The role of Dopamine in the Sensitised Locomotor Activating Effects of Methylenedioxymethamphetamine (MDMA) in Rats

D1 And D2 Receptors ◽

Hydroxyindoleacetic Acid ◽

Neurological Change ◽

Under certain regimens of repeated pre-exposure, psychostimulant drugs show an increase in locomotor activity across days of testing and, after abstinence from the drug, a greater responsiveness to a subsequent challenge dose of the drug. This phenomenon, termed behavioural sensitisation, is thought to underlie certain aspects of drug addiction such as drug seeking and relapse. Repeated administration of +/-3, 4-Methylenedioxymethamphetamine (MDMA, ecstasy) produced sensitised hyperactivity in rats suggesting a lasting neurological change. The present studies sought to evaluate some of the parameters around both the induction and expression of behavioural sensitisation to MDMA and to evaluate if the sensitivity of the dopamine (DA) D1 and D2 receptors had altered under the current pre-exposure regimen of MDMA. Further, following MDMA pre-exposure that results n behavioural sensitisation, changes in potency to the reinforcing effects of MDMA were investigated through the self administration paradigm. Finally, high performance liquid chromatography (HPLC) was used to evaluate changes in brain amine levels following sensitisation to MDMA locomotor activating effects. Rats received a pre-treatment regimen consisting of 5 daily injections of MDMA (0.0, 5.0 or 10mg/kg i.p). MDMA-produced locomotor activity was measured after 2, 9 or 28 days of withdrawal. In other groups, hyperactivity following administration the DA D1 agonist SKF81297 (0.0, 0.5, 1.0, 2.0, 4.0 or 8.0 mg/kg), or the D2-like DA agonist apomorphine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg) was measured in groups that received pre-exposure to MDMA (10.0 4mg/kg) or vehicle. The effects of the D1 antagonist SCH23390 (0.0, 0.01, 0.02, or 0.04 mg/kg), the D2 antagonist eticlopride (0.03, 0.01, 0.003, 0.05, 0.1, or 0.2 mg/kg) or the 5-HT2C antagonist RS102221 (0.0, 0.25, 0.5, or 1.0 mg/kg) on MDMA-produced hyperactivity in MDMA or vehicle pre-treated rats was also measured. In Experiment 3, effects of MDMA or vehicle pre-treatment on latency to acquisition of MDMA (0.5 or 1.0 mg/kg/infusion) selfadministration was measured. In Experiment 4 effects of pre-treatment on brain tissue levels of DA, its metabolite homovanillic acid (HVA), serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were determined. The regimen of 5 daily treatments of 10.0mg/kg produced persistent behavioural sensitisation and cross-sensitisation to hyperactivity produced by DA receptor agonists. These effects were not, however, reflected in sensitised responses to the ability of the antagonists to attenuate MDMA-produced hyperactivity. Pre-treatment with MDMA did not decrease latency to acquisition of self-administration. Rather, there was an increased latency to acquisition of self-administration in the MDMA pre-treated rats. MDMA pretreatment decreased levels of the serotonin metabolite 5-HIAA in the frontal cortex and hippocampus. Following the current pre-treatment regimen, MDMA produced behavioural sensitisation is mediated by neuroadaptations in central dopaminergic substrates. The persistent locomotor sensitisation is similar to that produced by other amphetamine-like stimulants and might underlie use and abuse of this compound.

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

10.26686/wgtn.17018813 ◽

2021 ◽

Author(s):

◽

Ross van de Wetering

Keyword(s):

Treatment Regimen ◽

Drugs Of Abuse ◽

Treatment Session ◽

Repeated Exposure ◽

Self Administration ◽

Acquisition Criterion ◽

Behavioural Effects ◽

Rationale. ±3, 4-methelynedioxymethamphetamine (MDMA) is the primary psychoactive ingredient of the increasingly popular recreational street drug, ecstasy. As with other drugs of abuse, repeated intermitted exposure to MDMA can lead to an increase in the subsequent behavioural effects of the drug. This phenomenon, termed behavioural sensitisation, has been attributed to sensitisation of central DAergic mechanisms considered to underlie several aspects of addiction. Objectives. The purpose of the present research was to investigate the role of DA D₂ receptor mechanisms in the development of MDMA sensitisation and the acquisition of MDMA self-administration in rats. Methods. Rats received daily i.p. injections of the selective D₂ antagonist, eticlopride (0.0, 0.05, 0.3 mg/kg), prior to injections of MDMA (0.0, 10.0 mg/kg) for five days. Two days following the final pre-treatment session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) were determined. Another group of rats were surgically implanted with i.v. jugular catheters before undergoing the same pre-treatment regimen. Two days following the final pre-treatment session, these rats were subsequently tested for acquisition of MDMA self-administration. The locomotor activating effects of MDMA (5 mg/kg i.p.) were determined two days following the last self-administration session. Results. Pre-treatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration, as evidenced by an increased likelihood to meet an acquisition criterion. Co-administration of eticlopride during pre-treatment completely blocked the development of sensitisation to MDMA-produced hyperactivity but failed to significantly attenuate the facilitation of MDMA self-administration. Interestingly, pre-treatment with eticlopride alone also facilitated the acquisition of self-administration. MDMA self-administration failed to alter MDMA-produced locomotor hyperactivity. Conclusions. These findings suggest that repeated activation of DA D₂ receptors is required for the development of sensitisation to MDMA-produced hyperactivity but not for the development of sensitisation to MDMA-produced reinforcement. D₂ receptor mechanisms evidently play some role, however, because repeated exposure to eticlopride also facilitated MDMA self-administration. It is suggested that both sensitised DAergic mechanisms and desensitised 5-HTergic mechanisms contribute to the acquisition of MDMA self-administration.

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

10.26686/wgtn.17018813.v1 ◽

2021 ◽

Author(s):

◽

Ross van de Wetering

Keyword(s):

Treatment Regimen ◽

Drugs Of Abuse ◽

Treatment Session ◽

Repeated Exposure ◽

Self Administration ◽

Acquisition Criterion ◽

Behavioural Effects ◽

Rationale. ±3, 4-methelynedioxymethamphetamine (MDMA) is the primary psychoactive ingredient of the increasingly popular recreational street drug, ecstasy. As with other drugs of abuse, repeated intermitted exposure to MDMA can lead to an increase in the subsequent behavioural effects of the drug. This phenomenon, termed behavioural sensitisation, has been attributed to sensitisation of central DAergic mechanisms considered to underlie several aspects of addiction. Objectives. The purpose of the present research was to investigate the role of DA D₂ receptor mechanisms in the development of MDMA sensitisation and the acquisition of MDMA self-administration in rats. Methods. Rats received daily i.p. injections of the selective D₂ antagonist, eticlopride (0.0, 0.05, 0.3 mg/kg), prior to injections of MDMA (0.0, 10.0 mg/kg) for five days. Two days following the final pre-treatment session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) were determined. Another group of rats were surgically implanted with i.v. jugular catheters before undergoing the same pre-treatment regimen. Two days following the final pre-treatment session, these rats were subsequently tested for acquisition of MDMA self-administration. The locomotor activating effects of MDMA (5 mg/kg i.p.) were determined two days following the last self-administration session. Results. Pre-treatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration, as evidenced by an increased likelihood to meet an acquisition criterion. Co-administration of eticlopride during pre-treatment completely blocked the development of sensitisation to MDMA-produced hyperactivity but failed to significantly attenuate the facilitation of MDMA self-administration. Interestingly, pre-treatment with eticlopride alone also facilitated the acquisition of self-administration. MDMA self-administration failed to alter MDMA-produced locomotor hyperactivity. Conclusions. These findings suggest that repeated activation of DA D₂ receptors is required for the development of sensitisation to MDMA-produced hyperactivity but not for the development of sensitisation to MDMA-produced reinforcement. D₂ receptor mechanisms evidently play some role, however, because repeated exposure to eticlopride also facilitated MDMA self-administration. It is suggested that both sensitised DAergic mechanisms and desensitised 5-HTergic mechanisms contribute to the acquisition of MDMA self-administration.

Impact of Cannabinoid Receptor Ligands on Sensitisation to Methamphetamine Effects on Rat Locomotor Behaviour

Acta Veterinaria Brno ◽

10.2754/avb200877020183 ◽

2008 ◽

Vol 77 (2) ◽

pp. 183-191 ◽

Cited By ~ 2

Author(s):

L. Landa ◽

K. Šlais ◽

A. Šulcová

Keyword(s):

Receptor Agonist ◽

Drugs Of Abuse ◽

Cannabinoid Receptor ◽

Behavioural Change ◽

Repeated Administration ◽

Receptor Ligands ◽

Locomotor Behaviour ◽

Stereotypic Behaviour ◽

The repeated administration of various drugs of abuse may lead to a gradually increased behavioural response to these substances, particularly an increase in locomotion and stereotypies may occur. This phenomenon is well known and described as behavioural sensitisation. An increased response to the drug tested, elicited by previous repeated administration of another drug is recognised as cross-sensitisation. Based on our earlier experiences with studies on mice, which confirmed sensitisation to methamphetamine and described cross-sensitisation to methamphetamine after pre-treatment with cannabinoid CB1 receptor agonist, we focused the present study on the use of another typical laboratory animal - the rat. A biological validity of the sensitisation phenomenon was expected to be enhanced if the results of both mouse and rat studies were conformable. Similar investigation in rats brought very similar results to those described earlier in mice. However, at least some interspecies differences were noted in the rat susceptibility to the development of sensitisation to methamphetamine effects. Comparing to mice, it was more demanding to titrate a dose of methamphetamine producing behavioural sensitisation. Furthermore, we were not able to provoke cross-sensitisation by repeated administration of cannabinoid CB1 receptor agonist methanandamide and similarly, we did not demonstrate the suppression of cross-sensitisation in rats that were repeatedly given combined pre-treatment with cannabinoid CB1 receptor antagonist AM 251 and methamphetamine. Finally, unlike mice, an alternative behavioural change was registered after repeated methamphetamine treatment instead: the occurrence of stereotypic behaviour (nose rubbing).

The effect of felbamate on behavioural sensitization to methamphetamine in mice

Veterinární Medicína ◽

10.17221/6265-vetmed ◽

2012 ◽

Vol 57 (No. 7) ◽

pp. 364-370 ◽

Cited By ~ 1

Author(s):

L. Landa ◽

K. Slais ◽

A. Sulcova

Keyword(s):

Nmda Receptors ◽

Open Field ◽

Field Test ◽

Open Field Test ◽

Repeated Administration ◽

Repeated Treatment ◽

Clinical Effects ◽

Challenge Dose ◽

It has been shown that methamphetamine (Met) similary to other psychostimulants induces a progressive augmentation of behavioural responses after repeated administration, so called behavioural sensitisation. Numerous studies refer to an important role for N-methyl-d-aspartate (NMDA) receptors in the development of behavioural sensitisation. Activating antiepileptic drugs of the newer second generation, such as felbamate (Fel), also invoke psychotropic effects. They may possess attention-enhancing and antidepressant activity, causing anxiety, insomnia, and agitation. Although not all pharmacological effects of felbamate are fully elucidated yet, many of its clinical effects may be related to the inhibition of NMDA currents. Thus, the present study was focused on investigating the influence of felbamate on sensitisation to the effects of methamphetamine on mouse locomotor behaviour in the Open field test. Mice of the albino out-bred strain ICR were randomly allocated into four groups and were administered drugs seven times (from the 7th to 13th day of the experiment) as follows: (a) n1, 2: 2.5 mg/kg/day of Met; (b) n3: 240 mg/kg/day of Fel; (c) n4: Met + Fel. Locomotion in the Open field test was measured (a) after administration of vehicle on the 1st experimental day, (b) after the first dose of drugs given on the 7th day, and (c) on the 14th day after the “challenge doses” given that way (as follows): n1: Met; n2: Met + Fel, n3: Fel; n4: Met. The following significant behavioural changes were observed: (1) stimulatory influence of Met and sensitisation after repeated treatment (n1); (2) inhibition of Met sensitisation in the case of a challenge dose combined with Fel (n2); (3) augmentation of the sensitising effect of Met when sensitisation was induced by pre-treatment with Met + Fel (n4); (4) no behavioural effect of the first dose of Fel, but inhibition of locomotion after repeated administration of the drug (n3). The prevention of the development of Met sensitization in the group n2 in which mice received the Met challenge dose with Fel mirrors the results of a majority of similar studies. Most findings are consistent with inhibitory effects of antagonists of the NMDA receptors on the development of sensitisation to amphetamines; nevertheless, also new findings are reported. In the presented paper, combined pre-treatment with Met + Fel in the group n4 facilitated the development of sensitisation to Met stimulatory effects.

The effect of MDMA self-administration on MDMA-produced hyperactivity and c-fos expression

10.26686/wgtn.17018618 ◽

2021 ◽

Author(s):

◽

Natasha Bukholt

Keyword(s):

Locomotor Activity ◽

Negative Correlation ◽

Dorsal Striatum ◽

Cingulate Cortex ◽

Repeated Exposure ◽

Infralimbic Cortex ◽

Self Administration ◽

Behavioural Test ◽

Fos Expression

Background: MDMA preferentially releases serotonin (5HT) but following repeated exposure there is a decrease in this MDMA-produced effect. At the same time, some studies suggest an increase in MDMA-produced dopamine (DA) release following repeated exposure. The sensitised DA response is often accompanied by sensitisation of MDMA-produced locomotor activity. Because DAergic mechanisms have been implicated in the positively reinforcing properties of MDMA, these neuroadaptations might be relevant to MDMA self-administration. Objectives: The main objective of this study was to determine whether MDMA self-administration and non-contingent MDMA exposure differentially affected the development of sensitisation to MDMA-produced hyperactivity. Additionally, the relationship between MDMA-produced hyperactivity and changes in c-fos expression in DA terminal regions was determined. Methods: Triads of rats were designated ‘master’, ‘yoked MDMA’, or ‘yoked saline’. Lever press responding by the master rat resulted in an intravenous infusion of MDMA for both the master rat and the yoked MDMA rat, as well as an equal infusion of vehicle for the yoked control rat. Daily tests continued until a total of 350 mg/kg MDMA had been self-administered. Three days following the last self-administration session, forward and vertical locomotion produced by MDMA (5.0 mg/kg, i.p) were measured during a 2 hr test. Rats were sacrificed immediately following the behavioural test, and c-fos immunohistochemistry was measured. Results: Repeated MDMA exposure resulted in sensitised forward and vertical locomotor activity. Sensitisation of the increase in forward locomotion was produced only in rats that self-administered MDMA; non-contingent MDMA administration failed to sensitise this behavioural response. In contrast, sensitisation to MDMA-produced vertical activity was produced following both contingent and non-contingent MDMA exposure. C-fos expression was reduced in ventrolateral, and ventromedial areas of the dorsal striatum, as well as the infralimbic cortex, after MDMA exposure, regardless of whether the exposure was via self-administration or yoked administration. A selective decrease in c-fos expression in the nucleus accumbens (NAc) core and the cingulate cortex was produced by MDMA self-administration. There was a negative correlation between MDMA-produced forward locomotor activity and MDMA-produced c-fos expression in the NAc core, cingulate cortex and infralimbic cortex. A negative correlation between rearing activity and MDMA-produced c-fos expression in the NAc core, NAc shell, cingulate cortex, and infralimbic cortex was also found. Conclusions: These data provide evidence of behavioural sensitisation as a result of repeated MDMA exposure. Furthermore, MDMA-produced behavioural sensitisation was associated with a decrease in c-fos expression that was evident in the NAc and prefrontal cortex. Finally, region-specific changes in c-fos expression suggest an important role of neuroadaptations in the NAc core and the infralimbic cortex as a consequence of MDMA self-administration.

The effect of memantine on behavioural sensitisation to methamphetamine in mice

Veterinární Medicína ◽

10.17221/6366-vetmed ◽

2012 ◽

Vol 57 (No. 10) ◽

pp. 543-550 ◽

Cited By ~ 2

Author(s):

L. Landa ◽

K. Slais ◽

A. Sulcova

Keyword(s):

Nmda Receptor ◽

Receptor Antagonist ◽

Repeated Administration ◽

Nmda Receptor Antagonist ◽

Nmda Glutamate Receptor Antagonist

Inward Currents ◽

Nmda Glutamate Receptor ◽

Psychotropic Effects ◽

Pre Treatment ◽

After repeated administration the psychostimulant methamphetamine (Met) produces a substantial increase in behavioural responses, which is termed behavioural sensitisation. Many studies have reported that N-methyl-d-aspartate (NMDA) receptors play an important role in the development and expression of behavioural sensitisation. Memantine (Mem) is used particularly for the treatment of Alzheimer’s disease and acts as a non-competitive NMDA glutamate receptor antagonist, possessing a variety of psychotropic effects. For example, there are studies indicating that memantine prevents the expression of withdrawal symptoms in mice and causes reversal of opioid dependence. Although not all pharmacological mechanisms of memantine have been clarified yet, it is known that memantine inhibits NMDA receptor inward currents. Thus, the present study was designed to assess whether memantine would influence behavioural sensitisation to the stimulatory effects of methamphetamine on mouse locomotion. Mice were randomly allocated into four groups. They were given vehicle on Day 1of the experiment and after five days without application they were administered seven drug daily doses (i.p.) from Day 7 to Day 13 of the study, as follows: (a) n1, 2: 2.5 mg/kg/day of Met; (b) n3: combination Met + Mem at the doses of 2.5 mg/kg/day and 5 mg/kg/day, respectively; (c) n4: Mem at the dose of 5 mg/kg/day. On Day 14 mice were given the first “challenge treatment” (a) n1: Met, (b) n2: Met + Mem, (c) n3: Met, (d) n4: Mem. The second “challenge treatment” was given after a six day wash-out period on Day 21: (a) n1: Met, (b) n2: Met + Mem, (c) n3: Met, (d) n4: Mem. Changes in locomotion were measured for a period of 3 min in the Open field on Days 1, 7, 14 and 21 to assess the sensitising phenomenon. Met pre-treatment significantly sensitised to the effects of the challenge doses (n1). Mem given alone did not change the measured behavioural parameters after the acute dose but it significantly decreased locomotion after its repeated administration (n4). Repeated pre-treatment with the Met + Mem combination (n3) did not produce sensitisation after Met challenge doses and similarly, repeated pre-treatment with Met did not induce sensitisation after the challenge dose of Met + Mem (n2). Thus, our results suggest that the role of the NMDA receptor antagonist memantine in the development and expression of behavioural sensitisation to Met seems to be an inhibitory one.

Exploring the side effect profile of 16-Ethynyl Salvinorin A

10.26686/wgtn.17135909 ◽

2021 ◽

Author(s):

◽

Stephen George Mathew

Keyword(s):

Locomotor Activity ◽

Side Effects ◽

Dose Response ◽

Forced Swim Test ◽

Salvinorin A ◽

Self Administration ◽

Swim Test ◽

Forced Swim ◽

Sedative Effects

Introduction: Drug addiction is a chronic and relapsing disorder that has widespread socioeconomic and health consequences. Globally, there are over 29.5 million people who are drug dependent, and New Zealand has one of the highest rates of drug use rates in the developed world. Currently, there are no Food and Drug Administration (FDA) approved pharmacotherapies that target psychostimulant addiction. Kappa opioid receptor (KOPr) agonists are being studied as a potential pharmacotherapy as it utilizes the brain’s own mechanism for controlling reward, however, KOPr agonists have unwanted side effects such as dysphoria and sedation. This thesis explores the KOPr agonists Salvinorin A (Sal A), a naturally-occurring, highly potent and short-acting non-nitrogenous KOPr agonist and a structural analogue, 16-Ethynyl Salvinorin A (16-Ethy). KOPr agonists, such as Sal A have known preclinical anti-addictive and anti-reward effects, therefore, this thesis focuses on evaluating Sal A and 16-Ethy in preclinical tests of reward and side effects. Methods: Male Sprague-Dawley rats were used in preclinical tests to evaluate common KOPr-mediated side-effects including anxiety (elevated plus maze), depression (forced swim test) sedation (locomotor activity) and aversion (conditioned place aversion). The anti-cocaine effects were also examined using self-administration, dose-response and drug-behavioural sensitisation tests. 16-Ethy was tested at 2 mg/kg in all experiments. Results: Acute pre-treatment of 16-Ethy induced sedative effects in non-habituated locomotor activity but when rats were habituated prior to administration, no sedation was observed. In contrast, Sal A (2 mg/kg) had sedative effects in habituated, but not in non-habituated locomotor activity (p = 0.0037). Compared to vehicle-treated rats, 16-Ethy and Sal A did not display pro-depressive effects in the forced swim test, show anxiogenic or aversive properties or modulate behavioural sensitisation to cocaine. Cocaine self-administration and dose-response tests were not successfully completed. Conclusion: At 2 mg/kg, 16-Ethy was found to display sedative effects in non-habituated locomotor activity but not in a habituated paradigm. Compared to vehicle-treated rats, 16-Ethy did not display pro-depressive effects in the forced swim test, or display anxiogenic or aversive properties and did not show significant cocaine sensitisation. Cocaine self-administration and dose-response tests were not successfully completed and will need to be repeated to ascertain the effects of 16-Ethy on them. However, 16-Ethy has shown glimpses of promise as a potential pharmacotherapy against addiction.

Exploring the side effect profile of 16-Ethynyl Salvinorin A

10.26686/wgtn.17135909.v1 ◽

2021 ◽

Author(s):

◽

Stephen George Mathew

Keyword(s):

Locomotor Activity ◽

Side Effects ◽

Dose Response ◽

Forced Swim Test ◽

Salvinorin A ◽

Self Administration ◽

Swim Test ◽

Forced Swim ◽

Sedative Effects

Introduction: Drug addiction is a chronic and relapsing disorder that has widespread socioeconomic and health consequences. Globally, there are over 29.5 million people who are drug dependent, and New Zealand has one of the highest rates of drug use rates in the developed world. Currently, there are no Food and Drug Administration (FDA) approved pharmacotherapies that target psychostimulant addiction. Kappa opioid receptor (KOPr) agonists are being studied as a potential pharmacotherapy as it utilizes the brain’s own mechanism for controlling reward, however, KOPr agonists have unwanted side effects such as dysphoria and sedation. This thesis explores the KOPr agonists Salvinorin A (Sal A), a naturally-occurring, highly potent and short-acting non-nitrogenous KOPr agonist and a structural analogue, 16-Ethynyl Salvinorin A (16-Ethy). KOPr agonists, such as Sal A have known preclinical anti-addictive and anti-reward effects, therefore, this thesis focuses on evaluating Sal A and 16-Ethy in preclinical tests of reward and side effects. Methods: Male Sprague-Dawley rats were used in preclinical tests to evaluate common KOPr-mediated side-effects including anxiety (elevated plus maze), depression (forced swim test) sedation (locomotor activity) and aversion (conditioned place aversion). The anti-cocaine effects were also examined using self-administration, dose-response and drug-behavioural sensitisation tests. 16-Ethy was tested at 2 mg/kg in all experiments. Results: Acute pre-treatment of 16-Ethy induced sedative effects in non-habituated locomotor activity but when rats were habituated prior to administration, no sedation was observed. In contrast, Sal A (2 mg/kg) had sedative effects in habituated, but not in non-habituated locomotor activity (p = 0.0037). Compared to vehicle-treated rats, 16-Ethy and Sal A did not display pro-depressive effects in the forced swim test, show anxiogenic or aversive properties or modulate behavioural sensitisation to cocaine. Cocaine self-administration and dose-response tests were not successfully completed. Conclusion: At 2 mg/kg, 16-Ethy was found to display sedative effects in non-habituated locomotor activity but not in a habituated paradigm. Compared to vehicle-treated rats, 16-Ethy did not display pro-depressive effects in the forced swim test, or display anxiogenic or aversive properties and did not show significant cocaine sensitisation. Cocaine self-administration and dose-response tests were not successfully completed and will need to be repeated to ascertain the effects of 16-Ethy on them. However, 16-Ethy has shown glimpses of promise as a potential pharmacotherapy against addiction.

The effect of MDMA self-administration on MDMA-produced hyperactivity and c-fos expression

10.26686/wgtn.17018618.v1 ◽

2021 ◽

Author(s):

◽

Natasha Bukholt

Keyword(s):

Locomotor Activity ◽

Negative Correlation ◽

Dorsal Striatum ◽

Cingulate Cortex ◽

Repeated Exposure ◽

Infralimbic Cortex ◽

Self Administration ◽

Behavioural Test ◽

Fos Expression

Background: MDMA preferentially releases serotonin (5HT) but following repeated exposure there is a decrease in this MDMA-produced effect. At the same time, some studies suggest an increase in MDMA-produced dopamine (DA) release following repeated exposure. The sensitised DA response is often accompanied by sensitisation of MDMA-produced locomotor activity. Because DAergic mechanisms have been implicated in the positively reinforcing properties of MDMA, these neuroadaptations might be relevant to MDMA self-administration. Objectives: The main objective of this study was to determine whether MDMA self-administration and non-contingent MDMA exposure differentially affected the development of sensitisation to MDMA-produced hyperactivity. Additionally, the relationship between MDMA-produced hyperactivity and changes in c-fos expression in DA terminal regions was determined. Methods: Triads of rats were designated ‘master’, ‘yoked MDMA’, or ‘yoked saline’. Lever press responding by the master rat resulted in an intravenous infusion of MDMA for both the master rat and the yoked MDMA rat, as well as an equal infusion of vehicle for the yoked control rat. Daily tests continued until a total of 350 mg/kg MDMA had been self-administered. Three days following the last self-administration session, forward and vertical locomotion produced by MDMA (5.0 mg/kg, i.p) were measured during a 2 hr test. Rats were sacrificed immediately following the behavioural test, and c-fos immunohistochemistry was measured. Results: Repeated MDMA exposure resulted in sensitised forward and vertical locomotor activity. Sensitisation of the increase in forward locomotion was produced only in rats that self-administered MDMA; non-contingent MDMA administration failed to sensitise this behavioural response. In contrast, sensitisation to MDMA-produced vertical activity was produced following both contingent and non-contingent MDMA exposure. C-fos expression was reduced in ventrolateral, and ventromedial areas of the dorsal striatum, as well as the infralimbic cortex, after MDMA exposure, regardless of whether the exposure was via self-administration or yoked administration. A selective decrease in c-fos expression in the nucleus accumbens (NAc) core and the cingulate cortex was produced by MDMA self-administration. There was a negative correlation between MDMA-produced forward locomotor activity and MDMA-produced c-fos expression in the NAc core, cingulate cortex and infralimbic cortex. A negative correlation between rearing activity and MDMA-produced c-fos expression in the NAc core, NAc shell, cingulate cortex, and infralimbic cortex was also found. Conclusions: These data provide evidence of behavioural sensitisation as a result of repeated MDMA exposure. Furthermore, MDMA-produced behavioural sensitisation was associated with a decrease in c-fos expression that was evident in the NAc and prefrontal cortex. Finally, region-specific changes in c-fos expression suggest an important role of neuroadaptations in the NAc core and the infralimbic cortex as a consequence of MDMA self-administration.