Non-drug Reinforcers Research Articles

Blocking of conditioning to a cocaine-paired stimulus: Testing the hypothesis that cocaine perpetually produces a signal of larger-than-expected reward

According to a recent account of addiction, dopaminergic effects of drugs like cocaine mimic the neuronal signal that occurs when a natural reward has a larger value than expected. Consequently, the drug's expected reward value increases with each administration, leading to an over-selection of drug-seeking behavior. One prediction of this hypothesis is that the blocking effect, a cornerstone of contemporary learning theory, should not occur with drug reinforcers. To test this prediction, two groups of rats were trained to self-administer cocaine with a nose-poking response. For 5 sessions, a tone was paired with each self-administered injection (blocking group), or no stimulus was paired with injection (non-blocking group). Then, in both groups, the tone and a light were both paired with each injection for 5 sessions. In subsequent testing, the light functioned as a conditioned reinforcer for a new response (lever-pressing) in the non-blocking group, but not the blocking group. Thus, contrary to prediction, pre-training with the tone blocked conditioning to the light. Although these results fail to support a potentially powerful explanation of addiction, they are consistent with the fact that most conditioning and learning phenomena that occur with non-drug reinforcers can also be demonstrated with drug reinforcers.

Effects of naltrexone on cocaine- and sucrose-seeking behaviour in response to associated stimuli in rats

The non-selective opioid receptor antagonist naltrexone reduces cocaine-induced reinstatement of drug-seeking behaviour in abstinent rats. The current study sought to determine whether the opioid system is also involved in cocaine-seeking behaviour induced by cocaine-associated stimuli in abstinent rats. Adult male rats were trained to press a lever either to self-administer cocaine or to obtain sucrose pellets in the presence of distinctive discriminative and conditioned stimuli. After a period of extinction, re-exposure to cocaine-associated cues selectively elicited robust and enduring responding at the active lever; sucrose pellet-associated cues revived seeking behaviour less pronouncedly. Pretreatment with naltrexone (0.25, 1, 2.5 mg/kg s.c., 20 min before reinstatement tests) dose dependently prevented cue-induced cocaine-seeking behaviour, whereas (2.5 mg/kg s.c.) did not affect the degree of cue-induced sucrose-seeking behaviour. These results provide the first evidence that naltrexone influences cocaine seeking induced by conditioned stimuli in abstinent rats; this effect appears selective for cocaine reinstatement as opposed to a non-drug reinforcer.

The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections

We have hypothesized that nicotine has two effects on reinforcement; it increases the probability of responses resulting in nicotine delivery (primary reinforcement) and enhances the apparent reward value of non-nicotine reinforcers (reinforcement enhancing effect). The present studies investigated two predictions generated by this hypothesis: (1) that the reinforcement enhancing effect will depend on apparent stimulus reward value and (2) that the temporal profile of this effect would depend on the pharmacological profile of nicotine. In Experiment 1, rats were trained to lever press for one of two audio-visual stimuli that differed in their intrinsic reinforcing value and then the effect of pre-session nicotine (0.4 mg/kg base) or saline injections was tested. The stimulus that supported very low rates of operant responding displayed smaller increases in responding after pre-session injections of nicotine. In Experiment 2 the effect of nicotine injected 5 min before the session was compared to the effect of nicotine injected 1 h after the session using the more reinforcing stimulus condition from the first experiment. A control group received only vehicle injections. In contrast to nicotine injected just prior to the session, post-session injections of nicotine had no detectable effect on responding for the more reinforcing stimulus. These results indicate that the reinforcement enhancing action of nicotine depends on the intensity of the primary reinforcer and that enhanced reinforcement by nicotine depends on coincident access to a stimulus with reinforcing properties.

Investigating the pharmacological and nonpharmacological factors that modulate drug reinforcement.

Drug use is driven by principles of reinforcement and is sensitive to influences in the environmental context in which it occurs. Although a wide range of factors has been shown to directly influence the reinforcing effects of commonly abused drugs, 2 general types include pharmacological and nonpharmacological factors. Both can assert a powerful impact on a drug's reinforcing effects and, therefore, the degree to which a particular drug comes to be used and abused. This invited review seeks to briefly describe some of the current psychopharmacology research on the interactions between these factors and drug abuse. Several pharmacological influences on drug use will be discussed, including the interactions between psychomotor stimulants and recent advances in the development of pharmacotherapies for opioid abuse. With regard to nonpharmacological factors, there is a large body of research demonstrating that nondrug reinforcers can exert a powerful influence on the reinforcing effects of commonly abused drugs. More specifically, identifying alternative nondrug sources of reinforcement can, if made available contingent on drug abstinence, produce robust decreases in drug self-administration. Presented here is a very brief review of some recent scientific efforts to develop and extend behavioral interventions targeting drug use across a wide range of clinical populations. In summary, understanding the interactions among the variables present in the context of drug use is critical to understanding risk factors for substance use disorders as well as developing efficacious treatments for drug dependence.

Contingency Management for the Treatment of Methamphetamine Use Disorders

Theory and some preliminary evidence suggest that contingency management may be an effective treatment strategy or adjunct to psychosocial treatment for methamphetamine use disorders. An experimentally rigorous investigation on the topic was provided by a large multisite trial conducted under the auspices of the Clinical Trials Network of the National Institute on Drug Abuse. The authors report data on 113 participants who were diagnosed with methamphetamine abuse or dependence. They were randomly assigned to receive 12 weeks of either treatment as usual or treatment as usual plus contingency management. Urine samples were tested for illicit drugs, and breath samples were tested for alcohol. The reinforcers for drug-negative samples were plastic chips, some of which could be exchanged for prizes. The number of plastic chips drawn increased with each week of negative samples but was reset to one after a missed or positive sample. The participants in both groups remained in treatment for equivalent times, but those receiving contingency management in addition to usual treatment submitted significantly more negative samples, and they were abstinent for a longer period of time (5 versus 3 weeks). These results suggest that contingency management has promise as a component in treatment strategies for methamphetamine use disorder.

Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys

Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice. The present study examined effects of delay between lever press and reinforcer presentation on the choice between a drug and non-drug reinforcer and between different drug doses. Monkeys (n=4) were allowed to choose 32 times/day between cocaine and four food pellets. The delay between lever press and a preferred dose of cocaine (0.05 mg/kg/injection) was increased systematically from 0 to 240 s, while the delay to food remained at 0 s. A second group of monkeys (n=4) was allowed to choose between 0.05 mg/kg/injection and a lower dose of cocaine (0.025 mg/kg/injection). Next, a delay that resulted in less than 20% choice of 0.05 mg/kg/injection cocaine was selected and delay to the alternative was varied. Results were similar across groups. The choice of 0.05 mg/kg/injection approximated 100% at 0 delay and decreased to near 0 as delay increased. As the delay to alternative was subsequently increased from 0 to 240 s, choice of 0.05 mg/kg/injection increased, though full cocaine choice was not generally restored. The delay estimated to maintain 50% choice (indifference point) was lower for the cocaine-food choice (mean=64 s) than for the cocaine-cocaine choice (mean=207 s). This experiment demonstrates that the choice between cocaine and a non-drug or drug alternative can be modified by increasing the interval between behavior and drug injection. Overall, the results are consistent with a temporal discounting model of drug choice.

18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats

The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of morphine and other drugs of abuse. Previous work has established that 18-MC is a potent antagonist at α3β4 nicotinic receptors. Because α3β4 nicotinic receptors in the brain are preferentially located in the medial habenula and the interpeduncular nucleus, the present study was conducted to determine if 18-MC could act in these brain areas to modulate morphine self-administration in rats. Local administration of 18-MC into either the medial habenula or the interpeduncular area decreased morphine self-administration while having no effect on responding for a non-drug reinforcer (sucrose). Similar results were produced by local administration into the same brain areas of two other α3β4 nicotinic antagonists, mecamylamine and α-conotoxin AuIB. Local administration of 18-MC into the ventral tegmental area had no effect on morphine self-administration. These and other data are consistent with the hypothesis that 18-MC decreases morphine self-administration by blocking α3β4 nicotinic receptors in the habenulo-interpeduncular pathway.

The attribution of incentive salience to a stimulus that signals an intravenous injection of cocaine

A central premise of a number of theories of addiction is that discrete environmental stimuli repeatedly paired with drugs of abuse acquire incentive salience as a result of Pavlovian learning. There is, however, no unequivocal evidence supporting this assumption. Thus, we employed a Pavlovian conditioning procedure known to imbue non-drug reinforcers with incentive salience and extended it to study the effects of intravenous cocaine. Specifically, we examined whether a cue paired with intravenous cocaine administration would come to elicit approach towards it (sign-tracking), even if no behavioral response were required to receive the cue or drug. We found that when a cue was paired with intravenous cocaine delivery (but not when it was unpaired) rats came to approach and investigate the cue, and did so with increasing rapidity. We conclude that Pavlovian learning can imbue drug-paired cues with incentive salience, making them attractive and “wanted” stimuli. Delineating the neurobiological mechanisms responsible for this process will be important for understanding and treating drug addiction.

Resurgence of alcohol seeking produced by discontinuing non-drug reinforcement as an animal model of drug relapse

Findings from basic behavioral research suggest that simply discontinuing reinforcement for a recently reinforced operant response can cause the recurrence (i.e. resurgence) of a different previously reinforced response. The present experiment examined resurgence as an animal model of drug relapse. Initially, rats pressed levers to self-administer alcohol during baseline conditions. Next, alcohol self-administration was discontinued and non-drug reinforcers (food pellets) were presented contingent on an alternative response (chain pulling). Finally, when the non-drug reinforcer was discontinued, alcohol seeking recurred even though alcohol was still unavailable for lever pressing. These results suggest that simply discontinuing non-drug reinforcement for a behavior may be sufficient to produce relapse to drug seeking. The resurgence procedure could provide a method to examine environmental, pharmacological, and neurobiological factors that lead to relapse following the loss of a non-drug source of reinforcement.

What Do We Know About Drug Addiction?

What Do We Know About Drug Addiction?

Effects of the 5-HT1A agonist (??)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on cocaine choice in cynomolgus monkeys

Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.

Ethanol-maintained responding of rats is more resistant to change in a context with added non-drug reinforcement.

Alternative non-drug reinforcers reliably decrease drug-maintained responding in self-administration procedures. Studies of the resistance to change of food-maintained behavior, however, have found that responding in the presence of a stimulus associated with an alternative reinforcer is more resistant to disruption. This increase in persistence occurs despite lower response rates when the alternative reinforcer is present. The present experiment examined if, in addition to decreasing response rates, an alternative non-drug reinforcer also increases the persistence of drug-maintained responding. Rats self-administered oral ethanol in a multiple schedule of reinforcement in which responding was reinforced in two components signaled by different stimuli. In one component, response-independent food was delivered in addition to the earned ethanol. The effects of the alternative food reinforcer on response rates and resistance to extinction in the two components were examined. As in previous experiments on the resistance to change of food-maintained operant behavior, response rates were lower, but more resistant to extinction in the presence of the stimulus associated with the alternative reinforcer. These findings suggest that all the reinforcers obtained in a context in which drugs are consumed may contribute to the persistence of drug seeking in that context. This increase in persistence may occur even if the alternative reinforcers interfere with drug seeking.

Cocaine pre-exposure produces a sensitized and context-specific c-fos mRNA response to footshock stress in the central nucleus of the AMYGDALA

In recent years, there has been growing interest in the putative relationship between stress and vulnerability to relapse in former drug addicts. In animal studies aimed at exploring this relationship, it has been shown that brief exposure to intermittent footshock stress produces reliable reinstatement of drug seeking after prolonged drug-free periods. Whereas footshock reinstates drug seeking, it does not reinstate behaviors maintained by non-drug reinforcers, suggesting that prior drug experience may produce a form of sensitization within neuronal systems that mediate stress-induced reinstatement. The primary objective of the present experiments was to determine whether pre-exposure to cocaine produces a long-lasting, sensitized neuronal response to footshock stress within two brain regions known to mediate footshock-induced reinstatement; the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In experiment 1, animals were injected for 7 days with cocaine (days 1 and 7 in test chambers; days 2–6 in homecages) or saline. After 21 drug-free days, they were exposed to footshock or no footshock. In experiment 2, rats were injected daily for 7 days with cocaine in one of two contexts and saline in the alternate context. After 21 drug-free days, they were given footshock either in the same context that they were given cocaine in or the alternate context. In CeA, footshock produced enhanced expression of c-fos mRNA in cocaine, but not saline, pre-exposed animals. Furthermore, this effect was gated by the environmental context in which cocaine was given; footshock only enhanced c-fos mRNA expression when it was given in a context that had previously been paired with cocaine. Although footshock induced c-fos mRNA expression in the BNST, its effects in this region were not dependent on drug history. The major findings are that a history of cocaine exposure produces sensitization to an acute stressor within CeA, and this effect is gated by environmental context.

The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies

Imaging studies have provided evidence of how the human brain changes as an individual becomes addicted. Here, we integrate the findings from imaging studies to propose a model of drug addiction. The process of addiction is initiated in part by the fast and high increases in DA induced by drugs of abuse. We hypothesize that this supraphysiological effect of drugs trigger a series of adaptations in neuronal circuits involved in saliency/reward, motivation/drive, memory/conditioning, and control/disinhibition, resulting in an enhanced (and long lasting) saliency value for the drug and its associated cues at the expense of decreased sensitivity for salient events of everyday life (including natural reinforcers). Although acute drug intake increases DA neurotransmission, chronic drug consumption results in a marked decrease in DA activity, associated with, among others, dysregulation of the orbitofrontal cortex (region involved with salience attribution) and cingulate gyrus (region involved with inhibitory control). The ensuing increase in motivational drive for the drug, strengthened by conditioned responses and the decrease in inhibitory control favors emergence of compulsive drug taking. This view of how drugs of abuse affect the brain suggests strategies for intervention, which might include: (a) those that will decrease the reward value of the drug of choice; (b) interventions to increase the saliency value of non-drug reinforcers; (c) approaches to weaken conditioned drug behaviors; and (d) methods to strengthen frontal inhibitory and executive control. Though this model focuses mostly on findings from PET studies of the brain DA system it is evident that other neurotransmitters are involved and that a better understanding of their roles in addiction would expand the options for therapeutic targets.

Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at α3β4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of α3β4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of α3β4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.

Experts Desperately Seeking Meth Abuse Prevention, Treatment

Experts Desperately Seeking Meth Abuse Prevention, Treatment

Selective Blockade of Drug-induced Place Preference Conditioning by ACPC, a Functional NDMA-receptor Antagonist

ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some clinical utility in the treatment of addiction, without affecting responses to natural rewards.

Effect of cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement, and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats.

Lever pressing during tests for resistance to extinction and cue-induced reinstatement of cocaine seeking in rats progressively increases over the first 2 months of withdrawal. In the present report, we investigated the generality of these findings in rats trained to self-administer sucrose, a non-drug reinforcer. We also examined whether the time-dependent changes in cocaine seeking correlate with the levels of the dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins in the amygdala, nucleus accumbens, prefrontal cortex and orbitofrontal cortex. Rats were trained to self-administer cocaine (0.5 mg/kg/i.v. infusion) or 10% sucrose (0.2 ml/infusion into a liquid drop receptacle) for 10 days (6 h/day); each reward delivery was paired with a tone+light cue. Tests for cocaine seeking were conducted following 1 or 15 reward-free days. On the test day, rats were initially tested for resistance to extinction during 6-7 60-min extinction sessions in the absence of the tone-light cue, until they reached the extinction criterion of less than 15 responses/60 min. Subsequently, rats were tested for cue-induced reinstatement during a 60-min session in which each lever press led to a contingent presentation of the tone-light cue. Lever pressing during the tests for reward seeking was significantly greater on day 15 than on day 1 following withdrawal from both cocaine and sucrose self-administration training. The levels of DAT, but not TH, were greater in the prefrontal cortex of cocaine-trained rats than in sucrose-trained rats on both days 1 and 15 of withdrawal. The levels of DAT and TH in other brain areas were not altered following withdrawal from cocaine or sucrose self-administration. These data suggest that the withdrawal can modulate reward seeking of both drug and non-drug reinforcers, and that alterations in DAT and TH levels in the brain regions examined do not mediate this effect.

Effects of Bremazocine on Self-Administration of Smoked Cocaine Base and Orally Delivered Ethanol, Phencyclidine, Saccharin, and Food in Rhesus Monkeys: A Behavioral Economic Analysis

There is increasing evidence that kappa-opioid receptor agonists modulate cocaine-maintained behavior, and limited findings implicate the involvement of kappa-opioid receptors in ethanol-maintained behaviors. The purpose of the present study was to investigate the effects of bremazocine, a kappa-opioid agonist, on the self-administration of smoked cocaine base and oral ethanol in rhesus monkeys (Macaca mulatta). To determine the selectivity of bremazocine, the effects of bremazocine pretreatment on the oral self-administration of phencyclidine (PCP), saccharin, and food were also examined. Adult male rhesus monkeys were trained to self-administer oral ethanol, PCP, saccharin (n = 8), food (n = 6), or smoked cocaine base (n = 6) and water during daily sessions. Bremazocine (0.00032-, 0.001-, and 0.0025-mg/kg i.m.) injections were given 15 min before session. The 4 days of stable behavior before pretreatment served as baseline. Demand curves (consumption x fixed ratio; FR) were obtained for smoked cocaine base, ethanol, and PCP by varying the cost (FR) of drug deliveries and measuring consumption (deliveries). Bremazocine (0.001 mg/kg) was administered at each FR value in nonsystematic order. Results indicate that bremazocine dose dependently reduced cocaine, ethanol, PCP, and saccharin intake. Food intake was affected less by bremazocine than the other substances in five of the six monkeys. Generally, bremazocine treatment reduced the demand for cocaine, ethanol, and PCP as well as other measures of response strength. These results extend the findings that kappa-agonists reduce the self-administration of drug and nondrug reinforcers to smoked cocaine base and oral ethanol, PCP, and saccharin in rhesus monkeys.

Conditioned suppression of behavior maintained by cocaine self-administration

Shock-paired stimuli have produced conditioned suppression of behavior maintained by a variety of reinforcers such as food, water, sucrose, and intracranial self-stimulation. With the ongoing pursuit of animal models for drug abuse treatment, it is surprising that this procedure for suppressing positively reinforced behavior has never been applied to drug-maintained behavior. The present study applied the conditioned suppression paradigm to behavior maintained by cocaine self-administration in rats. If shock-paired stimuli suppress ongoing cocaine self-administration, this would contrast with recent studies reporting that aversive stimuli can enhance the acquisition and reinstatement of behavior reinforced by cocaine. Rats were trained to bar-press for intravenous cocaine infusions on a variable-interval schedule. Then, a tone conditioned stimulus (CS) and a light CS were each paired with foot-shock while the rats were bar-pressing for cocaine. These CSs each came to reliably suppress responding in all subjects, just as shock-paired CSs suppressed responding by the positive reinforcers mentioned above. When the tone and the light were presented simultaneously in testing, suppression was significantly enhanced over that controlled by the single CSs. These results demonstrate that (1) cocaine-maintained behavior can be suppressed by environmental stimuli associated with non-drug reinforcers; and (2) combining stimuli that decrease drug self-administration can enhance their suppressive effects. Thus, the present findings can have implications for drug treatment.