Effects of methadone and morphine maintenance on drug-seeking behavior in the dog

The effects of methadone and morphine maintenance on morphine self-administration were studied in the dog. Methadone was given passively for 2 weeks by continuous i.v. infusion. The amount of methadone administered daily was the same in mg/kg as the mean daily mg/kg of morphine the dogs had self-administered during the premaintenance control week. Morphine self-administration was markedly reduced initially but returned to normal levels within 2 weeks of methadone administration. Following the methadone maintenance period, morphine self-administration was increased over the premaintenance period for 2 weeks. A result similar to that with methadone was obtained in a second experiment when morphine was used as the maintenance drug in an amount that was three times the amount the dogs had been self-administering during the premaintenance control week.A division of the US Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Administration     

Self-administration of nalbuphine,butorphanol and pentazocine by morphine post-addict rats

The purpose of the study was to define possible self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats. Rats were prepared with permanent EEG and EMG electrodes and indwelling IV cannulae ,made tolerant to and physically dependent on morphine, then trained to lever press for morphine IV self-injections on a fixed ratio (FR) 20 schedule of reinforcement. Rats were then spontaneously withdrawn from morphine. When these morphine post-addict rats were returned to the experimental cages three to four weeks later, they were found to reestablish self-administration of morphine as well as to establish self-administration of nalbuphine, butorphanol and pentazocine. Suppression of REM sleep for at least 30 min was apparent following self-injections of these agents. After the stabilization of self-injection patterns, withdrawal from morphine and pentazocine was found to be associated with intense abstinence symptoms. However, withdrawal from nalbuphine and butorphanol was not. It can be concluded that while drug-seeking behavior for the above narcotics in morphine post-addict rats was analogous as measured by self-administration, nalbuphine and butorphanol appeared to produce lower levels of physical dependence.     

Characteristics of chronic self-administration of morphine by dogs

Each of five dogs that had been trained to chronically self-administer IV morphine was tested with changes in the morphine dose from the baseline dose (1 mg/kg/infusion) to 0.125, 0.5, or 2 mg/kg/infusion, and with passive administration of the usual daily morphine intake while either continuing the morphine self-administration at the baseline dose or changing the self-administered solution to saline. Each treatment lasted 5 weeks. Results indicated that there is a significant negative regression of response on dose, and chronic self-administration of morphine is not entirely accounted for by a need to avoid abstinence or to obtain a direct drug effect. A third element, which may be an acquired need to obtain a response-contingent drug effect, is necessary to account for the chronic self-administration of morphine by the dog.     

Behavioral effects of l-Dopa in schizophrenic patients

Intravenous self-administration of morphine by dogs was studied before and during dependence on morphine, and after 1 to 6 months of enforced abstinence. In comparison to pedal response rates during a saline control period, 18 of 22 dogs studied showed decreased rates of responding for morphine during the initial 3-week exposure. Following subsequent passive establishment of dependence in 7 dogs, they self-administered morphine and maintained dependence. Following enforced abstinence for periods of 1 to 6 months the 7 dogs relapsed to self-administration of morphine when it was again made available. In contrast, additional dogs offered food or amphetamine reinforcements showed marked increases in pedal responding for these reinforcements within a few days after initial exposure. The results indicate that in post-dependent dogs that had maintained their dependence on morphine by self-administration, effects other than those experienced during the initial exposure to morphine are responsible for relapse.     

Generalization of drug-seeking behavior in dogs

Drug-naive dogs which do not spontaneously initiate morphine self-administration were given one of three treatments and tested for subsequent morphine self-administration. Neither the dogs given the treatment of response-contingent drinking water nor those given d-amphetamine by passive infusions subsequently showed significant self-administration of morphine. However, the third group which self-administered d-amphetamine did subsequently self-administer morphine. The data suggest that self-administration of one reinforcing psychoactive drug may increase the probability of subsequently self-administering another.     

The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking

In this study, the use-dependent, nicotinic receptor antagonist bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self-administer morphine (FR1 schedule) with an active response lever, on a 24 h basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self-administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self-administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction.     

Effects of high-dose selegiline on morphine reinforcement and precipitated withdrawal in dependent rats

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects. Several lines of evidence suggest that treatment with selegiline at doses that exceed levels required for inhibition of MAO can produce distinct pharmacologic effects. The purpose of this study was to evaluate the effects of chronic treatment with high-dose selegiline on extinction responding, cue-induced reinstatement, morphine reinforcement and naloxone-precipitated withdrawal. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of 3.2 mg/kg per injection of morphine under a progressive ratio schedule. Daily treatment with saline or 6.4 mg/kg per day of selegiline was then administered over extinction, reinstatement and re-acquisition of morphine self-administration. To enhance or diminish the potential for psychostimulant effects, selegiline was administered either immediately prior to (pre-session) or 1 h following (post-session) extinction, reinstatement and self-administration sessions. Pre-session selegiline decreased the number of ratios completed on days 2, 3 and 4 of extinction, and decreased morphine self-administration during all four re-acquisition sessions. When administered at the same dose level, post-session selegiline decreased responding on the fourth extinction session, and was ineffective in modifying re-acquisition of self-administration. Selegiline administered by either schedule did not modify cue-induced reinstatement. Daily treatment with 6.4 mg/kg per day of selegiline did not modify self-administration of food under a progressive ratio schedule. Acute treatment with single, 6.4 mg/kg doses of selegiline attenuated naloxone-induced increases in ptosis and global withdrawal score, but did not modify any other sign of withdrawal or global withdrawal score calculated without ratings of ptosis. In conclusion, high-dose selegiline can attenuate extinction responding and morphine-reinforced behavior, and these effects may be mediated by psychostimulant metabolites.     

Relapse to morphine self-administration in morphine,methadone, and levo-alpha-acetylmethadol (LAAM) post-addict rats

Adult female Sprague-Dawley rats were prepared with chronic intravenous cannulae and cortical and muscle electrodes for recording electroencephalograms and electromyograms, respectively. They were made physically dependent on morphine by automatic intravenous injections and then trained to lever press in order to self-administer morphine on a fixed ratio (FR-20) schedule of reinforcement. Upon stabilization of daily morphine self-administration, these rats were divided into three groups of eight rats each. One group continued to self-administer morphine for an additional three weeks. In the second and third groups methadone and levo-alpha-acetylmethadol (LAAM) were substituted for morphine. The dependence state was terminated by removal of the rats from the experimental cages and placement in their home cages where they underwent spontaneous withdrawal. Each rat was then returned to its experimental cage three to four weeks later and given the opportunity to lever press and to relapse to self-administration of morphine or saline with the same FR-20 schedule of reinforcement. It was found that by day six of relapse to morphine all three groups of post-addict rats had reestablished dependence; the rats had reached mean daily morphine intakes and acquired mean daily REM sleep times that were comparable to the mean values observed during the initial period of morphine dependence. In contrast, when post-addict rats were offered saline for self-administration, extinction patterns emerged; that is, high leverpressing activity and high numbers of saline self-injections were seen during the first day of relapse. Thereafter, saline self-injections continued to decline in number, and after two weeks of relapse only one or two saline self-injections were taken per day; these rats had normal daily REM sleep times during every day of relapse. These results demonstrate that even though, in earlier studies, LAAM-dependent rats had been found to experience milder withdrawal than morphine- and methadone-dependent rats, LAAM post-addict rats in the present study exhibited an analogous tendency to relapse to morphine self-administration as morphine and methadone post-addict rats.     

Adenosine A(2) receptors inhibit morphine self-administration in rats

In the present study, the effect of adenosine receptor agonists and antagonists on morphine self-administration was investigated. Intravenous administration of morphine (0.3-3 mg/kg/injection) induced dose-dependent self-administration. The adenosine receptor antagonists, theophylline (2.5, 5, 10 mg/kg) and 3, 7-Dimethyl-1-propargylxanthine (DMPX; 0.25, 0.5, 1 mg/kg), when injected 1 h before the start of the test, reduced the number of self-administered morphine infusions. The adenosine receptor antagonists when administered in the training period (11 days) greatly increased the number of morphine infusions, however, they did not induce any response by themselves. 5'-N-ethylcarboxamido-adenosine (NECA; 0.5, 1 mg/kg) and 4-[2-[[6-Amino-9-(N-ethyl-beta-D-ribofuranuronamidosyl)-9H-purin-2 -yl ]amino] ethyl]benzenepropanoic acid (CGS21680; 0.001, 0.01, 0.025, 0. 05 mg/kg), given 1 h before the start of the test, increased morphine self-administration. Although the adenosine agonists, when injected during training period (11 days), reduced morphine self-administration. Furthermore, NECA, but not CGS21680, induced significant self-administration. The adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA; 0.01, 0.1, 0.25, 0.5 and 1 mg/kg), and the adenosine A(1) receptor antagonist, 8-phenyletheophylline (2, 4, 6, 8 mg/kg), themselves neither altered morphine infusion nor induced any response. These results indicate a role for adenosine A(2) receptors in the expression and/or development of morphine self-administration.     

Chronic opioid exposure produces increased heroin self-administration in rats

The purpose of this study was to determine the significance of chronic opioid exposure on the level of heroin self-administration in the rat. Rats were divided into morphine (M, subcutaneous morphine pellets) and placebo (P, subcutaneous placebo pellets) groups and self-administered several different doses of heroin during daily limited access 1-h sessions and prolonged access 8-h sessions. No effects on heroin self-administration occurred when the rats were implanted with morphine pellets and allowed to self-administer heroin in a limited access paradigm (1-h group). However, rats with morphine pellet implantation showed a rapid escalation (Days 0-3 post-pellet) in heroin self-administration in the more prolonged access group (8 h group) compared to placebo-pelleted animals also with 8-h access. Ultimately, placebo-pelleted 8-h exposed animals showed an escalation in heroin self-administration but this effect was delayed until Days 16-18 post-pellet. These results suggest that passive administration of morphine sufficient to produce and maintain dependence facilitates escalation in heroin intake.     

Selegiline modifies the extinction of responding following morphine self-administration, but does not alter cue-induced reinstatement, reacquisition of morphine reinforcement, or precipitated withdrawal.

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects which can prevent decreases in dopamine efflux that follow opiate withdrawal. The present study evaluated effects of selegiline treatment on morphine-seeking behavior and morphine reinforcement in Wistar rats (n = 26). In additional animals (n = 30), the ability of single doses of selegiline to modify naloxone-precipitated withdrawal was determined. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of intravenous morphine. Daily intravenous treatment with saline or 2.0mg kg(-1) doses of selegiline was then initiated and continued over 14 days during extinction, reinstatement, and reacquisition of morphine self-administration. To reduce the potential for psychostimulant effects, selegiline was administered approximately 1h following self-administration, extinction, or reinstatement sessions. In some animals (n = 23), effects of saline or selegiline administration on locomotor activity were determined following extinction sessions. Daily selegiline treatment decreased the number of ratios completed and increased response latency during extinction, without modifying these measures during reinstatement or reacquisition of morphine self-administration. Chronic selegiline treatment increased locomotor activity recorded between 4 and 7h after selegiline administration on day 7 of extinction, but otherwise did not alter locomotor activity. Pretreatment with single, 2.0mg kg(-1) doses of selegiline did not modify naloxone-precipitated withdrawal. In conclusion, pretreatment with selegiline produced only a small decrease in responding during extinction of morphine self-administration and did not modify cue-induced reinstatement of morphine-seeking behavior, reacquisition or morphine reinforcement, or precipitated withdrawal.     

Differential effects of the dopamine D2/D3 receptor antagonist sulpiride on self-administration of morphine into the ventral tegmental area or the nucleus accumbens

RATIONALE: The involvement of dopamine neurotransmission in opiate reward remains controversial. OBJECTIVE: To investigate the dopaminergic basis of opiate reward by comparing the effect of systemic injection of the D2/D3 antagonist sulpiride on morphine self-administration (ICSA) into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) METHODS: BALB/c mice were unilaterally implanted with a guide cannula 1.5 mm above either the VTA or the NAc. On experimental days, a stainless-steel injection cannula was inserted via the guide cannula, and mice were trained to discriminate the arm of a Y-maze reinforced by intracranial morphine microinjections (6.5 pmol or 65 pmol/50 nl) from the neutral arm (no injection). Following acquisition of morphine ICSA, the dopamine D2/D3 receptor antagonist sulpiride (50 mg/kg, i.p.) was administered 30 min before testing. RESULTS: Sulpiride produced an extinction of intra-VTA, but not intra-NAC, morphine self-administration. Extinction in VTA subjects was followed by a re-appearance of ICSA, although mice continued to receive sulpiride injections. Extinction was re-induced when the dose of sulpiride was raised to 100 mg/kg, whereas no effect of this dose was detected on intra-NAc self-administration. CONCLUSION: Maintenance of intra-VTA, but not intra-NAc, morphine self-administration depends acutely on D2/D3 receptors. However, the deleterious effect of sulpiride on intra-VTA morphine self-administration is transient. Reappearance of ICSA under neuroleptic treatment in VTA subjects may be related to the sensitization effect of intra-VTA morphine infusions, combined with an upregulation of D2/D3 receptors and alterations of DA metabolism by repeated sulpiride injections.     

Effects of perinatal exposure to delta 9-tetrahydrocannabinol on operant morphine-reinforced behavior

The present study examined the effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) when administered during the perinatal period on morphine self-administration in adulthood. To this end, pregnant Wistar rats were daily exposed to Delta(9)-THC from the fifth day of gestation up to pup weaning, when they were separated by gender and left to mature to be used for analyses of operant food- and morphine-reinforced behavior in a progressive ratio (PR) schedule. We also analyzed dopaminergic activity (DOPAC/DA) in reward-related structures during specific phases of the behavioral study. In both reinforcement paradigms, food and morphine, females always reached higher patterns of self-administration than males, but this occurred for the two treatment groups, Delta(9)-THC or vehicle. These higher patterns measured in females corresponded with a higher DOPAC/DA in the nucleus accumbens prior to the onset of morphine self-administration in comparison to males. Interestingly, DOPAC/DA was lower in Delta(9)-THC-exposed females compared to oil-exposed females and similar to oil- and Delta(9)-THC-exposed males. In addition, Delta(9)-THC-exposed females also exhibited a reduction in DOPAC/DA in the ventral tegmental area, which did not exist in males. All these changes, however, disappeared after 15 days of morphine self-administration and they did not reappear after 15 additional days of extinction of this response. Our data suggest that females are more vulnerable than males in a PR schedule for operant food and morphine self-administration; perinatal Delta(9)-THC exposure is not a factor influencing this vulnerability. The neurochemical analysis revealed that the activity of limbic dopaminergic neurons prior to morphine self-administration was higher in females than males, as well as that the perinatal Delta(9)-THC treatment reduced the activity of these neurons only in females, although this had no influence on morphine vulnerability in these animals.     

Effect of propranolol on antinociceptive, tolerance- and dependence-producing properties of morphine in rodents and monkeys.

Since an abstinence syndrome may accompany the injection of opioids in addicts pretreated with propranolol the morphine antagonistic properties of this compound were investigated. Racemic propranolol did not significantly affect the antinociceptive ED50 of morphine in rodents and neither precipitated abstinence in morphine-dependent monkeys nor exacerbated the syndrome in 24 hr withdrawn monkeys. Multiple doses of propranolol did not alter the development of physical dependence on morphine in monkeys. Clinical narcotic antagonism would not be predicted from this profile. Evidence for a possible propranolol-morphine interaction came from studies using the mouse tail flick test. Thus, after 8 injections of propranolol (over 4 days) mice were tolerant to normally effective doses of morphine. Concurrent injections of naloxone antagonised this effect. When propranolol and morphine were administered concurrently the morphine ED50 (on day 5) was twice that of the group receiving morphine alone. Similar results were obtained with d-propranolol; practolol had a neutral effect.     

Intravenous self-administration of an enkephalin analog, EK-399, by rats

The novel enkephalin analog Tyr-D-Met (O)-Gly-EtPhe-NHNHCOCH3 . AcOH (EK-399) was examined for psychic dependence potential by a self-administration test in rats. Five groups of experimentally naive rats were given an intravenous dose of EK-399 (0.032, 0.064 or 0.125 mg/kg), morphine HCl (0.5 mg/kg) or cocaine HCl (0.5 mg/kg) via a cannula implanted in the jugular vein when they pressed a lever. No animals initiated self-administration of EK-399 in the first 3 or 4 weeks of the experimental period. In contrast, almost all of the animals receiving morphine or cocaine initiated a high rate of self-administration within 1 or 2 weeks. However, when the doses of EK-399 were subsequently decreased, 4 of the 10 animals increased their rate of self-administration slightly. Furthermore, an increase in the rate of EK-399 self-administration was observed in 1 of 4 rats made physically dependent on EK-399. These results suggest that EK-399 has a very weak reinforcing effect on drug-taking behavior, which is slightly enhanced by the development of physical dependence on the compound, and it may possess a low psychic dependence potential.     

A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats

Rationale and objectives In preliminary studies, we observed that opiate dependent rats self-administered only a small number of morphine injections under a PR (progressive ratio) schedule developed to study psychostimulant self-administration. Therefore, a new schedule was developed to support morphine self-administration by incrementing response requirements in a relatively gradual manner. The present study compared morphine self-administration under a commonly used PR schedule to self-administration maintained by our modified PR schedule. Methods After pretreatment with non-contingent morphine, rats acquired self-administration under fixed-ratio (FR) schedules of intravenous morphine delivery. Morphine-maintained behavior was evaluated under a standard PR schedule (termed "PR3–4", because the third response requirement was four lever presses), and our modified PR schedule (termed "PR9–4", because the ninth response requirement was four lever presses). The PR9–4 schedule was also evaluated for self-administration of morphine doses of 0.001–3.2 mg/kg per injection. Results The number of ratios completed for morphine self-administration on the PR9–4 schedule, but not the PR3–4 schedule, exceeded values obtained during extinction. Dose-related increases in completed ratios occurred for morphine self-administration on the PR9–4 schedule, with stable patterns emerging after three sessions. A relatively flat dose-response relationship was observed, which did not increase monotonically with morphine dose. Morphine self-administration on the PR9–4 schedule decreased mean inter-injection interval and prolonged the duration of responding during 6-h sessions. Conclusions In the present study, a schedule that incremented response requirement gradually (PR9–4) supported reliable self-administration across a range of morphine doses.     

Effects of levo-alpha-acetylmethadol (LAAM) on morphine self-administration in the rat

Rats bearing cerebrocortical electrodes for recording the electroencephalogram (EEG) were rendered tolerant to and physically dependent on morphine and subsequently trained to self-administer morphine (10 mg/kg/injection) through a chronic intravenous cannula. Morphine was available for selfadministration 24 h/day. Once morphine intake had stabilized (10–12 injections/day), levo-alpha-acetylmethadol (LAAM) was administered noncontingently via a chronic intragastric (IG) cannula as a single daily dose of either 1 or 4 mg/kg. These morphine self-administering rats were maintained on daily LAAM treatment for 12 consecutive days. Analysis of the patterns of lever pressing, morphine self-injections, and sleepawake behavior revealed that daily IG administration of LAAM effectively suppressed morphine self-administration. The 1 mg/kg dose of LAAM reduced morphine intake by 30%–50%, while 4 mg/kg produced an 80%–90% decrease. The reduction in morphine self-administration occurred in the absence of overt signs of narcotic withdrawal, behavioral toxicity, or disruption of sleep-awake behavior in these rats. Termination of LAAM maintenance resulted in a gradual return of lever pressing and morphine intake to pre-LAAM levels.Preliminary report of this study appeared in The Pharmacologist 21, 226 (1979)     

L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats; Insights towards selegiline's mechanism of action

Selegiline is an inhibitor of type B monoamine oxidase (MAO) with psychostimulant effects that can decrease morphine-reinforced and non-reinforced responding. The present study was undertaken to compare the effects of MAO inhibition and treatment with L-methamphetamine, the major psychostimulant metabolite of selegiline, on these behaviors. After rats acquired a stable pattern of morphine self-administration under a progressive ratio schedule, chronic treatment was initiated with vehicle, L-methamphetamine, clorgyline (a selective inhibitor of MAO-A), or rasagiline (a selective inhibitor of MAO-B); with both MAO inhibitors administered at a dose selective for one MAO isoform and a higher dose that inhibited both isoforms. Rats were evaluated for up to four cycles of opiate dependence maintained by morphine self-administration and withdrawal during which extinction responding was recorded. Most behavioral measures (92.4%) did not differ in animals evaluated during an initial and subsequent cycles of dependence and withdrawal. All active treatments attenuated non-reinforced responding during extinction. Morphine reinforcement was also decreased by each of the three active treatments, but greater and more prolonged effects were observed following inhibition of MAO-B with rasagiline. Responding during either cue- or morphine-induced reinstatement was attenuated by either clorgyline or rasagiline administered at nonselective doses, but not by either compound administered at selective dose levels. Treatment with L-methamphetamine did not produce significant effects on cue-induced reinstatement, but decreased non-reinforced responding during morphine-induced reinstatement. These findings indicate that morphine reinforcement and different non-reinforced behaviors differ greatly in their susceptibility to modification by psychostimulant treatment or MAO inhibition.     

Characterization of withdrawal syndrome of morphine-dependent rats prepared by intermittent infusion technique

The morphine withdrawal syndrome was studied in rats which had been made dependent on morphine administered by the intermittent infusion technique. Rats made rapidly dependent on morphine by an hourly infusion of 0.12–4 mg/kg/h showed a withdrawal syndrome when they were abruptly withdrawn, after infusion for 7 days, or when they were challenged by naloxone after infusion for 4 days. Abruptly withdrawn rats showed a marked weight loss and other mild symptoms. The weight loss seems mainly due to anorexia, partly because it was attenuated by IV feeding throughout the withdrawal and partly because the fasted rats showed a weight loss comparable to the withdrawn rats. The naloxone-precipitated withdrawal syndrome showed characteristics, which, from their time course of incidence and their modulation by other drugs, were tentatively classified into three groups; motor excitation, cholinergic signs, and others. These groups and their interrelationships were discussed. All characteristics were suppressed by deep anesthesia with ether or pentobarbital. A sudden fall in blood pressure was indicated in the anesthetized morphine-dependent rats immediately after the naloxone challenge. This suggests that the intrinsic withdrawal syndrome was progressing even under anesthesia.     

Agmatine blocks acquisition and re-acquisition of intravenous morphine self-administration in rats

Our previous studies showed that agmatine inhibits morphine-induced conditioned place preference, locomotor sensitization and drug discrimination in rats. In the present study, we investigated the effects of agmatine on intravenous morphine self-administration in rats. At a dose of 80 mg/kg/infusion, agmatine did not substitute for intravenous morphine (0.5 mg/kg/infusion) self-administration, suggesting that agmatine itself has no reinforcing effect. However, pretreatment with agmatine (40 or 80 mg/kg, i.g.) significantly inhibited the acquisition of intravenous morphine self-administration as assessed by the nose-poke response and morphine intake. The mean number of days required to meet the acquisition criteria for intravenous morphine self-administration was significantly prolonged. After acquisition of intravenous morphine self-administration, chronic administration of agmatine (40 or 80 mg/kg × 30 days, bid, i.g.) during the extinction period significantly prevented the re-acquisition of intravenous morphine self-administration. The ability of agmatine to inhibit the acquisition and re-acquisition of intravenous morphine self-administration suggests a possible use of agmatine in the treatment of opioid dependence.