Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

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)     

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

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

Cocaine self-administration increased by compounding discriminative stimuli

Presenting independently established discriminative stimuli in compound can substantially increase response rates under food and shock-avoidance schedules. To determine whether this effect extends to drug self-administration, rats were trained to press a lever to receive cocaine intravenously. A tone and a light were independently established as discriminative stimuli for cocaine self-administration, then presented in combination in a stimulus-compounding test. Compared to tone and light alone, the tone-plus-light compound stimulus increased responding approximately three-fold when cocaine was withheld during testing, and it increased drug intake approximately two-fold when cocaine was made available during testing. Compounding did not increase responding after training in a truly random control condition where tone and light were presented uncorrelated with the availability of cocaine. The results obtained with this animal model of drug abuse define conditions under which combinations of environmental stimuli might substantially increase human drug use.     

Regulation of intravenously self-administered nicotine in rats.

Ten male Wistar rats had access to 9 doses of nicotine (0.01–0.10 mg/kg iv) during daily 5-hr sessions. Once responding for nicotine stabilized, nicotine infusions were replaced with either cocaine infusions (0.0–2.4 mg/kg) or saline infusions. Saline substitution results indicate that nicotine functioned as a reinforcer. Regulation of nicotine intake was compared with that of cocaine by obtaining the correlation between mean interdose interval and preceding dose size. Results reveal that although this correlation was significant for both nicotine and cocaine self-administration, nicotine self-administration was less precisely regulated than cocaine self-administration. This procedure suggests that there are differences in regulation among self-administered drugs and that it may serve as a useful baseline for studying differences in vulnerability to drug abuse and potential treatment strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys.

The study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cloning of a thermostable ascorbate oxidase gene from Acremonium sp. HI-25 and modification of the azide sensitivity of the enzyme by site-directed mutagenesis

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.     

Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys

Dopaminergic agonists can decrease cocaine self-administration at doses that do not decrease food-maintained responding, a pre-clinical effect indicative of a potential treatment for human cocaine abuse. To assess whether similar effects could be obtained with medications currently used to treat substance abuse, phentermine and fenfluramine were given alone and in combination to rhesus monkeys responding under schedules of food and cocaine delivery. Phentermine decreased cocaine-maintained responding with no effect on food-maintained responding. Fenfluramine also selectively decreased cocaine-maintained responding, but only at the highest dose. Combining a lower dose of fenfluramine with phentermine selectively decreased cocaine-maintained responding, but not more than with phentermine alone. These results suggest that phentermine, as well as its combination with fenfluramine, may be useful in the treatment of cocaine abuse.     

Self-administration of cocaine, alfentanil, and nalbuphine under progressive-ratio schedules: Consumer demand and labor supply analyses of relative reinforcing effectiveness.

Progressive-ratio (PR) schedules of intravenous (IV) drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of the high-efficacy opioid alfentanil, the low-efficacy opioid nalbuphine, and cocaine using a PR schedule of IV drug injection in rhesus monkeys in which the response requirement increased during the experimental session and the initial response requirement (IRR) was varied. Analyses based on either consumer demand or labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of cocaine and alfentanil was greater than that of nalbuphine. These results suggest that PR schedules with varying IRRs can provide meaningful estimates of the relative reinforcing effectiveness of abused drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral pharmacological similarities between methylphenidate and cocaine in cocaine abusers.

Six human participants with recent histories of cocaine use were trained to discriminate 200 mg oral cocaine hydrochloride. A range of doses of oral cocaine (50–300 mg), methylphenidate (15–90 mg), triazolam (0.125–0.75 mg), and placebo were then tested to determine whether they shared discriminative–stimulus and participant-rated effects with 200 mg cocaine. Cocaine and methylphenidate dose-dependently increased cocaine-appropriate responding, produced prototypical stimulant-like participant-rated drug effects (e.g., increased participant ratings of Drug Liking), and increased heart rate and blood pressure. Triazolam produced low levels of cocaine-appropriate responding and impaired performance. Thus, consistent with previous studies, humans can reliably discriminate oral cocaine. Consistent with in vivo behavioral neuropharmacological data, the discriminative–stimulus, participant-rated, and physiological effects of oral cocaine and methylphenidate were similar. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine-like discriminative stimulus effects of bupropion in rats.

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

Nonhuman primate neuroimaging and cocaine medication development.

Given the important role of the dopamine transporter (DAT) in the addictive properties of cocaine, the development and use of compounds that target the DAT represents a reasonable approach for the pharmacological treatment of cocaine abuse. The present report describes a series of studies conducted in nonhuman primates that evaluated the effectiveness of DAT inhibitors in reducing cocaine self-administration. In addition, drug substitution studies evaluated the abuse liability of the DAT inhibitors. Positron emission tomography neuroimaging studies quantified DAT occupancy at behaviorally relevant doses, characterized the time-course of drug uptake in brain, and documented drug-induced changes in cerebral blood flow as a model of brain activation. Selective DAT inhibitors were effective in reducing cocaine use but high (>70%) levels of DAT occupancy were associated with significant reductions in cocaine self-administration. The selective DAT inhibitors were reliably self-administered but rates of responding were lower than those maintained by cocaine even at higher levels of DAT occupancy. A profile of slow rate of drug uptake in brain accompanied by a gradual increase in extracellular dopamine may account for the more limited reinforcing effectiveness of the DAT inhibitors. Selective serotonin transporter (SERT) inhibitors were also effective in reducing cocaine use and blocked cocaine-induced brain activation and increases in extracellular dopamine. Coadministration of SERT inhibitors with a selective DAT inhibitor was more effective than the DAT inhibitor administered alone, even at comparable levels of DAT occupancy. The results indicate that combined inhibition of DAT and SERT may be a viable approach to treat cocaine addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.     

Synergistic elevations in nucleus accumbens extracellular dopamine concentrations during self-administration of cocaine/heroin combinations (Speedball) in rats

The abuse of cocaine/opiate combinations (speedball) represents a growing trend in illicit drug use. Delineation of neurobiological substrates mediating the reinforcing effects of the combination may increase our knowledge of reinforcement mechanisms and provide useful new information for the development of pharmacotherapies. Several studies suggest dopaminergic innervations of the nucleus accumbens (NAc) have a central role in the brain processes underlying drug reinforcement. The present study was undertaken to determine the relationship between the self-administration of cocaine/heroin combinations and NAc extracellular dopamine concentrations ([DA]e) using in vivo microdialysis and microbore high-pressure liquid chromatography. Rats were assigned randomly to one of three groups to self-administer i.v. cocaine (125, 250, and 500 micrograms/infusion; n = 5), heroin (4.5, 9, and 18 micrograms/infusion; n = 5), or cocaine/heroin combinations (125/4.5; 250/9, and 500/18 micrograms/infusion; n = 4) under a fixed ratio (FR) 10: 20-s time-out schedule of reinforcement/multicomponent dosing session. After stable rates of responding were engendered and maintained, microdialysis samples were collected in 10-min intervals during the self-administration session. Self-administration of cocaine/heroin combinations produced synergisitic elevations in NAc [DA]e (1000% baseline) compared with cocaine (400% baseline) and heroin (not significantly different from baseline levels). Neither the number of infusions nor the interinfusion intervals was significantly different between the groups across the self-administration session. Moreover, cocaine concentrations were not significantly different between the cocaine and cocaine/heroin groups. These results demonstrate that heroin interacts with cocaine to produce synergistic elevations in [DA]e, providing a neurochemical basis for understanding the abuse liability of cocaine/opiate combinations.     

The influence of caffeine on nicotine's discriminative stimulus, subjective, and reinforcing effects.

Caffeine may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining the association of coffee intake with smoking status. In this study, smokers were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0). Then, generalization of nicotine discrimination was tested, using both 2- and 3-choice ("novel" option) procedures, across a range of doses (0-20 μg/kg) following pretreatment with 0, 2.5, and 5.0 mg/kg caffeine p.o. Nicotine reinforcement was assessed after the end of generalization testing using a choice procedure. Caffeine pretreatment did not alter nicotine discrimination and self-administration. Caffeine and nicotine influenced some subjective and cardiovascular responses, but there were no interaction effects except for diastolic blood pressure. These results do not support the notion that caffeine acutely alters nicotine's discriminative stimulus, subjective, or reinforcing effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Locomotion and self-administration induced by cocaine in 129/OlaHsd mice lacking galanin.

Previous studies have demonstrated that the galanin system modulates responses to drugs of abuse such as morphine. The current study examined whether genetic deletion of galanin could affect the locomotor and reinforcing effects of cocaine in mice. We analyzed spontaneous motor activity and cocaine-induced hyperactivity in wild-type (GAL-WT) and knockout mice lacking galanin (GAL-KO) maintained on the 129/OlaHsd background. Our results indicate that cocaine enhanced locomotion (defined as moving more than 5 cm) dose-dependently in GAL-WT and GAL-KO mice. However, general activity (total beam breaks) was increased by cocaine only in GAL-WT mice. An additional experiment indicated that galnon, a nonselective galanin receptor agonist, did not affect cocaine-induced hyperactivity. In a second set of experiments, mice of both genotypes were trained to self-administer cocaine under a fixed ratio schedule, tested with various doses of cocaine and under different schedules of reinforcement. This set of experiments showed that cocaine self-administration did not differ markedly between genotypes. However, while GAL-WT mice acquired cocaine self-administration, a median split analysis showed that mice could be divided into large and small drug takers, whereas all GAL-KO mice behaved as small drug takers. Our results indicate that wild-type and galanin knockout mice on a congenic 129/OlaHsd background are responsive to the locomotor effects of cocaine and can acquire intravenous cocaine self-administration. However, the phenotype observed in GAL-KO mice does not support a major role for galanin in cocaine-induced hyperlocomotion and self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Concurrent use of cocaine and alcohol is more potent and potentially more toxic than use of either alone--a multiple-dose study

BACKGROUND: Simultaneous abuse of cocaine and alcohol is widespread and increasingly detected in patients seeking emergent care. This double-blind, randomized, within-subjects study used a paradigm more closely approximating practices of drug abusers to better understand the pathogenesis of cocaine-alcohol abuse. METHODS: Subjects meeting DSM-IV criteria for cocaine dependence and alcohol abuse participated in three drug administration sessions: four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg) administered following the initial cocaine dose and a second dose (120 mg/kg) at 60 min calculated to maintain plasma alcohol concentration at approximately 100 mg/dL during cocaine administration; four doses of cocaine/placebo alcohol; four doses of cocaine placebo/alcohol. Pharmacokinetic, physiological, and behavioral effects were followed over 8 hours. RESULTS: Cocaine-alcohol produced greater euphoria and increased perception of well-being relative to cocaine. Heart rate significantly increased following cocaine-alcohol administration relative to either drug alone. Cocaine concentrations were greater following cocaine-alcohol administration. Cocaethylene had a longer halflife with increasing concentrations relative to cocaine at later time points. CONCLUSIONS: Enhanced psychological effects during cocaine-alcohol abuse may encourage ingestion of larger amounts of these substances over time placing users at heightened risk for greater toxicity than with either drug alone.     

Polydrug self-administration in rats: cocaine-heroin is more rewarding than cocaine-alone

The i.v. self-administration by rats of a polydrug combination of cocaine and heroin was explored. The rewarding efficacies of a range of cocaine doses (0.25-8 mg/kg/injection) alone or in combination with heroin (12.5 or 25 microg/kg/injection) were compared using a progressive ratio (PR) schedule of reinforcement. Breaking points (BP) for one group of rats were determined at each dose of cocaine alone and for two other groups at each of the same cocaine doses plus one of the heroin doses, respectively. The cocaine-heroin combination was associated with higher BPs than cocaine alone at all doses of cocaine. These data demonstrate that cocaine-heroin combinations (speedballs) are more rewarding than the identical doses of cocaine alone. Some possible mechanisms by which heroin increases cocaine reward are discussed.     

Smoked heroin and cocaine based (speedball) combinations in Rhesus monkeys.

The purpose of this investigation was to compare the self-administration of heroin and cocaine base, alone and in combination, in rhesus monkeys (Macaca mulatta) self-administering a combination of heroin (0.1 mg/kg/delivery) and cocaine base (1.0 mg/kg/delivery) via the smoking route. Smoke deliveries were contingent on completion of a chained fixed ratio (FR; lever press), FR 5 (inhalation) schedule. The lever press FR values (64, 128, 256, 512, and 1,024) represented increasing drug price. Demand functions (Consumption x Price) were obtained for the heroin and cocaine combination and compared with previously determined demand functions for smoked heroin and cocaine alone. As the FR increased and the number of responses emitted increased, the number of drug deliveries decreased. The demand functions were not different for heroin versus cocaine alone or for cocaine alone versus the cocaine-heroin combination. However, the demand for heroin alone was significantly less than the demand for the cocaine-heroin combination, suggesting that smoked cocaine base enhances the behavioral effects of smoked heroin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)