Passive immunization against nicotine attenuates nicotine discrimination

Ten rats were trained in a two lever operant chamber to press different levers after a nicotine injection (0.14 mg/kg s.c.) or a saline injection on an FR10 schedule. The rats were then injected i.p. with either 150 mg nicotine-specific IgG or the same amount of control IgG from non-immunized rabbits. On successive days, they were retested with both levers active after a saline injection, a full training dose of nicotine and a half dose of nicotine (0.07 mg/kg s.c.). After saline injection, both groups pressed the saline lever almost exclusively. After each of the nicotine doses, the immunized rats performed a significantly lower percentage of their lever presses on the nicotine lever than did non-immunized rats. The results suggest that passive immunization can interfere with the stimulus properties of nicotine.     

Fluoxetine-induced attenuation of amphetamine self-administration in rats

Daily injections of fluoxetine (5.0 mg/kg i.p.) to rats trained to self-administer intravenous d-amphetamine produced marked decreases in drug intake on three successive days of treatment. After fluoxetine injections were stopped, the number of daily amphetamine self-injections was still significantly reduced for an additional 2 days. When trained amphetamine self-administration animals were placed in an apparatus which delivered i.v. saline with each lever press, increased self-injection is observed. Acute fluoxetine injection did not alter this response. However, if fluoxetine is given prior to amphetamine exposure for 1 day and animals are then tested for the saline response, lever pressing activity is significantly reduced. These data might suggest that 5-hydroxytryptaminergic neurons mediate some aversive or negative reinforcing property of amphetamine. If true, this finding could be exploited clinically in cases of human psychomotor stimulant addiction.     

Vasopressin neuropeptides and acquisition of heroin and cocaine self-administration in rats

The effect of the vasopressin neuropeptide des-glycinamide (Arg8)-vasopressin (DGAVP) on reducing the acquisition of intravenous heroin self-administration in rats was analyzed. When rats reduced in body weight were allowed to self-administer heroin for 1 h per day in the presence of a fixed time, non contingent food delivery schedule, it appeared that heroin intake was related in an orderly way to the unit dose of heroin delivered. DGAVP decreased heroin intake during days 4 and 5 of acquisition, especially when a high dose of heroin was delivered. DGAVP decreased heroin intake more effectively when rats were tested without the food delivery schedule and for 6 h instead of 1 h sessions per day. Structure activity relationship studies revealed that the peptide (pGlu4, Cyt6)AVP-(4-8) was the shortest active sequence mimicking the effect of DGAVP and that this peptide was somewhat more potent than DGAVP in this respect. The peptide (pGlu4,Cyt6)AVP-(4-9) increased the heroin intake of the rats. DGAVP and (pGlu4,Cyt6)-AVP-(4-8) also decreased cocaine intake of body weight reduced rats given the opportunity to self-administer cocaine intravenously in daily 6 h sessions. It is concluded that vasopressin neuropeptides may decrease the reinforcing efficacy of heroin and cocaine during acquisition of drug self-administration rather than interact with nutritional and environmental factors influencing drug taking behavior.     

A Novel Procedure for Evaluating the Reinforcing Properties of Tastants in Laboratory Rats: Operant Intraoral Self-administration

This paper describes a novel method for studying the bio-behavioral basis of addiction to food. This method combines the surgical component of taste reactivity with the behavioral aspects of operant self-administration of drugs. Under very brief general anaesthesia, rats are implanted with an intraoral (IO) cannula that allows delivery of test solutions directly in the oral cavity. Animals are then tested in operant self-administration chambers whereby they can press a lever to receive IO infusions of test solutions. IO self-administration has several advantages over experimental procedures that involve drinking a solution from a spout or operant responding for solid pellets or solutions delivered in a receptacle. Here, we show that IO self-administration can be employed to study self-administration of high fructose corn syrup (HFCS). Rats were first tested for self-administration on a progressive ratio (PR) schedule, which assesses the maximum amount of operant behavior that will be emitted for different concentrations of HFCS (i.e. 8%, 25%, and 50%). Following this test, rats self-administered these concentrations on a continuous schedule of reinforcement (i.e. one infusion for each lever press) for 10 consecutive days (1 session/day; each lasting 3 hr), and then they were retested on the PR schedule. On the continuous reinforcement schedule, rats took fewer infusions of higher concentrations, although the lowest concentration of HFCS (8%) maintained more variable self-administration. Furthermore, the PR tests revealed that 8% had lower reinforcing value than 25% and 50%. These results indicate that IO self-administration can be employed to study acquisition and maintenance of responding for sweet solutions. The sensitivity of the operant response to differences in concentration and schedule of reinforcement makes IO self-administration an ideal procedure to investigate the neurobiology of voluntary intake of sweets.     

Carbon Disulfide Mediates Socially-Acquired Nicotine Self-Administration

The social environment plays a critical role in smoking initiation as well as relapse. We previously reported that rats acquired nicotine self-administration with an olfactogustatory cue only when another rat consuming the same cue was present during self-administration. Because carbon disulfide (CS₂) mediates social learning of food preference in rodents, we hypothesized that socially acquired nicotine self-administration is also mediated by CS₂. We tested this hypothesis by placing female adolescent Sprague-Dawley rats in operant chambers equipped with two lickometers. Licking on the active spout meeting a fixed-ratio 10 schedule triggered the concurrent delivery of an i.v. infusion (saline, or 30 µg/kg nicotine, free base) and an appetitive olfactogustatory cue containing CS₂ (0–500 ppm). Rats that self-administered nicotine with the olfactogustatory cue alone licked less on the active spout than on the inactive spout. Adding CS₂ to the olfactogustatory cue reversed the preference for the spouts. The group that received 500 ppm CS₂ and the olfactogustatory cue obtained a significantly greater number of nicotine infusions than other groups. After extinction training, the original self-administration context reinstated nicotine-seeking behavior in all nicotine groups. In addition, in rats that received the olfactogustatory cue and 500 ppm CS₂ during SA, a social environment where the nicotine-associated olfactory cue is present, induced much stronger drug-seeking behavior compared to a social environment lacking the olfactogustatory cue. These data established that CS₂ is a critical signal that mediates social learning of nicotine self-administration with olfactogustatory cues in rodents. Additionally, these data showed that the social context can further enhance the drug-seeking behavior induced by the drug-taking environment.     

Acute effects of nicotine amplify accumbal neural responses during nicotine-taking behavior and nicotine-paired environmental cues

Nicotine self-administration (SA) is maintained by several variables, including the reinforcing properties of nicotine-paired cues and the nicotine-induced amplification of those cue properties. The nucleus accumbens (NAc) is implicated in mediating the influence of these variables, though the underlying neurophysiological mechanisms are not yet understood. In the present study, Long-Evans rats were trained to self-administer nicotine. During SA sessions each press of a lever was followed by an intravenous infusion of nicotine (30 μg/kg) paired with a combined light-tone cue. Extracellular recordings of single-neuron activity showed that 20% of neurons exhibited a phasic change in firing during the nicotine-directed operant, the light-tone cue, or both. The phasic change in firing for 98% of neurons was an increase. Sixty-two percent of NAc neurons additionally or alternatively showed a sustained decrease in average firing during the SA session relative to a presession baseline period. These session decreases in firing were significantly less prevalent in a group of neurons that were activated during either the operant or the cue than in a group of neurons that were nonresponsive during those events (referred to as task-activated and task-nonactivated neurons, respectively). Moreover, the session decrease in firing was dose-dependent for only the task-nonactivated neurons. The data of the present investigation provide supportive correlational evidence for two hypotheses: (1) excitatory neurophysiological mechanisms mediate the NAc role in cue-maintenance of nicotine SA, and (2) a differential nicotine-induced inhibition of task-activated and task-nonactivated neurons mediates the NAc role in nicotine-induced amplification of cue effects on nicotine SA.     

Genetic factors control nicotine self-administration in isogenic adolescent rat strains

Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN) 32, and then nicotine (0.03 mg/kg/infusion, i.v.) reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions). Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45±0.36/d) during the last 3 d, while Lewis rats took the most nicotine (13.0±1.4/d). These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64) is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes.     

The Nicotinic α6-Subunit Selective Antagonist bPiDI Reduces Alcohol Self-Administration in Alcohol-Preferring Rats

Cigarettes and alcohol are the most abused substances in the world and are commonly co-abused. Nicotine primarily acts in the brain on nicotinic acetylcholine receptors (nAChR), which are also a target for alcohol. The alpha6 subunit of nAChR is expressed almost exclusively in the brain reward system and may modulate the rewarding properties of alcohol and nicotine. Recently, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI) was synthesized as a selective, brain penetrant α6 subunit antagonist that reduces nicotine self-administration. The current study aimed to examine the effects of bPiDI on alcohol self-administration in inbred alcohol-preferring (iP) rats. Adult, male iP rats were trained to self-administer alcohol or sucrose. Once stable responding was achieved, rats were injected with bPiDI (1, 3 mg/kg, i.p.) and tested for self-administration under fixed and progressive ratio schedules of reinforcement. They subsequently underwent extinction, in which no rewards or cues were presented in the operant chambers. Then, they were injected with bPiDI prior to testing for cue-induced reinstatement of reward seeking. bPiDI (3 mg/kg) significantly reduced alcohol self-administration in both fixed and progressive ratios without any effects on sucrose self-administration or locomotor activity. In contrast, bPiDI (3 mg/kg) did not inhibit cue-induced reinstatement of either alcohol or sucrose seeking. The results support the involvement of α6 containing nAChR in reinforcing effects of alcohol, but not relapse to alcohol-seeking, without any impact on responding for a natural reward or general activity. bPiDI may be a potential lead molecule for a therapeutic strategy to limit nicotine and alcohol consumption.     

Focus: Addiction: How Menthol Alters Tobacco-Smoking Behavior: A Biological Perspective

Mentholated cigarettes gained popularity in the 1950s and were often marketed as “healthy” cigarettes, attributable to their pleasurable mint flavor and cooling sensation in the mouth, lungs, and throat. While it is clear that nicotine is the primary psychoactive component in tobacco cigarettes, recent work has suggested that menthol may also play a role in exacerbating smoking behavior, despite original health claims. Recent evidence highlights four distinct biological mechanisms that can alter smoking behavior: 1) menthol acts to reduce the initially aversive experiences associated with tobacco smoking; 2) menthol can serve as a highly reinforcing sensory cue when associated with nicotine and promote smoking behavior; 3) menthol''s actions on nicotinic acetylcholine receptors may change the reinforcing value of nicotine; and 4) menthol can alter nicotine metabolism, thus increasing nicotine bioavailability. The purpose of this review is to highlight and evaluate potential biological mechanisms by which menthol can alter smoking behavior.     

A general method for evaluating incubation of sucrose craving in rats

For someone on a food-restricted diet, food craving in response to food-paired cues may serve as a key behavioral transition point between abstinence and relapse to food taking. Food craving conceptualized in this way is akin to drug craving in response to drug-paired cues. A rich literature has been developed around understanding the behavioral and neurobiological determinants of drug craving; we and others have been focusing recently on translating techniques from basic addiction research to better understand addiction-like behaviors related to food. As done in previous studies of drug craving, we examine sucrose craving behavior by utilizing a rat model of relapse. In this model, rats self-administer either drug or food in sessions over several days. In a session, lever responding delivers the reward along with a tone+light stimulus. Craving behavior is then operationally defined as responding in a subsequent session where the reward is not available. Rats will reliably respond for the tone+light stimulus, likely due to its acquired conditioned reinforcing properties. This behavior is sometimes referred to as sucrose seeking or cue reactivity. In the present discussion we will use the term "sucrose craving" to subsume both of these constructs. In the past decade, we have focused on how the length of time following reward self-administration influences reward craving. Interestingly, rats increase responding for the reward-paired cue over the course of several weeks of a period of forced-abstinence. This "incubation of craving" is observed in rats that have self-administered either food or drugs of abuse. This time-dependent increase in craving we have identified in the animal model may have great potential relevance to human drug and food addiction behaviors. Here we present a protocol for assessing incubation of sucrose craving in rats. Variants of the procedure will be indicated where craving is assessed as responding for a discrete sucrose-paired cue following extinction of lever pressing within the sucrose self-administration context (Extinction without cues) or as responding for sucrose-paired cues in a general extinction context (Extinction with cues).     

Developing human laboratory models of smoking lapse behavior for medication screening

Use of human laboratory analogues of smoking behavior can provide an efficient, cost-effective mechanistic evaluation of a medication signal on smoking behavior, with the result of facilitating translational work in medications development. Although a number of human laboratory models exist to investigate various aspects of smoking behavior and nicotine dependence phenomena, none have yet modeled smoking lapse behavior. The first instance of smoking during a quit attempt (i.e. smoking lapse) is highly predictive of relapse and represents an important target for medications development. Focusing on an abstinence outcome is critical for medication screening as the US Food and Drug Administration approval for cessation medications is contingent on demonstrating effects on smoking abstinence. This paper outlines a three-stage process for the development of a smoking lapse model for the purpose of medication screening. The smoking lapse paradigm models two critical features of lapse behavior: the ability to resist the first cigarette and subsequent ad libitum smoking. Within the context of the model, smokers are first exposed to known precipitants of smoking relapse (e.g. nicotine deprivation, alcohol, stress), and then presented their preferred brand of cigarettes. Their ability to resist smoking is then modeled and once smokers 'give in' and decide to smoke, they participate in a tobacco self-administration session. Ongoing and completed work developing and validating these models for the purpose of medication screening is discussed.     

Review. Context-induced relapse to drug seeking: a review

In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies by Bouton & Bolles on context-induced 'renewal' of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin-cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking.     

Effects of angiotensin II and captopril on rewarding properties of morphine

The effects of captopril and Ang II on morphine-induced conditioned place preference (CPP) and morphine self-administration in male Wistar rat were investigated. In CPP experiment, injection of captopril before test significantly decreased the difference of the time spent in compartment A between pre- and post-conditioning compared to morphine group. In self- administration experiment number of active lever pressing was significantly greater than passive in morphine group. In captopril group number of active lever pressing was significantly lower than morphine group however, there was not significant difference between active and passive lever pressed number. The results showed that captopril significantly decreased morphine-induced conditional place preference and morphine self-administration but the effect of Ang II was not significant. It can be concluded that RAS may have a role in rewarding properties of morphine.     

Effect of isradipine,a dihydropyridine-calcium antagonist on I.V. self-administration of morphine in rats

The effect of dihydropyridine calcium channel antagonist isradipine (PN 200-110) on morphine reinforcement has been investigated using i.v. self-administration test in rats. Rats were given the opportunity to self-administer a solution of morphine (1 mg/Ml, i.v.) in a 1 hr limited access paradigm (FR = 1). Within 5–7 days rats had learned to self-administer approximately 1 mg of morphine in 1 hr as evidenced by a plateau of responding. The administration of isradipine (1.2, 2.5 and 5.0 mg/kg s.c.) 90 min before the morphine self-administration session, induced dose-dependent increase in the number of morphine self-infusions with respect to basal values. This response pattern was very similar to the one observed when morphine solution was substituted by saline in trained rats not treated with isradipine. The results indicate that isradipine inhibits partially the reinforcing properties of morphine in self-administration test.     

Nicotine increases sucrose self-administration and seeking in rats

Associations between nicotine in cigarettes and food consumption may alter the incentive value of food such that food cue-reactivity is exaggerated during abstinence from smoking. This effect may contribute to the weight gain associated with cessation of smoking. We examined the effects of nicotine (0.4 mg/kg base subcutaneous) paired (NPD) or unpaired (NUP) with 10% sucrose self-administration (SA; 0.2 ml/delivery, 1 h/day for 10 days) on SA response rate and intake as well as sucrose cue-reactivity following either 1 or 30 days of forced abstinence. Rats were administered the training dose of nicotine prior to a second, consecutive cue-reactivity session. NPD rats responded at over three times the rate for sucrose and earned nearly twice the number of sucrose deliveries as NUP rats or saline controls. Sucrose cue-reactivity was greater after 30 days versus 1 day of forced abstinence for all groups. History of nicotine exposure had no effect on sucrose cue-reactivity. However, the subsequent injection of nicotine increased sucrose cue-reactivity only in the NPD groups. There were no abstinent-dependent effects of nicotine challenge on sucrose cue-reactivity. A study conducted in parallel with water as the reinforcer revealed a less dramatic effect of nicotine on intake. There was no history or abstinence-dependent effects of nicotine on water cue-reactivity. Nicotine increases the reinforcing effects of sucrose and sucrose-paired cues when nicotine is present. An implication of these findings is that relapse to nicotine (cigarettes) could substantially elevate food cue-reactivity.     

Responding maintained by primary reinforcing visual stimuli is increased by nicotine administration in rats

Nicotine has been shown to increase responding maintained by turning off a houselight. To examine whether this effect extends to other primary reinforcing visual stimuli, the present study assessed whether nicotine would increase responding maintained by the illumination, and not just the darkening, of a visual stimulus. One group of rats (n = 4) was initially trained to press two levers, using food as a consequence, while a separate group of rats (n = 4) was initially trained to press one lever. After training, all rats pressed an active lever to turn on or turn off a houselight for 10 s, while presses on an inactive lever had no programmed consequences. A third group of rats (n = 4) were never trained to press either of the two levers and did not experience any programmed consequences for pressing. Although nicotine slightly increased lever pressing on both levers in the third group, nicotine resulted in much greater increases in responding maintained by the visual stimuli in the first two groups. Nicotine selectively increased responding maintained by visual stimuli, regardless of which levers were originally trained and regardless of whether those stimuli consisted of turning on or turning off a houselight, suggesting that nicotine enhances the value of primary reinforcing visual stimuli.     

Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated pentameric ion channels that account for the effects of nicotine. Recent genetic studies have highlighted the importance of variants of the CHRNA5/A3/B4 genomic cluster in human nicotine dependence. Among these genetic variants those found in non-coding segments of the cluster may contribute to the pathophysiology of tobacco use through alterations in the expression of these genes. To discern the in vivo effects of the cluster, we generated a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster using a bacterial artificial chromosome. Transgenic mice showed increased functional α3β4-nAChRs in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine along with higher activation of the medial habenula and reduced activation of dopaminergic neurons in the ventral tegmental area after acute nicotine administration. Importantly, transgenic mice showed increased acquisition of nicotine self-administration (0.015 mg/kg per infusion) and a differential response in the progressive ratio test. Our study provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 genomic cluster in nicotine addiction through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug.     

Self-administration of estrogen and dihydrotestosterone in male hamsters

Anabolic-androgenic steroids (AAS) are drugs of abuse. Previous studies have shown that male and female hamsters self-administer testosterone (T) and other AAS, suggesting that androgens are reinforcing in a context where athletic performance is irrelevant. AAS are synthetic derivatives of T, which may be aromatizable to estrogen and/or reducible to dihydrotestosterone (DHT). However, we do not know which metabolites of T are reinforcing. To determine if DHT, estradiol (E(2)), or DHT + E(2) are reinforcing, we tested intracerebroventricular (icv) self-administration in male hamsters. The hypothesis was that androgen reinforcement is sensitive to both androgenic and estrogenic T metabolites. If so, hamsters would self-administer DHT, E(2), and DHT + E(2). Twenty four castrated male hamsters (n = 8/group) received icv cannulas and sc T implants for physiologic androgen replacement. One week later, hamsters self-administered DHT (0.1, 1.0, 2.0 microg/microl), E(2) (0.001, 0.01, 0.02 microg/microl), or DHT + E(2), each for 8 days in increasing concentration (4 h/day). Operant chambers were equipped with an active and inactive nose-poke. At the medium concentration, hamsters self-administered DHT (active nose-poke: 47.9 +/- 13.9 responses/4 h vs. inactive: 18.7 +/- 4.8), E(2) (active: 44.8 +/- 14.9 vs. inactive: 16.6 +/- 2.6), and DHT + E(2) (active: 19.1 +/- 2.4 vs. inactive: 10.4 +/- 2.4, P < 0.05). At the highest concentration, males self-administered DHT (active: 28.3 +/- 7.7 vs. inactive: 15.0 +/- 3.5, P < 0.05) and DHT + E(2) (active: 22.6 +/- 3.8 vs. inactive: 11.6 +/- 2.5, P < 0.05), but not E(2). Hamsters did not self-administer the lowest concentrations of DHT, E(2), or DHT + E(2). These results support our hypothesis that both androgenic and estrogenic T metabolites are reinforcing. Together, they do not exert synergistic effects.     

Environmental enrichment decreases responding for visual novelty

Previous research has demonstrated that rats reared in an enriched condition (EC) with novel objects and social partners self-administer less amphetamine compared to rats raised in an isolated condition (IC). However, it is unclear if the enrichment-induced decrease in stimulant self-administration generalizes to non-drug rewards such as those provided by novel environmental stimuli. In the current study, EC, IC, and social condition (SC) rats were raised from 21 to 51 days of age before being tested in a two-lever operant conditioning chamber in which responding on one lever (active lever) resulted in illumination of a cue light. In Experiment 1, rats were initially assessed for baseline responding (no contingency) and then the contingent light was introduced. EC rats responded less than IC rats for the contingent light stimulus; however, EC rats also displayed a lower rate of baseline responding. In Experiment 2, rats were trained initially to lever press for a sucrose reward to decrease differences in baseline responding. While sucrose pretraining decreased baseline response differences between groups, EC rats still responded less for the contingent light stimulus than IC or SC rats. These results suggest that environmental enrichment decreases the incentive value of visual novelty.     

Oxytocin reduces intravenous heroin self-administration in heroin-tolerant rats

Intravenous self-administration of heroin was studied in experimentally naive rats, as compared to this behavior in animals rendered tolerant to heroin by multiple injections. The tolerant rats also exhibited mild signs of spontaneous and naloxone-precipitated heroin withdrawal. Self-administration behavior developed earlier in the tolerant rats. In heroin-naive rats, oxytocin treatment did not influence the acquisition of heroin self-administration behavior. In the tolerant rats, on the other hand, oxytocin decreased the acquisition of heroin self-administration. When maintenance of heroin self-administration was studied in the tolerant rats, graded doses of oxytocin (0.05, 0.5 and 5 micrograms s.c.) decreased heroin intake. This finding, which is in agreement with previous data indicating that oxytocin attenuates the development of tolerance to and dependence on narcotic analgesics, suggests that the neuropeptide reduced the reinforcing efficacy of heroin in the tolerant organism.