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

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

10.26686/wgtn.16969174 ◽

2021 ◽

Author(s):

◽

Dave Gittings

Keyword(s):

Locomotor Activity ◽

Treatment Regimen ◽

High Performance ◽

Repeated Administration ◽

Self Administration ◽

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

10.26686/wgtn.16969174.v1 ◽

2021 ◽

Author(s):

◽

Dave Gittings

Keyword(s):

Locomotor Activity ◽

Treatment Regimen ◽

High Performance ◽

Repeated Administration ◽

Self Administration ◽

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.

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 Role of Serotonin in MDMA Self-administration in Rats

10.26686/wgtn.17008309 ◽

2021 ◽

Author(s):

◽

Sarah Bradbury

Keyword(s):

Negative Impact ◽

Primary Objective ◽

Repeated Exposure ◽

Lesion Group ◽

Control Group ◽

Self Administration ◽

Initial Exposure ◽

Abstinence Period

Rationale: The profile of acquisition for MDMA self-administration differs from that of amphetamine and cocaine self-administration in that fewer rats meet an acquisition criterion and the latency to acquisition is longer. These characteristics of MDMA self-administration may be because it preferentially stimulates serotonin (5HT) release whereas self-administration has generally been attributed to enhanced dopamine (DA) neurotransmission. Because 5HTergic agonists are not self-administered and increased synaptic 5HT decreased self-administration of other drugs, MDMA self-administration may be initially inhibited by the pronounced 5HT response. Accordingly, the acquisition of MDMA self-administration might proceed as a result of deficits in 5HT neurotransmission and a corresponding disinhibition of DA neurotransmission. Objective: The primary objective was to determine the role of 5HT in the acquisition and maintenance of MDMA self-administration. Methods: MDMA-induced increases of extracellular 5HT and DA and their primary metabolites were measured in the DA terminal regions of the nucleus accumbens (NAc) using in vivo microdialysis, prior to the commencement of MDMA self-administration. The relationship between MDMA-induced increases of neurotransmitter levels and the acquisition of MDMA self-administration was assessed. A subsequent study depleted brain 5HT by administering the neurotoxin, 5,7 – DHT, or vehicle into the lateral ventricle of the left hemisphere, prior to the commencement of MDMA self-administration. The proportion of subjects that acquired MDMA self-administration and the latency to acquire MDMA self-administration was compared for the two groups. In order to determine effects of MDMA self-administration on 5HT and DA responses, behaviours that reflect 5HT and/or DA neurotransmission were measured 5 or 14 days after self-administration of 165 mg/kg MDMA, or 14 days after vehicle self-administration. These time periods were chosen because they reflect a period of 5HT deficits (5 days) and recovery (14 days). Finally, the effect of abstinence on MDMA self-administration was measured. Results: The MDMA-induced increase of extracellular 5HT was significantly lower for the group that subsequently acquired MDMA self-administration but the MDMA-induced increase in DA was not different from the group that failed to acquire self-administration. 5, 7-DHT administration significantly decreased tissue levels of 5HT, but not DA. MDMA self-administration was facilitated by the lesion; 100% of the lesion group acquired MDMA self-administration, whereas only 50% of the control group acquired self-administration. Five days following the last MDMA self-administration session, DAergic behaviours were enhanced and 5HTergic behaviours were reduced relative to the control group. These differences in 5HTergic mediated behaviours were not apparent 14 days after self-administration but the DAergic behaviours remained elevated. The pattern of self-administration did not differ as a function of the length of the abstinence period. Conclusions: The variability in acquisition of MDMA self-administration was related to the magnitude of the 5HT response evoked by initial exposure to MDMA. These findings suggested that predisposing differences in the 5HT response might explain differences in the variability in acquisition of MDMA self-administration. The negative impact of 5HT on the acquisition of MDMA self-administration was clearly demonstrated following a 5, 7-DHT lesion. Thus, 5HT limits the development of MDMA self-administration. With repeated exposure to self-administered MDMA, behavioural responses indicative of 5HT activation were reduced whereas behavioural indices of DA activation were increased. The maintenance of MDMA self-administration was comparable regardless of whether there was a forced abstinence period or not. These data are consistent with the hypotheses that 5HT is inhibitory to the acquisition, but not the maintenance, of MDMA self-administration. Rather, the maintenance of self-administration might reflect sensitised DA responses that became apparent following repeated exposure.

The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

10.26686/wgtn.17014775 ◽

2021 ◽

Author(s):

◽

Dane Aronsen

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Drugs Of Abuse ◽

Receptor Activation ◽

Self Administration ◽

Response Curves ◽

Ru 24969 ◽

Gr 127935 ◽

Way 100635

Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse. Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed. Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed. Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors. Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.

The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

10.26686/wgtn.17014775.v1 ◽

2021 ◽

Author(s):

◽

Dane Aronsen

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Drugs Of Abuse ◽

Receptor Activation ◽

Self Administration ◽

Response Curves ◽

Ru 24969 ◽

Gr 127935 ◽

Way 100635

Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse. Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed. Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed. Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors. Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.

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.

Effect of repeated MDMA exposure on rat brain and behaviour

10.26686/wgtn.17148296.v1 ◽

2021 ◽

Author(s):

◽

Ross van de Wetering

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Ventral Tegmental Area ◽

Drugs Of Abuse ◽

Dorsal Striatum ◽

Behavioural Response ◽

Self Administration ◽

Nucleus Accumbens Core ◽

Dorsomedial Striatum

Rationale. ±3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is a popular recreational drug of abuse. Like other drugs of abuse, a proportion of users develop symptoms that are characteristic of a Substance Use Disorder (SUD). The behavioural and neurobiological consequences of repeated misuse of MDMA are not well understood, however. Objectives. The purpose of the present thesis was to investigate behaviourally relevant neuroadaptations that develop with repeated MDMA exposure in laboratory rats. Methods. First, the effect of chronic, long-access (6 hour) self-administration of MDMA on the accumulation of the transcription factor, ΔFosB, in the nucleus accumbens (core, shell), dorsal striatum (dorsomedial, dorsolateral, ventromedial, ventrolateral), prefrontal cortex (anterior cingulate, prelimbic, infralimbic, orbitofrontal), amygdala (central, basolateral), ventral tegmental area (anterior, posterior), and raphe (dorsal, median) was measured using immunohistochemistry. Second, the behavioural relevance of these findings was determined by examining the effect of bi-lateral intra-striatal (nucleus accumbens, dorsomedial striatum, dorsolateral striatum) microinjections of MDMA (200 μg/1 μL/side) on the expression of behavioural sensitisation following two days of withdrawal from a regimen of repeated, systemic MDMA exposure (10 mg/kg/day, i.p., for 5 days). Third, a procedure was developed to examine neurochemical correlates of sensitised MDMA-produced behaviour (0, 5, 10 mg/kg, i.p.) following the same regimen of repeated MDMA exposure. Samples were collected from the medial striatum using in vivo microdialysis and the extracellular concentrations of serotonin, dopamine, MDMA, and their metabolites were quantified using liquid chromatography coupled with quadrupole time-of-flight (Q-TOF) mass spectrometry. Lastly, a unique untargeted metabolomics procedure was developed to further analyse these microdialysis samples and to identify novel or unexpected metabolites that were relevant to the sensitised behavioural response produced by MDMA. Results. MDMA self-administration produced region-dependant increases in ΔFosB. Significant increases in ΔFosB were observed in the nucleus accumbens core, the medial areas of the dorsal striatum, as well as all areas of the prefrontal cortex and amygdala. Small, but significant increases were also observed in the dorsal raphe. Increases were observed in the nucleus accumbens shell and the posterior tail of the ventral tegmental area, but these increases were not significant following statistical correction for multiple comparisons. Acute exposure to MDMA increased locomotor activity only when the drug was infused into the nucleus accumbens. Following repeated systemic exposure, behavioural sensitisation was expressed when MDMA was infused into both the nucleus accumbens or the dorsomedial striatum, but not the dorsolateral striatum. Analysis of microdialysates from the medial striatum indicated that behavioural sensitisation was accompanied by small increases in baseline levels of extracellular serotonin and decreased MDMA-produced increases in serotonin, but these changes were not statistically significant. Behavioural sensitisation was also accompanied by increased extracellular concentrations of dopamine at baseline and following acute MDMA exposure, but these data were not statistically analysed due to small sample sizes. MDMA-produced extracellular concentrations of MDMA did not change with repeated exposure. Untargeted metabolomics revealed potential changes in MDMA and dopamine metabolism that might be relevant to the sensitised behavioural response. Conclusions. The findings of the current research suggest that repeated MDMA exposure results in many of the same neuroadaptations that result from repeated exposure to other drugs of abuse. These included increased ΔFosB expression in many brain regions that are relevant to addiction, such as the nucleus accumbens, dorsal striatum, and prefrontal cortex. Dopaminergic mechanisms also appeared to be influenced and were associated with sensitised MDMA-produced behaviour. Surprisingly, serotonergic mechanisms were not significantly impacted by repeated MDMA exposure under the current conditions. Some of the procedures developed in this thesis are unique and may be of value for future research investigating the neurochemical underpinnings of addictive behaviour or other disease states.

Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

10.26686/wgtn.16997890.v1 ◽

2021 ◽

Author(s):

◽

Caleb Carati

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Sch 23390 ◽

High Dose ◽

Gbr 12909 ◽

Self Administration ◽

Drug Seeking ◽

Skf 81297 ◽

It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.