Modulation of drug reinforcement by behavioral requirements following drug ingestion

Eight volunteers with histories of drug abuse participated in two experiments examining the modulation of drug choice by behavioral requirements following drug ingestion. Each morning subjects ingested colorcoded capsules containing triazolam (0.25 mg),d-amphetamine (15 mg), or placebo and then engaged in a relaxation or a computer vigilance activity. Experiment 1 involved two phases (i.e. a triazolam and ad-amphetamine phase), presented in counterbalanced order. Within each phase, subjects were first exposed to each of two compounds (placebo and either triazolam ord-amphetamine) once with each activity. Then every other day for 20 days subjects chose which compound they ingested with the vigilance and relaxation activities, with the restriction that they could not choose the same compound with both activities. Seven of eight subjects reliably chosed-amphetamine with the vigilance activity; all subjects always chose triazolam with the relaxation activity. In experiment 2 (5 days' duration), after re-exposure to the color-coded compounds used in experiment 1, subjects chose which compound (placebo,d-amphetamine or triazolam) they ingested with the vigilance activity, and on another occasion (in counterbalanced order), which they ingested with relaxation activity. Seven of eight subjects chosed-amphetamine with the vigilance activity; all subjects chose triazolam with the relaxation activity. The relaxation and vigilance activities modulated triazolam andd-amphetamine reinforcement, thereby demonstrating a new class of environmental variable that can influence drug self-administration.Portions of these data were presented at the annual meeting of the Association for Behavior Analysis, Atlanta, June, 1991     

Effects of pergolide on intravenous cocaine self-administration in men and women

Clinical evidence suggests that pergolide, a D₁/D₂ dopamine receptor agonist, may be useful in maintaining cocaine abstinence. We investigated pergolide’s effects in a laboratory model of IV cocaine self-administration by humans. Twelve inpatient volunteers (7M, 5F), who reported spending an average of $170/ week on cocaine, received pergolide (0.05 mg BID) for 8 days and placebo for 8 days, with drug order balanced across subjects. Self-administration sessions occurred on the last 4 days of maintenance on each medication. A modified seven-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine versus $5) was utilized, with sessions consisting of: (a) two sample trials, where participants responded to receive the dose and tokens available that day, and (b) five choice trials, where participants chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide 1) decreased cocaine-induced increases in ratings of “High,”“Stimulated,” cocaine “Potency,” estimates of street value, and heart rate, 2) increased ratings of “I want cocaine,” and 3) had no effect on cocaine self-administration. The increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose, but given the attenuation of cocaine’s subjective and cardiovascular effects, an investigation of a wider range of pergolide doses on cocaine self-administration and subjective effects is warranted. Received: 29 April 1997/Final version: 14 October 1997     

An experimental paradigm for studying the discriminative stimulus properties of drugs in humans

An experimental paradigm for studying the discriminative stimulus effects of drugs in human subjects is presented. The paradigm was tested by training subjects to discriminate 10 mg d-amphetamine from placebo. Subjects who successfully learned the discrimination were then tested with two lower doses of d-amphetamine and with 10 mg diazepam. The discriminative stimulus properties of d-amphetamine were dose-dependent, and in two of five subjects the d-amphetamine stimulus generalized to diazepam. The simplicity and versatility of the paradigm give it the potential for use in a wide variety of experimental and clinical situations.     

Effect of d-amphetamine,secobarbital, and marijuana on choice behavior: social versus nonsocial options

The effects of oral d-amphetamine and secobarbital and smoked marijuana on human social conversation and preference for socializing were studied in three separate experiments. During experimental sessions, active drug or placebo was administered using an acute or divided dosing procedure. Subjects who received drug then engaged in a discrete-trial choice procedure in which they made a series of mutually exclusive choices between a social (talking with their nondrugged partner) and nonsocial (sitting quietly alone) option. Lapel microphones and voice operated relays measured seconds of speech. Subjects engaged in greater amounts of conversation and chose the social option more frequently following acute dosing of d-amphetamine and secobarbital compared with placebo. Acute administration of marijuana did not significantly affect social speech or choice behavior, producing slight decreases in both measures. Acute dosing of all drugs significantly increased subjective drug effect or drug high; however, only secobarbital affected the circular lights task, producing significant performance decrements. The shifts in preference toward the social option observed with d-amphetamine and secobarbital suggest that these drugs increased the reinforcing effects of socializing relative to sitting alone. This may be one mechanism by which psychoactive drugs facilitate social conversation.     

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration ofd-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2:d-amphetamine, 0.25 µg/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not primed with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration ofd-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a fulld-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses ofd-amphetamine. In experiment 2c, the infusate (1 µgd-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbicstriatal systems, with particular reference to the mesoaccumbens dopamine projection.     

Evaluation of the psychotropic effect of Etifoxine through pursuit rotor performance and GSR

Six volunteer normal subjects, aged 18–25 years, were selected from a university student population to compare the psychotropic effects of Etifoxine, d-amphetamine and placebo. All of them received Etifoxine 300 mg, d-amphetamine 5 mg and placebo in a double-blind randomly crossover design involving a single dose weekly.The criteria studied were the GSR and performance on the pursuit-rotor. The subjects were tested before (TO), 2 (T2) and 6 (T6) hrs after drug administration. At T2, both the GSR and pursuit-rotor performance obtained with each drug differed significantly from placebo, but not between drugs. The effects of Etifoxine were similar to those of d-amphetamine in reducing the GSR and improving pursuitrotor performance.     

A comparative assay of nefopam,morphine and d-amphetamine

Nefopam is a non-opioid analgesic reported to have some stimulant properties. The subjective, behavioral and physiological effects of nefopam, morphine and d-amphetamine were compared in seven non-dependent substance abusers to assess the abuse potential of nefopam. Morphine and d-amphetamine had significant effects on a number of measures generally consistent with the effects of drugs of the opioid and psychomotor stimulant drug classes. Subjects correctly discriminated between morphine and d-amphetamine. Nefopam was most frequently identified by subjects as being amphetamine-like, though several measures indicated that nefopam produced some sedation. Little or no liking of the effects of nefopam was reported by subjects. Overall, nefopam was one fifth as potent as morphine and one quarter as potent as d-amphetamine in producing subjective and physiological effects. The results indicate that nefopam is neither entirely morphine-like nor d-amphetamine-like. In our opinion, nefopam has a lesser potential to be abused than morphine or d-amphetamine. Offprint requests to: Librarian, NIDA Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, USA     

Sleep deprivation deficits and their reversal by d-and l-amphetamine

Vigilance performance, waking EEG patterns and mood were studied before and after one night of sleep deprivation in normal males. The effects of d-amphetamine 10 mg, l-amphetamine 10 mg and placebo on these measures were compared. Changes were found in all three measures after one night of sleep-deprivation. d-Amphetamine was more powerful than l-amphetamine in reversing sleep deprivation effects on vigilance and on waking EEG.     

Self-administration of CNS stimulants by dog

Drug-naive dogs were trained to respond for intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.     

Effect of d-amphetamine on prepulse inhibition of the startle reflex in humans

Rationale: Prepulse inhibition of the startle reflex (PPI) is attenuated in animals after administration of d-amphetamine and other drugs that stimulate mesolimbic dopamine activity. Objective: The aim of the present study was to evaluate the effects of d-amphetamine (20 mg) on a variety of psychophysiological and subjective measures, including PPI, in humans. Method: Thirty-six participants (18 women) participated in a double-blind, placebo controlled, repeated measures study. In one session, participants received d-amphetamine (20 mg) orally, and in the other session, participants received an identical appearing placebo. Participants were assessed at 60, 90, and 120 min after ingestion with a 5-min block of startle trials (six control trials and six prepulse trials) followed by subjective measures of stimulation and mood. Results: d-Amphetamine increased subjective measures of stimulation and euphoria, attenuated PPI, and increased heart rate, relative to placebo treatment. Conclusions: The effect of d-amphetamine on the subjective measures was substantial and consistent over time, while the effect on PPI was only observed at 90 min after ingestion, and the effect on heart rate was limited to 90 and 120 min after ingestion. Received: 22 June 1998/Final version: 23 November 1998     

Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans

Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week inpatient study comparing the effects of intranasal (IN) (placebo, 12.5, 25, 50, 100 mg) and intravenous (IV) (placebo, 6.25, 12.5, 25, 50 mg) heroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon they had the opportunity to self-administer all or part of the morning heroin dose or money amount. Participants responded under a modified progressive-ratio schedule (PR 50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800) during a ten-trial self-administration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/10th of the money amount. The total amount of heroin and/or money chosen during the self-administration task was given at the end of the task. Thus, participants received drug and/or money twice each day: once during the morning sample session and once during the afternoon self-administration session. Participants received IV solution and IN powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related increases in break point values by both routes of administration. Although IV heroin was approximately four-fold more potent than IN heroin, the maximal break point values for both routes were not significantly different. A similar difference in potency between the IV and IN routes was found for several ratings of subjective effects (e.g., “I feel a good drug effect,”“I feel high”), but maximal subjective ratings were lower for IN compared to IV heroin. These results suggest that the reinforcing efficacy of heroin is similar by the two routes of administration, but that IN heroin is less potent than IV heroin. The results also underscore the importance of evaluating drug self-administration in the evaluation of the abuse liability of drugs. Received: 20 May 1997/Final version: 13 November 1998     

Clozapine and prazosin slow the rhythm of head movements during focused stereotypy induced by <Emphasis Type="Italic">d</Emphasis>-amphetamine in rats

Rationale Clozapine is an efficacious, symptom-ameliorating, atypical antipsychotic drug with few extrapyramidal side effects. Clozapine has been reported either not to affect or to increase d-amphetamine-induced stereotypy, a behavior that is blocked by typical antipsychotic drugs. Objectives This work used a high-resolution measurement system to reassess clozapine’s effects on d-amphetamine-induced focused stereotypy (FS) in rats. Materials and methods A force-plate actometer permitted the quantitation of the rhythm and vigor of movements during FS. Eight rats received a sensitizing series of doses of 5.0 mg/kg d-amphetamine sulfate, and this dosing regimen induced head movements with a rhythm near 10 Hz. Thirty minutes after d-amphetamine treatment, rats received acute clozapine (2.5–10.0 mg/kg), followed by eight, daily clozapine injections (5.0 mg/kg) given with d-amphetamine on days 2, 5, and 8. Effects of acute doses of the α₁-noradrenergic antagonist prazosin (0.5–2.0 mg/kg) on the d-amphetamine response were also examined. Results Clozapine dose-dependently slowed the near 10-Hz rhythm and reduced the vigor of the d-amphetamine-induced FS. Clozapine significantly lengthened the duration of the FS phase, but the rhythm remained slowed. No evidence for tolerance to clozapine’s rhythm-slowing effects was seen in the subchronic phase. Prazosin dose-dependently reduced the near 10-Hz rhythm induced by d-amphetamine, but prazosin did not lengthen the FS phase. Conclusions The results show that clozapine diminished the rhythm and vigor of d-amphetamine-induced stereotyped head movements but, at the same time, lengthened the duration of the expression of the stereotypy. α₁ antagonism is a likely contributor to the rhythm-modulating effects of clozapine. Supported by MH43429 and HD02528     

Effects of d-amphetamine on human aggressive behavior

Male research subjects were administered placebo and three doses of d-amphetamine (5, 10 and 20 mg/70 kg) in a laboratory situation which provided both aggressive and non-aggressive response options. The non-aggressive response was button pressing maintained by presentation of points exchangeable for money at the end of the session. The aggressive response was button pressing on a separate manipulanda which ostensibly subtracted points from a fictitious partner. Aggressive responding was elicited by subtracting points from the research subjects which was attributed to the fictitious partner. d-Amphetamine increased both aggressive and non-aggressive responding, particularly at 5 and 10 mg/70 kg. At the highest dose (20 mg/70 kg), aggressive responding decreased to levels similar to those observed during placebo sessions, while monetary reinforced responding remained elevated.     

Dopamine D1 and D2 mediation of the discriminative stimulus properties ofd-amphetamine and cocaine

Evidence suggests that stimulants such asd-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D₁ and D₂) exist, we investigated the role of both of these receptor subtypes in mediating the internal state produced by these stimulants. Two groups of rats (N=8/group) were trained to discriminate intraperitoneal (IP) injections of eitherd-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D₁ and D₂ agonists and antagonists. The D₂ agonist quinpirole (0.0313–0.125 mg/kg) mimicked both stimulant cues while the D₁ agoinst SKF 38393 (5–20 mg/kg) substituted partially for cocaine but notd-amphetamine. Combination tests with DA antagonists indicated that both the D₁ antagonist SCH 23390 (0.0063–0.25 mg/kg) and the D₂ antagonist haloperidol (0.125–0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) ford-amphetamine was blocked by both DA antagonists. The ability of both D₁ and D₂ antagonists to attenuate the stimulus effects ofd-amphetamine and cocaine raises the possibility that a synergistic (enabling) interaction between D₁ and D₂ receptors may modulate stimulant cues.     

Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule

 Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug. Received: 16 July 1997 / Final version: 22 October 1997     

Effects of amphetamine on local cerebral metabolism in normal and schizophrenic subjects as determined by positron emission tomography

The effects of d-amphetamine (0.5 mg/kg PO) on regional cerebral glucose utilization were measured with Positron Emission Tomography (PET). Subjects included ten chronic schizophrenics and six controls who received amphetamine, and six chronic schizophrenics and nine controls who received placebo or no treatment. Amphetamine decreased glucose metabolism in all regions studied (frontal, temporal, and striatal) in normal and schizophrenic subjects. The metabolic effects of amphetamine were correlated with plasma level of the drug. Cortical atrophy was associated with a blunted metabolic response.     

Abolition of latent inhibition by a single 5 mg dose ofd-amphetamine in man

The performance of healthy volunteer subjects on an auditory latent inhibition (LI) paradigm was assessed following administration of a single oral dose ofd-amphetamine or placebo. It was predicted that a low (5 mg), but not a high (10 mg), dose ofd-amphetamine would disrupt LI. The prediction was supported with left ear presentation of the preexposed stimulus only. When the preexposed stimulus was presented to the right ear the predicted pattern of findings was not obtained. It is concluded that the dopaminergic system is involved in the mediation of LI in man and it is speculated that the interaction between amphetamine dose and ear of presentation of the preexposed stimulus may reflect normally occurring dopaminergic hemisphere asymmetry.     

Facilitation of sexual behavior in male rats following d-amphetamine-induced behavioral sensitization

The present study investigated the effect of sensitization, induced by repeated injections of d-amphetamine, on sexual behavior in the naive male rat tested in a drug-free state. Injections of either d-amphetamine (1.5 mg/kg, IP) or saline were given every other day for a total of ten injections, and this regimen induced behavioral sensitization of locomotor activity in drug-treated rats. After a 3-week post-drug period, d-amphetamine-treated rats exhibited facilitated sexual behavior, as indicated by shorter latencies to mount and intromit, and a greater percentage of rats copulating. These rats also exhibited a general increase in the amount of copulation. Furthermore, sensitized rats displayed a facilitated acquisition of sexual behavior (i.e. mount and intromission latency <300 s for 3 consecutive days). After repeated sexual experience, rats pre-treated with d-amphetamine also showed an augmented increase in level changes made in anticipation of the presentation of a receptive female. Finally, enhanced sexual behavior was independent of the environment in which repeated administration of d-amphetamine occurred, indicating that facilitation was not a consequence of conditioned associations between drug and test environment. These results demonstrate that behavioral sensitization due to repeated psychostimulant administration can “cross-sensitize” to a natural motivated behavior, such as sex. Furthermore, the subsequent facilitation of anticipatory sexual behavior (i.e. level changes) after repeated experience in rats previously treated with d-amphetamine suggests that behavioral sensitization can influence incentive learning. Received: 10 June 1998/Final version: 7 August 1998     

Caffeine reinforcement: the role of withdrawal

This study examined caffeine’s acute and withdrawal effects in moderate caffeine consumers (mean = 379 mg/day caffeine) to compare the relative contributions each might have to caffeine reinforcement. Subjects were caffeine restricted on the night before each of three sessions, which generally occurred at weekly intervals; these restrictions lasted until the session was completed approximately 19 h later. During the first two sessions, subjects received either placebo or caffeine (each subject’s average daily intake). These two conditions occurred using a double-blind, quasi-random, crossover design. At the end of each session subjects completed the POMS, a caffeine withdrawal questionnaire, and a Multiple-Choice Form on which subjects made a series of discrete choices between receiving the drug again or receiving varying amounts of money. This form also included negative money amounts to assess how much subjects would forfeit to avoid placebo (e.g., withdrawal symptoms after placebo). During the third session, one of the previous choices was randomly selected and the consequence of that choice was implemented. Placebo increased self-reported feelings of “worn out,”“headache,” and “flu-like feelings,” and decreased “alert,”“upset stomach,”“helpful,” and “well-being” relative to caffeine. On the Multiple-Choice Forms, subjects chose to receive caffeine rather than an average of $0.38 and to forfeit $2.51 to avoid receiving placebo again. “Headache” was significantly correlated with amount of money forfeited to avoid placebo. These results suggest that, under these conditions, choice of caffeine is more potently controlled by avoiding withdrawal than it is by the positive effects of caffeine. Received: 21 December 1995 / Final version: 26 October 1996     

Non-specific effect of naltrexone on ethanol consumption in social drinkers

Rationale: Clinical studies have shown that the opioid antagonist naltrexone is effective in the treatment of alcoholism. However, the mechanism by which it produces this effect is not understood. Objective: This study was designed to investigate the effect of acute naltrexone on consumption of ethanol in healthy, non-problem social drinkers. Methods: Subjects (n=24) participated in an eight-session, within-subject, placebo-controlled choice procedure which measured ethanol preference and consumption. The procedure consisted of two blocks of four sessions in which subjects received either naltrexone (50 mg oral) or placebo 1 h before consuming an ethanol or placebo beverage. On the first two sessions of each block, subjects received a color-coded beverage containing ethanol (0.75 g/kg) or placebo, in five equal portions at 15-min intervals. On the next two sessions of each block, subjects chose which beverage they preferred (i.e., placebo or ethanol) and how much they wished to take, in unit doses (placebo or ethanol 0.15 g/kg/dose). The primary behavioral measures were (1) the number of times subjects chose ethanol over placebo, and (2) the number of doses they consumed. Subjects rated their mood states and subjective drug effects at regular intervals during each session. Results: Naltrexone did not alter the frequency of ethanol (versus placebo) choice. Although naltrexone did decrease the total number of ethanol doses subjects took (mean 2.7 doses after naltrexone; 3.4 doses after placebo), it also decreased the number of placebo ”doses” subjects took on sessions when they chose the placebo beverage (mean 1.6 placebo doses after naltrexone; 2.8 doses after placebo). Ethanol produced its prototypic subjective effects (e.g., increased ratings of ”feel drug”, ”like drug” and ”high”), and these effects were not altered by naltrexone. Naltrexone produced mild sedative-like effects, and several subjects reported adverse effects such as nausea. Conclusions: These findings show that naltrexone reduces ethanol consumption in healthy volunteers, as it does in alcoholics. However, this reduction was not specific to alcohol; subjects also consumed less of a non-alcoholic, placebo beverage. These findings suggest that naltrexone may reduce alcohol consumption by a non-specific mechanism. Received: 17 September 1998 / Final version: 14 April 1999