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PubMed1996

Phasic firing of single neurons in the rat nucleus accumbens correlated with the timing of intravenous cocaine self-administration.

To examine potential neural mechanisms involved in cocaine self-administration, the activity of single neurons in the nucleus accumbens of rats was recorded during intravenous cocaine self-administration. Lever pressing was reinforced according to a fixed-ratio 1 schedule. On a time base comparable to the interinfusion interval, half the neurons exhibited phasic firing patterns time locked to the cocaine reinforced level press. For almost all neurons, this pattern consisted of a change in firing rate postpress, typically a decrease, followed by a reversal of that change. The postpress change was closely related to the lever press. Typically, it began within the first 0.2 min postpress and culminated within the first 1.0 min postpress. For a small portion of responsive neurons, the reversal of the postpress change was punctate and occurred within 1-3 min of either the last lever press or the next lever press so that firing was stable during much of the interinfusion interval. For the majority of neurons, the reversal was progressive; it began within 2 min after the previous level press, and it was not complete until the last 0.1-2.0 min before the next lever press. The duration of this progressive reversal, but not of the postpress change, was positively correlated with the interinfusion interval. Thus, in addition to exhibiting changes in firing related to the occurrence of self-infusion, the majority of neurons also exhibited progressive changes in firing related to the spacing of infusions. In a structure that has been shown to be necessary for cocaine self-administration, such a firing pattern is a likely neurophysiological component of the mechanism that transduces declining drug levels into increased drug-related appetitive behavior. It is, thus, a neural mechanism that may contribute to compulsive drug-maintained drug taking.

Animals↗
PubMed2001

Influence of a conditioned light stimulus on cocaine self-administration in rats.

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.

Animals↗
PubMed1996

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement.

Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09-1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Influence of buprenorphine, butorphanol and nalbuphine on the initiation of intravenous cocaine self-administration in drug naive mice.

The influence of different mixed mu-kappa-opioid receptor agonists-antagonists on cocaine reinforcement was studied using the method of initiation of intravenous cocaine self-administration in naive mice. Self-administration of cocaine was readily initiated according to an inverted U-shaped unit dose-response curve. Buprenorphine, butorphanol and nalbuphine tested against the optimal unit dose of cocaine (0.8 microg per infusion), inhibited initiation of cocaine self-administration in a dose-dependent manner. When tested against a scale of cocaine unit doses (0.2 -1.6 microg per infusion) buprenorphine (0.1 mg/kg, s.c.) and nalbuphine (2 mg/kg, s. c.) produced a shift of the optimal cocaine dose from 0.8 to 0.4 microg/inf, while butorphanol (1 mg/kg, s.c.) shifted the optimal unit dose of cocaine to the right along the cocaine unit doses axis. Co-administration of naloxone (0.1 mg/kg, s.c.) significantly reduced the effect of buprenorphine but failed to influence the effect of nalbuphine and butorphanol on cocaine intake. Taken together, these results suggest that nalbuphine is capable of affecting cocaine's reinforcing properties in the same manner as buprenorphine during the initiation phase of cocaine self-administration behavior, while butorphanol causes the opposite effect. Although the exact opioid profile of action of the mixed opioid receptor agonists-antagonists is as yet not precisely known, the present findings suggest that multiple opioid receptor systems (i.e. mu and kappa) play a role in reinforcing properties of cocaine and that a co-operative interaction between mu- and kappa-opioid systems may be of importance during initiation of cocaine self-administration.

Analysis of Variance↗
PubMed1998

Corticosterone facilitates the acquisition of cocaine self-administration in rats: opposite effects of the type II glucocorticoid receptor agonist dexamethasone.

The effect of corticosterone on the acquisition of cocaine-seeking behavior was investigated in rats using ascending dose-response curves for intravenous cocaine self-administration. Rats pretreated daily with corticosterone (2.0 mg/kg i.p.) acquired cocaine self-administration at a lower dose compared with vehicle-treated controls. In contrast, daily corticosterone pretreatment did not alter food-maintained responding. Cocaine self-administration was not affected by the type I (mineralocorticoid) receptor agonist, aldosterone (100 microgram/kg). However, rats treated with the type II (glucocorticoid) receptor agonist, dexamethasone (10 or 100 microgram/kg) did not acquire self-administration at any dose tested. The 100 microgram/kg dose of dexamethasone attenuated food-reinforced behavior and decreased body weight, but these effects were not observed with the 10 microgram/kg dose. Dexamethasone dose-dependently attenuated the plasma corticosterone response to self-administered infusions or intraperitoneal injections of cocaine, indicating that the ability of dexamethasone to block cocaine-induced corticosterone secretion may have contributed to its effects on self-administration. Administration of aldosterone (100 microgram/kg) together with 10 microgram/kg dexamethasone restored self-administration to the level of vehicle-treated rats, suggesting that type I receptor occupation by corticosterone may be required for the acquisition of this behavior. These results indicate that stress-induced corticosterone secretion may provide a substrate through which stressors interact with cocaine reinforcement. Additionally, the finding that dexamethasone blocks the acquisition of cocaine self-administration may be relevant to the development of novel approaches to the treatment of cocaine addiction.

Adrenal Glands↗
PubMed1999

Effects of calcium channel blockade on intravenous self-administration of ethanol in rats.

In the present study the involvement of voltage-operated calcium channels (VOCCs) in the acquisition and maintenance of operant i.v. ethanol (EtOH) self-administration was investigated in rats. Rats readily learned to self-administer EtOH (unit dose range: 0.5-4% v/v) within five daily 2-h sessions, when infusions were made contingent upon nose-poking in a hole containing infrared sensors. Response rate was related to the EtOH concentration in an inverted U-shaped manner, the maximal rate and intake being observed at a unit dose of 1% v/v (0.27 mg EtOH/infusion). Self-administration of EtOH appeared to be behaviorally specific, as responding in the reinforced hole did not coincide with increased responding in a nonreinforced hole. Daily treatment with the dihydropyridine VOCC blocker nimodipine (2.5-20 mg/kg, i.p., t-15 min) dose-dependently attenuated acquisition of EtOH self-administration; the 5 mg/kg dose resulting in a partial, and the 10 and 20 mg/kg doses in a complete prevention of i.v. self-administration behavior. The effects of nimodipine (2.5-5.0 mg/kg) were considered to be relatively specific, as an inhibition of the reinforced responding could be demonstrated in the absence of a significant effect on nonreinforced responding. When tested in rats showing stable self-administration behavior (unit dose: 1% v/v EtOH), nimodipine showed biphasic dose-response effects; with 2.5 and 5 mg/kg resulting in a mild increase, and 10 and 20 mg/kg resulting in a decrease of self-administration behavior, respectively. The present study suggests that blockade of VOCCs attenuates the reinforcing stimulus effects of EtOH; and, as such, the data may offer an explanation for the previously reported EtOH intake-reducing effects of dihydropyridine calcium channel ligands obtained in two-bottle choice paradigms. Dihydropyridine derivatives, such as nimodipine, may therefore offer an interesting approach to the pharmacotherapy of alcoholism.

Animals↗
PubMed1997

Binge cocaine self-administration by humans: smoked cocaine.

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.

Adult↗
PubMed1997

Acquisition of i.v. amphetamine and cocaine self-administration in rats as a function of dose.

The effect of dose on the acquisition of i.v. amphetamine and cocaine self-administration was examined. Three unit doses of amphetamine (0.03, 0.06 and 0.12 mg/kg) and three unit doses of cocaine (0.05, 0.2 and 0.8 mg/kg) were tested in separate groups of ten (amphetamine) or 13 (cocaine) rats. Autoshaping methods were used to train rats to press a lever that resulted in drug infusion under a fixed-ratio (FR) 1 schedule. A daily 6-h autoshaping component non-contingently delivered 60 infusions according to a 60-s random time schedule with ten infusions delivered during the first half of each h. Each day autoshaping sessions were followed by a 6-h self-administration session. The criterion for acquisition was a 5-day period during which a daily mean of 100, 50 or 25 infusions for the three amphetamine doses and 400, 100 or 25 infusions were earned during the 6-h self-administration period for the three cocaine doses, respectively. As dose increased, more rats per group acquired drug self-administration and the mean number of days to meet the acquisition criterion decreased. The percentage of rats acquiring amphetamine self-administration increased with dose and ranged from 80 to 100%. Only one rat at the lowest cocaine dose met the acquisition criterion, but 100 percent of the rats at the two higher doses acquired. During the last 2 days of acquisition, mean infusions decreased and mean drug intake (mg/kg) increased as dose increased. On the last day of acquisition, the time course of infusions during the 6-h self-administration component was characterized by a steady rate of infusions per hour, and number of infusions was inversely related to dose. These findings indicate that the initial available dose of a drug is an important determinant of the rate and probability that successful acquisition will occur.

Animals↗
PubMed2002

Voluntary self-administration of both morphine and cocaine by rats.

Voluntary self-administration of cocaine and/or morphine was studied in rats. Male rats were offered water bottles or bottles containing either cocaine or morphine, both cocaine and morphine (combination) or cocaine and morphine as a mixture. Alternating the three drug-containing bottles had no effect on drug choice. When offered alone, rats consumed about 12 +/- 8 mg/kg/day of cocaine or 0.3 +/- 0.3 mg/kg/day of morphine. When both drugs were offered in combination, they consumed a higher amount of cocaine (22 +/- 7), but the same amount of morphine (0.4 +/- 0.3). Availability of cocaine/morphine mixture kept morphine consumption constant (0.3 +/- 0.1), but markedly decreased cocaine intake (0.3 +/- 0.2). Addition of saccharin to the drug solutions only slightly increased consumption of both drugs, whereas saccharin added as a competitor or distracter to the drug solution reduced cocaine but not morphine self-administration. Animals showed wide interindividual variations but surprisingly small intraindividual variations in self-administration of cocaine or morphine under all conditions. No correlation between cocaine and morphine intake was apparent in the combination situation. Forcing animals first with cocaine had no effect on subsequent intake of cocaine or morphine presented in combination. However, forcing animals first with morphine subsequently increased morphine and reduced cocaine intake. In conclusion, morphine intake was the same if offered alone, in combination or as a mixture, whereas cocaine intake increased during a combination but decreased in the mixture situation. Cocaine pre-exposure had no effect on subsequent voluntary morphine or cocaine choice, whereas morphine pre-exposure increased subsequent voluntary morphine but decreased cocaine intake. These results suggest the possibility of two reward centers, one for each drug, the morphine center exerting a dominant influence over the cocaine center.

Administration, Oral↗
PubMed1986

Alcohol and food self-administration by female Macaque monkeys as a function of menstrual cycle phase.

Female Macaque monkeys were trained to self-administer food (1 g banana pellet) and alcohol (0.12 g/kg/inj IV) in an operant paradigm. Alcohol and food-maintained responding were controlled by a second order schedule of reinforcement FR 4 (VR 16:S) that required an average of 64 responses for delivery of one food pellet or alcohol injection. Alcohol self-administration at average dose levels of 0-1.5, 1.5-3.0, 3.0-4.0 and 4.0 to 5.5 g/kg/day did not vary systematically as a function of menstrual cycle phase in a sample of 30 menstrual cycles. But alcohol self-administration was significantly lower during menstruation (p less than 0.002) in comparison to mid-cycle or the late luteal phase. Monkeys that self-administered high doses of alcohol (3.0-5.5 g/kg/day) also showed stable patterns of food self-administration across the menstrual cycle. Monkeys that self-administered low to moderate doses of alcohol (0-3.0 g/kg/day) showed a consistent decrease in food self-administration at mid-cycle. The implications of these data for hypotheses concerning estrogen modulation of food intake and the influence of the premenstruum on alcohol self-administration are discussed.

Animals↗
PubMed2000

Nornicotine pretreatment decreases intravenous nicotine self-administration in rats.

RATIONALE: Nicotine has been shown to be effective as a treatment for reducing tobacco dependence. However, few studies have examined the effect of other nicotinic agonists to determine if they can also decrease nicotine self-administration. OBJECTIVE: The present study determined if nornicotine, a tobacco alkaloid and major nicotine metabolite in brain, could reduce nicotine self-administration in rats. METHODS: Each rat was prepared with an indwelling jugular catheter and trained to self-administer intravenous nicotine (0.03 mg/kg per infusion). After nicotine self-administration stabilized, rats were pretreated with either (-)-nicotine (0, 0.1, 0.3, and 1.0 mg/kg free base) or (+/-)-nornicotine (0, 1, 3, 5.6, and 10.0 mg/kg free base) and assessed for nicotine self-administration. A separate group of rats was maintained on sucrose reinforced responding and pretreated with nornicotine to determine the specificity of the pretreatment effect. In another group of rats, the time course of the pretreatment effect of either (-)-nicotine (0.56 and 1.0 mg/kg) or (+/-)-nornicotine (5.6 and 10.0 mg/kg) was examined. RESULTS: Nicotine and nornicotine each produced a dose-dependent decrease in nicotine self-administration. Furthermore, the decrease in nicotine self-administration in response to the 5.6 mg/kg nornicotine pretreatment was specific to nicotine self-administration, as this dose did not decrease sucrose reinforced responding in tolerant animals. In addition, within the dose range tested, the suppressant effect of nornicotine had a two-fold longer duration than that of nicotine (120 versus 60 min). CONCLUSION: These results suggest that nornicotine may be an effective treatment for tobacco dependence.

Animals↗
PubMed1992

Cocaine self-administration: pharmacology and behavior.

I would like to stress several major points. The first is that CNS pharmacology is important in drug self-administration. In the case of cocaine, the necessary effect seems to be blockade of reuptake of DA rather than blockade of reuptake of NE or 5-HT or local anesthetic effects. An action of that DA on the D2 subtype of DA receptors appears to play an important role. The second point is that increased DA in synapses in the CNS is not sufficient to explain drug-maintained behavior. The schedule of reinforcement critically determines rates and patterns of drug-maintained behavior. Barrett (this volume) has presented convincing evidence that behavioral history, i.e., the sequential exposure to alternative behavioral conditions, can dramatically alter drug effects. What I hope to have made clear is that the simultaneous opportunity to engage in other behaviors can dramatically alter the reinforcing effects of drugs. Indeed, under appropriate conditions, a drug can function as both a positive and a negative reinforcer simultaneously in the same animal. The drug-choice studies I have described emphasize the dynamic nature of the interaction between behavioral and pharmacologic variables. The frequency of choosing to self-administer cocaine varied with the magnitude of the dose of cocaine (a pharmacologic variable) and the magnitude of an alternative positive reinforcer that was available (a behavioral variable). Increasing the magnitude of the alternative reinforcer decreased cocaine choice, but increasing the magnitude of the cocaine dose reestablished drug preference. In a sense, this is not a surprising result. The rhetoric of the times, however, would have it that drug self-administration, particularly cocaine self-administration, is somehow a different class of behavior that is not subject to the usual laws governing the behavior of organisms. As our understanding of drug self-administration evolves, however, that position will become increasingly untenable. These experimental findings challenge simple neurobiological assumptions about the determinants of drug self-administration. Clearly, a reinforcing effect, like any other behavioral effect of a drug, is not simply an immutable effect of a pharmacologic property of the drug. Given the pivotal role of reinforcing effects in drug abuse, this realization is critical to a comprehensive understanding of drug abuse. Any complete neurobiological model of drug abuse will have to account for these effects. Apparently, increasing the concentration of DA in synapses in the brain is not sufficient to account for drug-maintained behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Effect of 5-HT(1B) receptor ligands on self-administration of ethanol in an operant procedure in rats.

Recent evidence suggests that 5-HT(1B) receptor activation modifies ethanol's reinforcing, intoxicating and discriminative stimulus effects. The present study further explored the role played by 5-HT(1A/1B) receptors by examining their influence on oral ethanol self-administration. Male Wistar rats were trained on an FR 4 schedule to obtain a reinforcer of 0.1 12% w/v ethanol solution. Once responding was stable, the effect of the 5-HT(1A/1B) agonist RU24969 alone and in combination with the 5-HT(1B) antagonist GR127935 or the 5-HT(1A) antagonists (+) WAY100135 and (+) WAY100635 was assessed. The effect of RU24969 on ethanol's pharmacokinetic profile and on operant oral saline self-administration was also examined to assess if alterations in oral ethanol self-administration were due to nonspecific effects on level pressing. For comparison, we examined the effect of another 5-HT(1A/1B) agonist, CGS12066B, on oral ethanol self-administration. Both RU24969 (0.1 to 1 mg/kg) and CGS12066B (0.1 to 1 mg/kg) significantly suppressed oral ethanol self-administration. Administration of GR127935 (1 mg/kg), significantly reversed the effects elicited by RU24969, whereas neither WAY100635 (1 mg/kg) nor (+)WAY100135 (1 mg/kg) had any effect. The effects of lower doses of RU24969 on oral ethanol self-administration were selective as oral saline self-administration and blood ethanol levels were not altered by these doses. These data demonstrate that 5-HT(1B) receptor activation suppresses oral ethanol self-administration. These studies provide further evidence that 5-HT(1B) receptors play a modulatory role in ethanol's behavioral effects.

Alcohol Drinking↗
PubMed1997

Alcohol self-administration: further examination of the role of dopamine receptors in the nucleus accumbens.

One of the functions of the mesolimbic dopamine (DA) system is to regulate the process of reinforcement, a process that is thought to influence drug self-administration. This study tested the effects of centrally administered DA receptor ligands on ethanol self-administration behavior. Long-Evans rats were trained to lever press on a fixed-ratio 4 schedule of ethanol (10% v/v) reinforcement. DA agonists and antagonists were then bilaterally microinjected (0.5 microliter/side) into the nucleus accumbens (N Acc) 10-min before sessions to test for effects on the onset, maintenance, and termination of ethanol self-administration. Infusions of the D1-like agonist SKF 38393 (0.03 to 3.0 micrograms) produced no effect on ethanol self-administration. The D1-like antagonist SCH 23390 (0.5 to 2.0 micrograms) reduced total responding by decreasing the time course of self-administration without altering response rate. The D2-like agonist quinpirole produced a biphasic effect on self-administration. Quinpirole (1.0 microgram) increased total responses and response rate, whereas higher doses (4.0 to 10.0 micrograms) decreased total responding as a result of early termination. The D2-like antagonist raclopride (0.1 to 1.0 microgram) reduced total responding by decreasing time course and response rate. Co-administration of either SKF 38393 or SCH 23390 with quinpirole prevented the behavioral effects observed with the low doses of quinpirole. Thus, in the N Acc either increased activation of D1-like receptors or their blockade can affect the expression of the behavioral effects of the D2-like agonist. This suggests that some intermediate level of D1 activation is required to observe the D2 effect. The decreases in total responding produced by raclopride were enhanced by co-administration of SKF 38393, but not altered by SCH 23390, thus suggesting that D1-like and D2-like receptors in the N Acc interact in the regulation of ethanol self-administration in a manner similar to their interactive regulation of other behaviors.

Alcohol Drinking↗
PubMedDate not supplied

Muscimol injected into the medial prefrontal cortex of the rat alters ethanol self-administration.

The role of the rodent prefrontal cortex in the regulation of ethanol self-administration has not been widely explored. Understanding the role of GABAergic transmission in this area in relation to ethanol self-administration is important, as the GABA system may be one of several targets for alcohol's actions in the brain. Rats were initiated to drink 10% ethanol from a dipper using a sucrose-substitution procedure. When baseline behavior was stable, bilateral microinjections of muscimol (a GABA(A) agonist) into the prefrontal cortex were tested at doses of 17.5, 30, 100 and 300 ng/microl. Ethanol self-administration was decreased by approximately 40% at the 30-ng dose and 30% at the 100-ng dose. No effects were observed at either the 17.5- or 300-ng dose. The effect on the pattern of self-administration was to shorten the size of the first run of drinking without affecting the rate of drinking. The hypothesis is put forward that the injections increased glutamatergic output to the nucleus accumbens (nAcc) that in turn increased accumbens output. This increased output is proposed as similar to the effects of dopaminergic (DA) manipulations within this system.

Alcohol Drinking↗
PubMed2001

Satiety threshold regulates maintained self-administration: comment on Lynch and Carroll (2001).

In this commentary the authors argue that the satiety threshold is the only mechanism that is sufficient and necessary to explain the regulation of maintained self-administration. The other mechanisms have been proposed mainly because of 2 sources of confusion surrounding the self-administration paradigm: the failure to distinguish between separate phases of a self-administration session and the assumption that positive reinforcement underlies drug self-administration. The authors of this commentary emphasize that the direct effects and aversion mechanisms have been proven to be untenable for the reasons reviewed by W. J. Lynch and M. E. Carroll (2001) and that the "ascending limb" of the dose-response curve is an experimental artifact. These ideas have persisted only to salvage a role for positive reinforcement in drug self-administration. The authors conclude that reinforcement is not relevant to the regulation of maintained self-administration.

Dose-Response Relationship, Drug↗
PubMed2004

Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys.

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(-)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S+-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.

Animals↗