of the beverage conditions significantly decreased energy intake derived from carbohydrate, the proportion of energy derived from fat, carbohydrate, and protein without the energy content of the beverages was essentially unaffected by dextrose- or ethanol-containing beverages. These results suggest that the effects of ethanol on intake of other foods can be accounted for by the energy content of ethanol as a beverage and by ethanol consumption in the evening when there is little time for daily caloric compensation, rather than by the pharmacological effects of ethanol.

Effects of smoked marijuana on heart rate, drug ratings and task performance by humans.

Six subjects, reporting marijuana use between two and 30 times per month, participated in studies of the acute effects of smoked marijuana (0.0%, 2.0% and 3.5% Delta(9)-THC, w/w) on heart rate, ratings of drug effect and task performance. Marijuana was administered using a uniform-puffing procedure with monetary contingencies associated with puff and breathhold duration. In general, heart rate and ratings, of "High" and dose "Potency" were increased by marijuana, and performance on some tasks was altered by drug administration. The relative sensitivity of the measures varied across subjects, and no single measure, such as heart rate or verbal rating of drug effect, could be used to predict the behavioral effects of marijuana. Marijuana puff durations were decreased at the highest dose, but dose-related changes in heart rate and task performance indicated that the change in smoking topography did not result in complete compensation for increased cannabinoid concentrations in marijuana smoke.

Behavioral response to diazepam in a residential laboratory.

Two groups of three healthy adult male volunteers without histories of sedative or other drug abuse participated in 15-day residential studies. Each day consisted of a private work period (10 AM to 4:30 PM), during which subjects participated in traditional laboratory performance tasks, and a social period (5 to 11:30 PM), during which subjects had access to recreational activities available under social or private conditions. Tobacco cigarettes and food were available throughout each day (9 AM to 12 PM). Diazepam (5 or 10 mg/70 kg) or placebo was administered orally twice daily in alternating three-consecutive-day intervals. Dosing order varied between groups. Diazepam had no effect on the total amount of time subjects spent in social conditions; however, the low dose increased verbal interaction, while the high dose decreased verbal interaction. Both doses disrupted performance on a second-order repeated-acquisition task but produced no effects on the other performance measures. Five of six subjects increased caloric intake following at least one dose, with the largest increases observed in subjects with the lowest baseline intake. Increases in subject reports of dose "Potency" and "Sedated" were also observed following the high dose. Diazepam doses routinely used in clinical settings influenced a variety of behaviors that are observed in the natural ecology, but not performance on accepted laboratory tasks.

Caloric, but not macronutrient, compensation by humans for required-eating occasions with meals and snack varying in fat and carbohydrate.

Six subjects participated in a residential study assessing the effects of covert macronutrient and energy manipulations during three required-eating occasions (breakfast, lunch, and afternoon snack) on total macronutrient and energy intakes. Overall, energy content of the occasions varied between approximately 3000 and approximately 7000 kJ (approximately 700 and approximately 1700 kcal) with the majority of the differential derived from either fat or carbohydrate (CHO). Each condition (high, medium, and low fat; high, medium, and low CHO; and no required eating) was examined for 2 d. Subjects compensated for the energy content of the required occasions such that only under the low-CHO condition (11,297 +/- 3314 kJ) was total daily energy intake lower than that observed in the absence of required occasions (13,297 +/- 1356 kJ). Only total energy intake under the high-fat condition (12,326 +/- 2548 kJ) was significantly different from its matched CHO condition (high-CHO condition: 14,665 +/- 2686 kJ). In contrast to the clear evidence for caloric compensation, there were no differential effects of condition on macronutrient intake, ie, there was no macronutrient compensation.