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Joyce Colussi-Mas, Richard J. In laboratory animals, exposure to priming injections of 3,4-methylenedioxymethamphetamine MDMA produced drug seeking following extinction of MDMA self-administration. This study aimed to evaluate whether the magnitude of drug seeking was related to latency to acquisition of MDMA self-administration and increases in striatal dopamine, as measured by in-vivo microdialysis. Twelve of the 20 rats acquired self-administration within the temporal limits of the study and the latency to meet the criterion ranged from 9 d to 37 d. An experimenter-administered injection of MDMA For rats that met the criterion, drug seeking was negatively correlated with the number of days to self-administer the criterion number of MDMA infusions and positively correlated with MDMA-produced dopamine in the dorsal striatum. Importantly, MDMA-produced dopamine overflow was greater for the rats that met the criterion. These findings suggest that drug seeking is influenced by initial sensitivity to the reinforcing effects of MDMA and to drug-produced increases in striatal dopamine. Drug abuse is a chronic relapsing disorder characterized by a compulsive cycle of drug seeking and drug taking. In laboratory studies of abusers, craving and drug seeking have been produced by exposure to cues associated with self-administered drugs as well as by exposure to the drug itself Childress et al. Prevalence of use is, however, increasing worldwide and several investigators have recently reported that some users met criteria for abuse and dependence Abdallah et al. A number of studies have demonstrated that MDMA is self-administered by laboratory animals Banks et al. Drug seeking has also been demonstrated following MDMA self-administration in laboratory rats exposed to cues that had been paired with self-administered MDMA Ball et al. Some studies have suggested that the initial response to the reinforcing effects of drugs of abuse is a good predictor of subsequent drug seeking Mantsch et al. Accordingly, an increase in dopamine DA release was observed in the dorsal but not the ventral striatum during drug seeking Ito et al. In the present study, we aimed to determine whether the drug-seeking behaviour produced by exposure to a priming injection of MDMA was related to sensitivity to the reinforcing properties of MDMA and MDMA-produced increases in dorsal striatal DA levels. Self-administration sessions were run daily until rats self-administered a criterion number of infusions. Drug-seeking tests were conducted only after the criterion number of infusions had been self-administered. In this manner, the design ensured that drug seeking was not confounded by different levels of exposure to self-administered MDMA. Adult male Sprague—Dawley rats weighing — g were used. The rats were bred in the vivarium at Victoria University of Wellington and were housed in groups of four until they reached — g. All tests were conducted during the light portion of the cycle beginning hours. Food and water were available ad libitum except during testing. All procedures were approved by the Animal Ethics committee at Victoria University. All doses refer to the salt weight. The external jugular vein was isolated and the tubing was inserted and fixed in place. The distal end of the tubing was passed subcutaneously to an exposed portion of the skull. The Silastic tubing was fitted onto a 2-cm length of gauge stainless-steel tubing and the entire assembly was then secured to the skull using jeweller's screws embedded in acrylic dental cement. A dummy cannula extending 0. Self-administration testing began 5—7 d following surgery. Each day following surgery, the catheters were infused with 0. The active dialysis length of the probe was 4 mm. In-vitro probe recovery was Self-administration tests were conducted at the same time each day in operant conditioning chambers Med Associates, ENV, USA equipped with two levers see Schenk et al. Daily test sessions were 2 h duration on Monday—Friday. Each session began with an experimenter-administered infusion of the dose of MDMA that was available for self-administration in order to displace the solution that was in the line; the initial infusion did not actually result in the delivery of MDMA to the rat. Thereafter infusions were delivered according to a fixed ratio 1 schedule of reinforcement. On Sunday of each week, each rat received an intravenous infusion of 5. An immediate loss of the righting reflex confirmed catheter patency. Initially, responding was reinforced by delivery of 1. For rats that met this criterion number of infusions within a d period, the dose was reduced to 0. The number of days required to self-administer the initial 90 infusions and the subsequent infusions was obtained for each rat. Of the 20 rats that completed the experiment, 12 met the initial criterion number of 90 responses within the d cut-off range 6—23 d and were tested for an additional period at the 0. Eight rats failed to meet the criterion for self-administration within 25 d and were removed from the operant chambers after 25 d of self-administration at the 1. The group that met the criterion for self-administration did not receive significantly greater exposure to the operant chambers because they met the criterion for acquisition quite rapidly. Thus, the number of test days for the rats that met the criterion ranged from 9 to However, an additional group was tested to ensure that any differences in drug seeking could not easily be attributed to exposure to substantial quantities of self-administered MDMA while in the self-administration chambers that were subsequently used to measure drug seeking. Of the seven yoked rats, six were yoked to self-administering rats that met the criterion range of days at 1. All three groups rats that met the criterion, rats that did not meet the criterion, and yoked rats were subsequently tested to determine MDMA-produced drug seeking. Following acquisition of MDMA self-administration or yoked-administration, drug-seeking tests were conducted. These tests were comprised of three phases conducted during a 5-d period, as we have previously reported Schenk et al. Phase 1 days 1 and 2 consisted of the last 2 d of self-administration the dose of 0. The yoked rats did not self-administer MDMA and so there are no data from phase 1 for this group even though they were in the self-administration chambers and received passive infusions of MDMA. At the end of the session on the second day of phase 2 day 4 , a microdialysis probe was inserted into the guide cannula of the rats that met or did not meet the criterion of acquisition of self-administration. The following day phase 3 , three baseline samples were collected at min intervals in tubes containing 2. The rat was then moved into the self-administration chamber and injected with saline i. During phase 3, only vehicle solution was available for self-administration but the stimulus light that had been paired with self-administered MDMA was illuminated with each response on the active lever. Dialysis samples were collected and responding was measured at min intervals for 2 h following the injection of saline and for 6 h following the injection of MDMA. The microdialysis data of three rats were missing because of technical problems during the sample collection outlet tubing chewed or broken. Drug-seeking tests in yoked control rats were conducted the same way as above but only behavioural data were collected. Thus, behavioural data were collected from 27 rats 12 rats that met the criterion, eight rats that did not meet the criterion, and seven yoked rats and microdialysis data from 17 rats 11 that met the criterion, and six that did not meet the criterion. Chromatograms were acquired with ChemStation software and peak heights of samples were compared to peak heights of standards with known concentrations of DA. The limit of detection of the assay was 3 fmol. At the end of the experiments, animals were killed by CO 2 asphyxiation. Slices were mounted and stained with Neutral Red. Placement of the microdialysis probes was checked under a light microscope. All probes were localized in the striatum see Fig. Responses on the lever that had previously resulted in an infusion of MDMA and on the inactive lever were recorded during all phases. The number of days to self-administer 90 responses at the dose of 1. Linear correlations between the number of responses following the MDMA injection during the drug-seeking test and these two measures were conducted. DA levels following the injection of saline or MDMA were expressed as a percentage of pre-injection values, calculated as the average of the three samples preceding the saline or MDMA injection. Linear correlations between the number of responses following the MDMA injection during the drug-seeking test and the area under the curve for DA overflow following the MDMA injection were conducted. Rats that met the criterion self-administered the initial 90 infusions of 1. Figure 2 shows the pattern of responding as a function of test day during acquisition of self-administration of MDMA for two rats. Figure 2 a shows the data from a rat that met the criterion relatively rapidly and Fig. During the first days of testing, responding on both levers was low. However, with repeated daily testing a preference for the active lever developed. Once the 90 infusions had been self-administered and the dose of MDMA was reduced to 0. Figure 3 shows the mean number of lever responses during phases 1 and 2 of the drug-seeking test in rats that met or did not meet the MDMA self-administration criterion. Phase 1 comprised the last 2 d of self-administration training. Phase 2 was conducted during the next 2 d, when the MDMA solution was replaced with vehicle solution and the stimulus light that had been paired with self-administered infusions was omitted. Figure 4 shows the lever responses during phases 2 and 3 of the drug-seeking test in rats that met or did not meet the MDMA self-administration criterion and in yoked control rats. Following the injection of saline at the start of phase 3, no significant change in responding was found. Moreover, the time-course of the drug-seeking responses was different for the rats that met or did not meet the criterion Fig. The number of lever responses in phase 2 was calculated as the average of responses from days 3 and 4. Phase 3 represents the drug-seeking behaviour produced by an injection of saline i. Time-course of lever responses during phase 3 of the drug-seeking test in rats that met or did not meet the MDMA self-administration criterion and in yoked control rats. Animals were injected with saline i. Figure 6 shows the relationship between responses produced during drug seeking following the MDMA injection and the number of days required to produce the initial 90 responses for rats that met the criterion. Rats that took longer to acquire self-administration produced fewer responses during the drug-seeking test. Relationship between the number of active lever responses produced following the MDMA Each symbol represents the data from an individual rat. The correlation coefficient r and p value are shown. The basal concentrations of extracellular DA in the striatum at the start of phase 3 were not significantly different for rats that met the criterion 2. The saline injection Fig. Time-course of dopamine release in the striatum following an injection of a saline i. After the collection of three baseline samples in their home cage, animals were moved to the self-administration chamber and injected with saline i. Data are expressed as a percentage of pre-injection values, calculated as the average of the three samples preceding the saline or MDMA injection. Figure 8 shows the time-course for MDMA-produced drug seeking and DA levels in rats that met or did not meet the criterion. Considerable overlap in the time-course for these behavioural and neurochemical responses to MDMA is observed in rats that met the criterion Fig. This relationship was not observed in rats that did not meet the criterion Fig. Time-course of MDMA-produced drug seeking and dopamine release in the striatum during phase 3 of the drug-seeking test in rats that a met or b did not meet the MDMA self-administration criterion. Dopamine levels are expressed as a percentage of pre-injection values, calculated as the average of the three samples preceding the saline or MDMA injection. Figure 9 shows the relationship between active lever responses and the area under the curve for DA overflow following the MDMA injection at the start of phase 3 for rats that met the criterion. Relationship between the number of active lever responses and the area under the curve AUC of dopamine release in the striatum produced following the MDMA Dopamine levels are expressed as a percentage of pre-injection values, calculated as the average of the three samples preceding the MDMA injection. The correlation coefficients r and corresponding p value are shown. The present study provides a number of novel findings concerning MDMA-produced drug seeking. The number of responses produced during drug seeking was directly related to the number of test sessions required to acquire MDMA self-administration and to DA overflow in the dorsal striatum, as measured by in-vivo microdialysis. As we have previously reported Schenk et al. Some rats met the criterion of 90 infusions of 1. In this regard, acquisition of MDMA self-administration proceeded over a longer time period than is typically observed during acquisition of self-administration of other drugs and a lower percentage of rats met the acquisition criterion, even after 25 d of testing Schenk et al. Only the rats that progressed to high levels of intake those that met the criterion within the limits of this study exhibited high levels of drug seeking in response to the priming injection of MDMA and the magnitude of the drug-seeking behaviour for these rats was directly related to sensitivity to the initial reinforcing effects of MDMA. Rats that self-administered the criterion number of infusions most quickly also produced the greatest number of responses during the drug-seeking test. Other studies have shown that initial sensitivity to the reinforcing effects of cocaine is a good predictor of cocaine-produced drug seeking Perry et al. The present data obtained following MDMA self-administration are consistent with these findings. Drug intake during acquisition of cocaine self-administration has also been shown to predict the magnitude of cocaine-seeking behaviour Baker et al. Accordingly, the total drug intake does not appear to be the main variable involved in MDMA-produced drug seeking under the conditions used in the present study. As a group, the rats that met the criterion within the d limit of this study produced a higher number of responses following the priming injection of MDMA at the start of phase 3 than rats that did not meet the criterion. The higher number of responses produced by the rats that met the criterion cannot be explained by greater conditioning effects as a result of repeated exposure to MDMA in the operant chambers because the two groups of rats were exposed to the self-administration chambers for roughly the same number of test days. Of interest, drug seeking was less for rats that failed to meet the criterion but these rats still produced a larger number of responses following MDMA when compared to responding during phase 2. This might suggest a small, but significant drug-seeking response despite the failure to self-administer substantial amounts of MDMA. However, this does not seem likely since 1 the highest number of responses occurred late in the drug-seeking session, as opposed to what was exhibited by rats that met the criterion, and was driven by a small number of rats, as evidenced by the large variability in Fig. Despite the relationship between initial responses and drug seeking, these phases of drug taking have often been attributed to the activation of different neural substrates. The magnitude of the initial reinforcing effect of psychostimulant drugs has been attributed to dopaminergic mechanisms in the ventral striatum, particularly in the nucleus accumbens. Studies have differentiated the role of the nucleus accumbens shell and core in these initial reinforcing effects of drugs of abuse. Microdialysis studies have shown a preferential increase in synaptic DA in the nucleus accumbens shell following exposure to drugs of abuse Pontieri et al. With extended self-administration experience, other brain areas became activated, including the dorsal striatum Letchworth et al. Accordingly, inactivation of the lateral dorsal striatum prevented drug seeking induced by a cocaine priming injection Kantak et al. If the drug-seeking response represents a switch from ventral to dorsal striatal DA control of behaviour and if the switch occurs as a result of some cumulative level of activation of the ventral striatum, then it is reasonable to expect that the rats that are most sensitive to the initial effects of a drug would display the most rapid progression, thereby demonstrating the greatest drug-seeking response and DA release in the dorsal striatum. Although not tested in this study, some of the data are consistent with this possibility. However, following repeated exposure to MDMA, deficits in various indices of serotonin neurotransmission were observed Baumann et al. Self-administration also led to decreased serotonin transporter binding densities Schenk et al. Schenk, D. Colussi-Mas, unpublished data. Thus, following repeated exposure, MDMA shifts from being predominantly an indirect serotonin agonist to being more of an indirect DA agonist. In line with this hypothesis, our results showed that drug seeking during the 6-h period following the priming injection of MDMA was associated with a DA response to MDMA that was significantly higher in the rats that met the criterion for self-administration. Moreover, the magnitude of drug seeking, as indicated by the number of responses produced, was positively and significantly related to the magnitude of the DA response. Importantly, baseline dorsal striatal DA overflow was comparable for rats that acquired self-administration and those that did not, and did not explain the difference in MDMA-induced DA release. In summary, there was substantial between-subject variability in the latency to acquisition of MDMA self-administration. Two groups of rats were produced: those that met a criterion for acquisition of self-administration within a d test period and those that did not. MDMA-produced drug seeking and DA overflow in the dorsal striatum was greater in rats that met the criterion. Brennan for helpful comments. A psycho-economic model of ecstasy consumption and related consequences: a multi-site study with community samples. Google Scholar. Ahmed SH Cador M Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsychopharmacology 31 , — Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats. 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Victoria University of Wellington, School of Psychology. Oxford Academic. Richard J. Alex Howard. Susan Schenk. Address for correspondence: Professor S. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract In laboratory animals, exposure to priming injections of 3,4-methylenedioxymethamphetamine MDMA produced drug seeking following extinction of MDMA self-administration. Microdialysis , relapse , self-administration , striatum. Open in new tab Download slide. Google Scholar Crossref. Search ADS. Di Ciano. Google Scholar PubMed. Issue Section:. Download all slides. Views 2, More metrics information. Total Views 2, Email alerts Article activity alert. Advance article alerts. New issue alert. In progress issue alert. Receive exclusive offers and updates from Oxford Academic. Citing articles via Web of Science Working memory performance predicts, but does not reduce, cocaine- and cannabinoid-seeking in adult male rats. More from Oxford Academic. 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Ecstasy in the city: Synthetic drug markets in Europe

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Which are the characteristics of synthetic drug suppliers? How are they organized, owned and managed? This article summarizes the outcomes of a cross-national study which investigated three urban synthetic drug markets at a different stage of development: Amsterdam, Barcelona and Turin. Hence, the role played by more structured, mafia-type organizations, even in Italy, needs to be reconceived. The wide use of primary sources, altogether the adoption of qualitative interpretative tools, contributed to shed some light on a phenomenon which is still poorly investigated both at national and international levels. This is a preview of subscription content, log in via an institution to check access. Rent this article via DeepDyve. Institutional subscriptions. Adelaars, A. Google Scholar. Bagozzi, F. Beck, J. Hrlow, D. McDonnell, M. Douglas, P. Morgan, M. Rosenbaum and L. Blickman, T. Korf, D. Siegel and D. Commissione Parlamentare di inchiesta sul fenomeno della mafia e sulle associazioni criminali similari, Relazione sulle risultanze del gruppo di lavoro incaricato di svolgere accertamenti su insediamenti ed infiltrazioni di soggetti ed organizzazioni mafiose in aree non tradizionali , XI Legislatura Roma: Tipografia del Senato, Barruti, Informe. Observatori de nous consums de drogues en l'ambit juvenil Barcelona: Institut Genus, Observatori de nous consums de drogues en L'a mbit juvenil Barcelona: Institut Genus, Gamella, J. Nabben and A. Benschop, Antenne — Trends in alcohol, tabak, drugs en gokken bij jonge Amsterdammers Amsterdam: Rozenberg Publishers, Lewis, R. Strang and M. Gossop eds. Massari, M. Becucci and M. Massari eds. Mareso, P. Monzini and M. Barruti, J. Moore, M. Nabben, T. Portanova, M. Rossi and F. Preble, E. Reuter, P. Sciarrone, R. Radicamento ed espansione Roma: Donzelli, Smuraglia, C. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Monica Massari. Reprints and permissions. Ecstasy in the city: Synthetic drug markets in Europe. Crime Law Soc Change 44 , 1—18 Download citation. Received : 16 June Accepted : 22 March Published : 13 May Issue Date : August Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Access this article Log in via an institution. Vietnamese drug networks in the Czech Republic: Development, share in the illicit market, structures, and modi operandi Article 17 August References Adelaars, A. Google Scholar Beck, J. Google Scholar Blickman, T. Google Scholar Commissione Parlamentare di inchiesta sul fenomeno della mafia e sulle associazioni criminali similari, Relazione sulle risultanze del gruppo di lavoro incaricato di svolgere accertamenti su insediamenti ed infiltrazioni di soggetti ed organizzazioni mafiose in aree non tradizionali , XI Legislatura Roma: Tipografia del Senato, Google Scholar Gamella, J. Google Scholar Korf, D. Google Scholar Lewis, R. Google Scholar Massari, M. Google Scholar Moore, M. Google Scholar Nabben, T. Google Scholar Portanova, M. Google Scholar Preble, E. Google Scholar Reuter, P. Google Scholar Sciarrone, R. Google Scholar Smuraglia, C. Rights and permissions Reprints and permissions. About this article Cite this article Massari, M. Copy to clipboard. Search Search by keyword or author Search. Navigation Find a journal Publish with us Track your research.

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