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Director's Report to the National Advisory Council on Drug Abuse
September, 1995

Research Findings

Intramural Research

Molecular Pharmacology Section, Neuroscience Branch

A desirable feature of cocaine-like agonist-substitute medications is that they have a long duration of action, reducing cost and simplifying dosing schedule. In collaboration with the Brookhaven National Lab PET scanning group, Dr. Kuhar has shown that a potential cocaine analog medication termed RTI-55 has such a long duration of action. Using PET scanning with a babboon, it was possible to show that this compound occupies dopamine transporters (a cocaine receptor) with a half life of clearance of 2-3 days. This supports findings with rodents suggesting that a large number of medication candidates identified by Dr. Kuhar and collaborators are long lasting. Interest in these compounds continue and many of them are being considered for industrial development. Key collaborators in this work include Dr. Ivy Carroll and Dr. Nora Volkow.

Neuroimaging and Drug Action Section, Neuroscience Branch

This paper describes findings from positron emission tomographic studies on effects of exposure to cocaine-related stimuli on brain metabolism. Exposure to the stimuli (videotape related to cocaine and paraphernalia) and anticipation of cocaine self-administration produce a widespread activation of glucose metabolism in the cerebral cortex, most prominently in occipital and frontal regions. Metabolism in subcortical regions is not affected. The findings support the view that environmental cues can trigger drug craving and measurable changes in brain activity. The distribution of the cerebral effects suggests that non-dopaminergic systems may be important therapeutic targets for antagonizing drug craving and relapse. ED London, S Grant, and D Newlin (1995): Identifying the Substrates in Brain that Underlie Cocaine Craving. NIH Catalyst: Jun/Jul.

Studies which measure regional cerebral glucose metabolism in rats using the 2-deoxy-D-[114C]glucose autoradiographic method and those in human volunteers using PET and 2-deoxy-[218F]fluoro-D-glucose are reviewed. Acute nicotine increases cerebral glucose metabolism in brain regions containing high densities of nicotinic acetylcholine receptors in rats; the drug has similar effects after chronic administration. In contrast, acute nicotine administration to human volunteers produces a generalized reduction in cerebral metabolic activity. ED London (1995): Mapping the Cerebral Metabolic Responses to Nicotine. In: Brain Imaging of Nicotine and Tobacco Smoking, pp 153-166, EF Domino, ed., NPP Books Inc., Ann Arbor, MI.

To assess the neuroprotective effects of sigma (s) receptor ligands in transient focal ischemia, 4phenyl-1-(4-phenylbutyl)piperidine (PPBP), a potent s receptor ligand, was evaluated in the cat. Intravenous administration of PPBP beginning at 75 min after the infusion of a 90 min focal ischemia insult and continuing for 240 min of reperfusion substantially reduced the volume of acute brain injury in the cerebral hemisphere and caudate nucleus. Recovery of somatosensory evoked potentials was greater in cats treated with PPBP as compared to controls. It is concluded that s receptors have an important role in the mechanism of acute ischemic injury within the brain, and the protective effect of PPBP suggests s receptors may contribute to the progression of injury in ischemic border regions. H Takahahsi, JR Kirsch, K Hashimoto, ED London, RC Koehler, and RJ Traystman: PPBP[4-Phenyl-l-(4-phenylbutyl) piperidine], A Potent Sigma-Receptor Ligand, Decreases Brain Injury Following Transient Focal Ischemia in Cats. Stroke, in press.

A modulatory role for nitric oxide (NO) in the mediation opioid withdrawal is supported by the ability of four inhibitors of nitric oxide synthase (NOS) to partially attenuate signs of the naloxone precipitated morphine abstinence syndrome. Effects of the NOS inhibitors were similar to clonidine, a drug used clinically to treat opioid withdrawal. Additional evidence has linked NOS with the development of opioid tolerance. Thus, two lines of pharmacologic evidence demonstrate a role for NO in phenomena associated with chronic opiate use and suggest that future studies care warranted to explore the potential clinical application of NOS inhibitors to treat opioid dependence. DB Vaupel, AS Kimes, and ED London: Nitric Oxide Synthase Inhibitors: Preclinical Studies of Potential Use for Treatment of Opiate Addiction. Neuropsychopharmacol., in press.

Molecular Neuropsychiatry Section, Neuroscience Branch

p53-knockout transgenic mice provide a useful toxicity model because p53 has been shown to be involved in the development of apoptosis in a number of cell lines. In order to assess if p53 is involved in the neurotoxicity caused by methamphetamine (METH) on the dopaminergic systems, scientists have evaluated the effects of this drug in male wild-type as well as heterozygous and homozygous p53-knockout mice. The status of dopaminergic terminals was determined after the administration of 3 different doses of METH (2.5, 5.0, and 10mg/kg were given 2 hours apart for a total of 4 injections in one day). In wild-type mice, METH caused dose-dependent decreases in DA uptake sites in both the striatum and nucleus accumbens. The percentage of decrease was greater in the striatum. In p53-knockout mice, the depletion caused by METH was attenuated in a strain-dependent fashion, with the homozygous mice showing the greatest protection. These results provide evidence for a role of p53 in the neurotoxic effects of METH on the dopaminergic system. They also suggest a role for p53 in the development of neurodegenerative disorders such as Parkinson's disease.

Molecular Neurobiology Branch

During the latter part of Fiscal Year 1995 the Branch completed a CRADA with Guilford/Gel Pharmaceuticals and has begun exciting collaborative work with novel approaches to cocaine antagonist development. Investigators have licensed dopamine transporter cDNAs and expressing cells, and mu receptor cDNAs and expressing cells.

The Branch has now identified more than 200 candidate drug-related genes using techniques developed and refined at the NIDA/DIR. They have reported detailed structures of human and mouse dopamine transporter gene loci and identified details of the dopamine transporter and mu receptor distributions in brain identified at light and ultrastructural levels. In addition, investigators have described behavioral effects of morphine and cocaine to be altered by manipulations of single genes in transgenic mouse models.

Psychobiology Section, Behavioral Pharmacology Laboratory

Studies of benztropine analogs continue to provide interesting leads for a better understanding of how actions at the dopamine transporter may or may not be translated into physiological effects that lead to drug abuse. Several benztropine analogs, most notably the 4',4"-dihalogenated compounds, demonstrate high affinity binding (Ki<30 nM) to the dopamine transporter that is selective (>100-fold) over the other monoamine transporters. These compounds block dopamine uptake in vitro but do not produce behavioral effects like those produced by cocaine. For example, the drugs are not effective locomotor stimulants nor do they produce subjective effects like cocaine. A recently synthesized analog within this series is distinctive from the others in that it has cocaine-like behavioral activity. As a result, we now have a lead for the development of structure-activity relations that may reveal the pharmacophore for cocaine-like behavioral effects. Further, studies of the interaction of these drugs with the dopamine transporter will provide models of specific sites on the transporter that are responsible for cocaine-like behavioral effects. Further, radiolabelled ligands are being prepared that may be suitable for imaging the dopamine transporter in mammalian brain using SPECT and PET. These compounds represent an unprecedented class of dopamine uptake inhibitors that may have potential as cocaine-abuse therapeutics.

Cocaine binding curves have two components (high and low affinity) and the inhibition of dopamine uptake can exhibit two components. One of these components, comprising approximately 25% of the total dopamine uptake, exhibits a high sensitivity to cocaine and is inhibited by low concentrations of the drug. The other component is much less sensitive to inhibition. We have recently shown that meperidine, an atypical opioid agonist that shares some structural features with the phenyltropane (WIN) analogs of cocaine, selectively inhibits only the high affinity component of dopamine uptake. This effect is mediated by the dopamine transporter and is not produced by opioid mechanisms. Further, meperidine, in the presence of naltrexone to block its prepotent opioid actions, produces subjective effects like those of cocaine in primates trained to discriminate cocaine from saline. These data suggest that the actions of meperidine that are atypical of opioids are due at least in part to activity at the dopamine transporter. In addition, meperidine appears to interact predominantly with the high-affinity component of the dopamine transporter, and this high-affinity component may be the site of importance for the production of cocaine's behavioral effects.

Recent preclinical findings and anectodal clinical reports have suggested the potential for ibogaine to treat drug dependence, however, its mechanism of action has remained elusive. In conjunction with collaborators in the Laboratory of Neuroscience, NIDDK, NIH, we have demonstrated, a plausible mechanism of action of ibogaine. Electrophysiological, neurochemical, and behavioral data indicate that ibogaine functions as a low affinity blocker of the NMDA-associated ion channel. Current efforts are focused on the discovery of other compounds in this class that do not have the ancillary side-effect profile of ibogaine (tremor, ataxia, and phencyclidine-like effects). Studies of strychnine-insensitive glycine site antagonists have shown that low-efficacy partial agonists, block the development and expression of behavioral and toxicological sequalae of abused drugs and produce subjective effects that are driven by agonist binding to that site.

These effects are distinct from the sedative and psychotomimetic effects produced by other drugs which produce functional blockade of NMDA-associated neurotransmission.

Chemistry and Drug Metabolism Section, Clinical Pharmacology Branch

Despite the current popularity of smoking as a route of drug self-administration, there have been no human studies characterizing the pharmacokinetics and pharmacodynamics of smoked heroin. Researchers administered heroin by the smoking route to human subjects and found that this route of administration produced effects similar to those produced by the intravenous route. The rapid onset of pharmacologic effects together with the early appearance of heroin and metabolites in blood following smoked heroin demonstrated the effectiveness of this route of drug administration. Heroin abuse by this route could increase as the price of illicit heroin decreases and its purity increases.

Researchers have demonstrated that adults exposed to cocaine smoke under naturalistic or artificial conditions absorbed small amounts of cocaine that were insufficient to produce positive urine specimens at standard DHHS cutoffs. However, passive exposure conditions could be produced that would result in absorption of cocaine in amounts exceeding one milligram. This could result in the production of cocaine positive urine specimens and would be especially important if passive exposure of small children was involved.

A dramatic shift has occurred over the last decade in the route of cocaine administration by drug abusers in the United States. The favored route has changed from intranasal and intravenous use to administration of cocaine ("crack") by the smoking route. Researchers have demonstrated that cocaine administration by the smoked route produced substantially higher behavioral responses than an equivalent dose of cocaine administered by the intravenous route. This finding suggests that smoked cocaine ("crack") has a higher abuse liability and greater dependence-producing properties than equivalent doses of cocaine administered by the intravenous or intranasal route.

Assays have been developed to evaluate in vitro binding of drugs to hair. Preliminary studies have shown significant differences in cocaine binding between Caucasoid and Africoid hair, between male and female Africoid hair, and between dark colored and light colored hair. These studies also provided evidence that supported the use of in vitro studies to evaluate the binding of drugs to hair.

Clinical Psychopharmacology Section

1. Novel binding sites for cocaine in mammalian brain.
[125I]RTI-55 is a cocaine analog with high affinity for the DA and 5-HT transporters. Its high specific activity (2200 Ci/mmol) and low nonspecific binding (typically less than 100 dpm) makes it an extremely useful ligand for detecting and characterizing multiple binding sites for biogenic amine transporter ligands. Quantitative binding studies in rat, guinea pig, monkey and human brain have identified two additional [125I]RTI-55 binding sites which are not associated with the classic DA, 5-HT and NE transporters. These sites, termed DATsite2 and SERTsite2 are associated with the DAergic and 5-HTergic nerves, respectively. Each site has a unique anatomical distribution and structure-activity profile. Cocaine, the prototypical addictive DA uptake inhibitor, has Ki values at these sites ranging from 500 to 1000 nM. The functional role of these sites remains to be determined. Efforts to clone DATsite2 and SERTsite2 will soon be underway.

2. Modulation of µ-opiate receptor density by the anti-opioid peptide, NPFF.
A variety of data support the hypothesis that endogenous neuropeptides act as part of a homeostatic mechanism to attenuate the effects of morphine. Previous studies from this laboratory indicated that whereas chronic i.c.v. infusion of NPFF down-regulated, chronic i.c.v. infusion of polyclonal anti-NPFF IgG up-regulated mu opioid receptors. The aim of this study was 1) to determine the effect of chronic i.c.v. infusion of the purified mouse monoclonal anti-NPFF IgG on the mu receptors using whole brain homogenate binding technique and 2) to characterize the anatomical distribution of [125I]DAMGO binding sites in discrete brain nuclei of rats treated chronically with anti-NPFF IgG. The data indicate that chronic i.c.v. infusion of mouse monoclonal anti-NPFF IgG up-regulated mu receptors labeled with [3H]DAMGO to 102%, 128%, and 172% of control at the 0.001, 0.01, and 0.1 µg/µl doses, respectively. At the level of the caudate, a significant increase in the number of [125I]DAMGO binding sites was observed in specific anatomical regions for the anti-NPFF IgG treated animals, while brain regions caudal to the striatum showed no changes from control. These data suggest that the density of mu opioid receptors in rat brain is tonically controlled by NPFF. Viewed collectively with other information, the pharmacological manipulation of µ-opiate receptor density by the anti-opioid system may provide a novel clinical approach in treatment of nociception, opiate addiction, and psychiatric disorders.

3. Attenuation of cocaine-seeking behavior in the rhesus monkey by administration of phentermine, a clinically available DA releasers.
The combination of the dopamine (DA) releaser, phentermine, and the serotonin releaser (5-HT), fenfluramine, have been reported in case series to decrease craving for alcohol and cocaine and to facilitate abstinence in self-referred patients motivated to stop using cocaine and alcohol. The present study reports the effects of these medications alone and together (0.3 - 3.0 mg/kg, i.v. slow infusion) on cocaine-maintained responding in 8-9 kg male rhesus monkeys. Lever-pressing was maintained under multiple FR 30-response schedules of food and intravenous cocaine delivery. Intermediate unit doses of cocaine (10-30 µg/kg/inj) maintained high levels of responding in the drug delivery components, comparable to those maintained by food presentation. Cumulative doses of fenfluramine produced slight, dose-related decreases in both behaviors that were nonselective. Cumulative doses of phentermine produced selective decreases in cocaine-maintained responding. When assessed as a single bolus dose (i.v., given over 15 min, 15 min before the testing session), the effect of both agents in combination (1 mg/kg fenfluramine + 0.3 to 3.0 mg/kg phentermine) was similar to that of phentermine alone. The effect of phentermine determined as a single dose confirmed the selective decreases on cocaine self-administration produced by cumulative dosing with phentermine, and these effects could be sustained with repeated daily administration. These results demonstrate that clinically available DA releasers with low abuse liability such as phentermine can suppress cocaine self-administration in an animal model of cocaine-seeking behavior. These findings are consistent with case series (J. Subst. Abuse Treatment 11:273-275, 1994) reporting therapeutic effects of phentermine combined with fenfluramine in the treatment of cocaine addiction. The apparent inactivity of fenfluramine in the self-administration paradigm may reflect the fact that this paradigm does not mimic some aspects of the compulsive drug use often seen in humans. Viewed collectively, these results provide a preclinical rationale for clinical trials of non-addicting DA releasers as substitution-type medications for cocaine addiction.

4. GBR12909 Attenuates Cocaine-Induced Activation Of Mesolimbic Dopamine Neurons In The Rat.
Previous studies have shown that the dopamine (DA) reuptake inhibitor GBR12909 (1-{2-[bis(4fluorophenyl)-[methoxy]ethyl}-4-(3-phenylpropyl)piperazine) antagonizes the increase in extracellular DA evoked by local perfusion of cocaine into the striatum. In the present work, in vivo microdialysis methods were used to examine the effects of i.v. cocaine, GBR12909, and combinations of the 2 drugs on DA overflow in the nucleus accumbens of awake rats. Both cocaine and GBR12909 (0.3-3.0 mg/kg) caused dose-related elevations in extracellular DA when given alone. However, the temporal profile of DA overflow was different with each drug: cocaine caused a rapid and short-lived increase in DA whereas GBR12909 caused a slow and sustained elevation of transmitter. In drug combination studies, the rise in extracellular DA after a modest dose of cocaine (1.0 mg/kg) was significantly reduced from 250% to 175% of baseline by pretreatment with a subthreshold dose of GBR12909 (0.3 mg/kg). A high dose of cocaine (3.0 mg/kg) increased dialysate DA by 600%; this massive surge in DA was decreased to 450% and 325% of baseline by pretreatment with 0.3 and 1.0 mg/kg GBR12909, respectively. The neurochemical effect of the combination of GBR12909 plus cocaine was clearly not additive. GBR12909 also dramatically blocked the DA-releasing action of amphetamine (1.0 mg/kg). Our findings show that GBR12909 antagonizes the rise in extracellular DA produced by systemic cocaine, and these results provide further evidence that DA reuptake inhibitors may be useful pharmacological adjuncts in the treatment of cocaine addiction and withdrawal in human patients.

5. Effects Of Phentermine And Fenfluramine On Extracellular Dopamine And Serotonin In Rat Nucleus Accumbens.
Preliminary evidence suggests that combined administration of the amphetamine derivatives, phentermine (PHEN) and fenfluramine (FEN), may be useful for treating cocaine and alcohol addiction. In open-label studies, some addicts report marked decreases in drug craving within hours of taking this medication. While these medicines are thought to modulate monoamine neurotransmission, the precise mechanism of action has not been characterized. In the present work, we used in vivo microdialysis methods to assess the neurochemical effects of PHEN, FEN, and PHEN/FEN combinations in rat nucleus accumbens. Microdialysis experiments were performed in awake rats, and dialysate samples were analyzed for dopamine (DA) and serotonin (5-HT) using high pressure liquid chromatography followed by electrochemical detection. All drugs were dissolved in Ringers' perfusion fluid (148 mM NaCl, 4 mM KCl and 2 mM CaCl2) and infused locally via the probe (0-100 µM). PHEN selectively increased DA at 1 µM, but at higher doses, both DA and 5-HT levels were elevated. FEN selectively increased 5-HT at all doses, and even at 100 µM, effects on DA were minimal. Infusion of the PHEN/FEN combination elevated extracellular DA and 5-HT to a similar degree at all doses. Our data support the notion that PHEN/FEN treatment causes dual stimulation of DA and 5-HT neurotransmission. Moreover, this action may underlie the ability of PHEN/FEN to reduce drug craving and alleviate withdrawal symptoms in abstinent addicts.

6. Identification of a Novel d Opioid Receptor Binding Site in Rat Brain Membranes
Our laboratory was among the first to propose the existence of d receptor subtypes: a d site thought to be associated with a µ-d opioid receptor complex termed the dcx binding site and d site not associated with the µ-d opioid receptor complex, termed the dncx site. In previous studies we assayed the dcx site with [3H][D-Ala2,D-Leu5]enkephalin using rat brain membranes depleted of dncx sites by pretreatment with the site-directed acylating agent, (+)-trans-SUPERFIT. In the present study we investigated, using (+)-trans-SUPERFIT-pretreated membranes, the possibility of heterogeneity of the dcx binding site. Two sites were resolved: the dcx-1 site at which µ-ligands are potent non-competitive inhibitors and d-ligands are weak competitive inhibitors and the dcx-2 site where d-ligands are potent and µ-ligands are weak, mixed competitive-noncompetitive inhibitors. Although the dcx-2 site has a d-like ligand-selectivity profile, several experiments distinguished it from the dncx site. Two lines of evidence suggest that the dncx site corresponds to the cloned d receptor. One, the d receptor was cloned from the NG108-15 cell line, and this receptor, like the dncx binding site, irreversibly binds SUPERFIT and (+)-trans-SUPERFIT. Secondly, administration of d-antisense DNA selectively decreases dncx binding. Viewed collectively, the major finding of this study is the discovery of a novel SUPERFIT-insensitive and d-antisense-insensitive dcx-2 binding site. Efforts to clone this receptor will soon be underway.

7. Discovery Of A Novel Chiral Benzazepine Derivative, RTI-4793-41, Whose Enantiomers Bind Potently And With Moderate Enantioselectivity To PCP Site 2 And Cloned DA Transporters.
Recently, we reported that RTI-14, a novel pyrrole compound, showed high affinity (IC50 = 38 nM) and selectivity for the MK801-insensitive [3H]TCP binding site (PCP site 2) and moderate affinity for the biogenic amine transporters (BAT). These findings provided further evidence that PCP site 2 may be associated with the BAT system. In the present study, we determined the IC50 values of RTI-14, the novel benzazepine derivative RTI-41 and their enantiomers at PCP site 1 & 2 and the cloned human and rat DA transporters. Using guinea pig membranes, PCP site 1 was labeled with [3H](+)-MK801, while [3H]TCP in the presence of 500 nM (+)-MK801 was used to label PCP site 2. The DA transporter was labeled with [125I]RTI-55. RTI-41 bound potently and selectively to PCP site 2 (IC50 = 15 nM). The enantiomers of both RTI-14 and RTI-41 demonstrated moderate enantioselectivity at PCP site 2. The enantiomers of RTI-41 showed opposite enantioselectivity at PCP site 2 and the DA transporter, supporting the hypothesis that PCP site 2 and the cocaine recognition site on the DA transporter may be different.

The behavioral effects of these novel drugs are just now being explored. In one study an in vivo model was used which detects antidepressant activity by monitoring the effects of drugs on brain beta-adrenergic receptors. According to this well accepted model, drugs with antidepressant properties down-regulate beta receptors. Employing the technique of quantitative receptor autoradiography we showed that continuous i.c.v. infusion of RTI-4793-14 down-regulated beta receptors by about 50% in several nuclei measured at the striatal level.

Other behavioral studies performed in this laboratory attempted to investigate the ability of RTI4793-41 and its enantiomers to alter the conditioned psychomotor stimulant properties of cocaine. Dose response curves showed (+)-RTI-4793-41 increased locomotor activity while the (-)-isomer was devoid of any activity. Preliminary experiments showed that (-) RTI-4793-41 had cocaine antagonist activity - it blocked the conditioned locomotor effect of cocaine. Viewed collectively, these studies suggest that PCP site 2 ligands are promising candidates for the design and synthesis of potential treatment medications for cocaine addiction and depression.

Treatment Branch

P Buprenorphine is an opiate agonist/antagonist with demonstrated efficacy as short-term maintenance treatment for opiate dependence. It has been suggested that it also reduces the cocaine use common in opiate addicts. Scientists in the Treatment Branch have recently completed one of the first controlled clinical trials evaluating buprenorphine's efficacy and safety in outpatients dually dependent on both opiates and cocaine. Preliminary results indicate that buprenorphine is effective in reducing both opiate and cocaine use in such patients, with the highest buprenorphine dose (16 mg daily) more effective than lower doses in reducing cocaine use.

HIV infection is a frequent medical co-morbidity among injection drug users, but relatively little is known about the influence of such infection on pharmacotherapy for drug abuse. In the course of evaluating buprenorphine as a detoxification or short-term maintenance treatment for opiate dependence, scientists in the Treatment Branch have treated some patients with asymptomatic HIV infection. Such patients had a similar treatment response and similar frequency of medication side-effects as did non-infected patients, suggesting that buprenorphine can be safely and effectively used in HIV-infected opiate addicts.

The use of combinations of medications has been suggested as an approach to pharmacotherapy of drug abuse that might enhance medication efficacy while minimizing side-effects. Scientists in the Treatment Branch recently completed an open-label pilot study of outpatient treatment for cocaine dependence, using bromocriptine + bupropion, two medications which increase dopamine activity by different mechanisms. Results suggest that this medication combination is safe in cocaine addicts, and can reduce cocaine use.

Plasma butyrylcholinesterase (BChE) is the main cocaine-metabolizing enzyme in humans. In theory, changes in BChE activity might alter an individual's response to cocaine, but there is little information available on BChE activity in cocaine addicts. Scientists in the Treatment Branch recently completed an evaluation of endogenous plasma BChE activity in a convenience sample of cocaine addicts, abusers of other substances (alcohol, tobacco, heroin, marijuana), and normal controls. Preliminary results suggest that cocaine addicts do not differ from others in their level of BChE activity, and that such activity remains stable over time (up to one year).

Heroin dependence remains a serious and costly public health problem, even in patients receiving methadone maintenance treatment. A within-subject reversal design was used to assess the effectiveness of a voucher-based abstinence reinforcement contingency in reducing opiate use in methadone patients of the Archway Clinic, National Institute on Drug Abuse Intramural Research Program. Throughout the study subjects received standard methadone maintenance treatment involving methadone, counseling, and urine monitoring (three times per week). Thirteen patients who continued to use opiates regularly during a 5-week baseline period were exposed to a 12-week program in which they received a voucher for each opiate-free urine sample provided; the vouchers had monetary values that increased as the number of consecutive opiate-free urines increased. Subjects continued receiving standard methadone maintenance for 8 weeks after discontinuation of the voucher program (return-to-baseline). The percentage of urine specimens positive for opiates decreased significantly when the voucher program was instituted and then increased significantly when the voucher program was discontinued during the return-to-baseline condition. Voucherbased reinforcement contingencies can decrease opiate use in heroin dependent patients receiving methadone maintenance treatment.

A schedule of voucher-based reinforcement involving escalating pay for sustained abstinence has been effective in treating cocaine abuse. Under this schedule, patients receive a voucher for each cocaine-free urine; vouchers have monetary values that increase with the number of consecutive cocaine-free urines. While this schedule has been effective for many patients, some patients have failed to achieve sustained abstinence. A modification of this schedule was tested in an effort to improve abstinence outcomes. Cocaine abusing methadone patients were randomly assigned to receive vouchers for 12 weeks under 1) an escalating pay schedule, 2) an escalating pay schedule with start-up bonuses, or 3) a noncontingent schedule. The start-up bonuses were designed to provide substantial immediate reinforcement for initiating abstinence. The contingent voucher interventions significantly increased subjects' longest duration of sustained cocaine abstinence and the percent of subjects who were cocaine abstinent across the 12 weeks of the voucher intervention, and significantly decreased craving for cocaine. In addition, a significantly larger percent of subjects receiving the voucher intervention were opiate abstinent. Unexpectedly, adding start-up bonuses significantly decreased the percent of subjects who were cocaine abstinent, relative to abstinence rates under the escalating pay schedule alone. These results replicate the efficacy of voucher-based reinforcement of cocaine abstinence, show that it can have broad beneficial effects as evidenced by its effects on opiate use, and demonstrate that the schedule of reinforcement can be an important determinant of efficacy.

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