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Investigating the anti-cocaine effects of novel kappa opioid receptor agonists: Behavioural and cellular actions of Salvinorin A analogues
<p>Acute kappa opioid receptor (KOPr) activation by traditional agonists produces antiaddiction properties, but side effects such as sedation and depression prevent their clinical use. The novel KOPr agonist salvinorin A (Sal A), isolated from the plant Salvia divinorum, is a potent and selective KOPr agonist with a unique non-nitrogenous structure. Sal A possesses anti-addiction effects with less side effects than traditional KOPr agonists, but its short duration of action limits its therapeutic usefulness. To test the hypothesis that longer acting structural analogues of Sal A may yield a new class of therapeutics, the anti-cocaine effects of Sal A analogues such as 16-bromosalvinorin A (16-brSal A), ethoxymethyl ether salvinorin B (EOM Sal B), and methoxymethyl ether salvinorin B (MOM Sal B) were evaluated. 16-brSal A (1.0 mg/kg) displayed a longer duration of action in mice compared to Sal A, evidenced using the tail flick test (p<0.05). Both 16-brSal A and EOM Sal B produced dose-dependent decreases in cocaine-induced reinstatement of drug seeking (p<0.05). On the other hand, 16-brSal A (1.0 mg/kg) but not MOM Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity (p<0.05), although both compounds showed no sedative effects in the locomotor activity test in rats. This indicates the superior behavioural anti-cocaine profile of 16-brSal A at its minimum effective dose. These three compounds, together with another analogue that also decreased cocaineinduced drug seeking, β-tetrahydropyran salvinorin B (β-THP Sal B), were screened for typical KOPr-mediated side effects using the minimal effective doses that attenuated drug seeking. MOM Sal B but not EOM Sal B (0.1 mg/kg), β-THP Sal B (1.0 mg/kg), or 16-brSal A produced depressive-like effects in the forced swim test (FST) in rats (p<0.05). However, EOM Sal B displayed a reduction in swimming time coupled with an increase in climbing duration in the FST (p<0.05). On the other hand, β-THP Sal B (p<0.001, between 30 – 45 min) and EOM Sal B (p<0.05, between 15 – 30 min) significantly increased sucrose intake in the rat sucrose self-administration model at different time intervals. 16-brSal A, however, produced no significant changes in natural reward intake measured by sucrose self-administration. The improved behavioural profile of 16-brSal A extended to a lack of anxiogenic effects. No significant anxiety-like behaviour was seen in the light dark or elevated plus maze, although aversion was observed in the conditioned place aversion paradigm (p<0.05). The low incidence of adverse effects of 16-brSal A compared to other iv Sal A analogues in behavioural models prompted additional cellular studies of this KOPr agonist. As the anti-cocaine effects of KOPr agonists have been attributed to their ability to modulate dopamine (DA) levels, 16-brSal A was examined for its ability to regulate dopamine transporter (DAT) function. DAT function was determined in vitro by determining uptake of a fluorescent substrate, ASP+, in HEK-293 cells expressing YFP-DAT and myc-KOPr. Ex vivo studies were also conducted by measuring DA uptake in isolated, minced rat dorsal striatum and nucleus accumbens using rotating disk electrode voltammetry. 16-brSal A significantly increased DAT function in both the in vitro (10 μM) and ex vivo (500 nM) models (p<0.05), an effect that was dependent on extracellular regulated kinase 1/2 (ERK1/2). Since late phase ERK1/2 and p38 kinase activation have been attributed to negative KOPr behavioural responses, the effects of 16-brSal A on these pathways were also examined. Western blotting studies revealed that 16-brSal A selectively activated only the early (5 – 15 min) but not late phase (120 – 180 min) ERK1/2 pathway in HEK-293 cells as well as rat dorsal striatum, prefrontal cortex, and nucleus accumbens (p<0.05). 16-brSal A also produced no significant activation of p38 kinase in the dorsal striatum or prefrontal cortex of rats, although significant phosphorylation was seen in the nucleus accumbens (p<0.05). The ability of 16-brSal A to produce desired behavioural anti-addiction effects with fewer adverse effects, matched with its regulation of KOPr signalling pathways, suggests that it may possibly be a functionally selective agonist that preferentially activates the G-protein signalling pathway at the KOPr. Since understanding the potential use of novel KOPr agonists in different phases of the addiction cycle is crucial to ensure effective administration of therapies, Sal A and 16-brSal A were tested in rats self-administering cocaine on the long access (Sal A) and progressive ratio (Sal A and 16-brSal A) schedules. Although no differences in cocaine responding were seen with KOPr agonist treatment in either paradigms, a higher dose or concurrent infusions of KOPr agonist with cocaine may improve the responses observed. Overall, the novel KOPr agonist, 16-brSal A has excellent potential as a pharmacotherapy due to its anti-cocaine effects and minimal adverse side effect profile. This is the first study to examine in detail the behavioural and cellular actions of 16-brSal A, and supports previous reports of Sal A-derived KOPr agonists as prospective therapeutics for cocaine abuse.</p>
<p>Acute kappa opioid receptor (KOPr) activation by traditional agonists produces antiaddiction properties, but side effects such as sedation and depression prevent their clinical use. The novel KOPr agonist salvinorin A (Sal A), isolated from the plant Salvia divinorum, is a potent and selective KOPr agonist with a unique non-nitrogenous structure. Sal A possesses anti-addiction effects with less side effects than traditional KOPr agonists, but its short duration of action limits its therapeutic usefulness. To test the hypothesis that longer acting structural analogues of Sal A may yield a new class of therapeutics, the anti-cocaine effects of Sal A analogues such as 16-bromosalvinorin A (16-brSal A), ethoxymethyl ether salvinorin B (EOM Sal B), and methoxymethyl ether salvinorin B (MOM Sal B) were evaluated. 16-brSal A (1.0 mg/kg) displayed a longer duration of action in mice compared to Sal A, evidenced using the tail flick test (p<0.05). Both 16-brSal A and EOM Sal B produced dose-dependent decreases in cocaine-induced reinstatement of drug seeking (p<0.05). On the other hand, 16-brSal A (1.0 mg/kg) but not MOM Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity (p<0.05), although both compounds showed no sedative effects in the locomotor activity test in rats. This indicates the superior behavioural anti-cocaine profile of 16-brSal A at its minimum effective dose. These three compounds, together with another analogue that also decreased cocaineinduced drug seeking, β-tetrahydropyran salvinorin B (β-THP Sal B), were screened for typical KOPr-mediated side effects using the minimal effective doses that attenuated drug seeking. MOM Sal B but not EOM Sal B (0.1 mg/kg), β-THP Sal B (1.0 mg/kg), or 16-brSal A produced depressive-like effects in the forced swim test (FST) in rats (p<0.05). However, EOM Sal B displayed a reduction in swimming time coupled with an increase in climbing duration in the FST (p<0.05). On the other hand, β-THP Sal B (p<0.001, between 30 – 45 min) and EOM Sal B (p<0.05, between 15 – 30 min) significantly increased sucrose intake in the rat sucrose self-administration model at different time intervals. 16-brSal A, however, produced no significant changes in natural reward intake measured by sucrose self-administration. The improved behavioural profile of 16-brSal A extended to a lack of anxiogenic effects. No significant anxiety-like behaviour was seen in the light dark or elevated plus maze, although aversion was observed in the conditioned place aversion paradigm (p<0.05). The low incidence of adverse effects of 16-brSal A compared to other iv Sal A analogues in behavioural models prompted additional cellular studies of this KOPr agonist. As the anti-cocaine effects of KOPr agonists have been attributed to their ability to modulate dopamine (DA) levels, 16-brSal A was examined for its ability to regulate dopamine transporter (DAT) function. DAT function was determined in vitro by determining uptake of a fluorescent substrate, ASP+, in HEK-293 cells expressing YFP-DAT and myc-KOPr. Ex vivo studies were also conducted by measuring DA uptake in isolated, minced rat dorsal striatum and nucleus accumbens using rotating disk electrode voltammetry. 16-brSal A significantly increased DAT function in both the in vitro (10 μM) and ex vivo (500 nM) models (p<0.05), an effect that was dependent on extracellular regulated kinase 1/2 (ERK1/2). Since late phase ERK1/2 and p38 kinase activation have been attributed to negative KOPr behavioural responses, the effects of 16-brSal A on these pathways were also examined. Western blotting studies revealed that 16-brSal A selectively activated only the early (5 – 15 min) but not late phase (120 – 180 min) ERK1/2 pathway in HEK-293 cells as well as rat dorsal striatum, prefrontal cortex, and nucleus accumbens (p<0.05). 16-brSal A also produced no significant activation of p38 kinase in the dorsal striatum or prefrontal cortex of rats, although significant phosphorylation was seen in the nucleus accumbens (p<0.05). The ability of 16-brSal A to produce desired behavioural anti-addiction effects with fewer adverse effects, matched with its regulation of KOPr signalling pathways, suggests that it may possibly be a functionally selective agonist that preferentially activates the G-protein signalling pathway at the KOPr. Since understanding the potential use of novel KOPr agonists in different phases of the addiction cycle is crucial to ensure effective administration of therapies, Sal A and 16-brSal A were tested in rats self-administering cocaine on the long access (Sal A) and progressive ratio (Sal A and 16-brSal A) schedules. Although no differences in cocaine responding were seen with KOPr agonist treatment in either paradigms, a higher dose or concurrent infusions of KOPr agonist with cocaine may improve the responses observed. Overall, the novel KOPr agonist, 16-brSal A has excellent potential as a pharmacotherapy due to its anti-cocaine effects and minimal adverse side effect profile. This is the first study to examine in detail the behavioural and cellular actions of 16-brSal A, and supports previous reports of Sal A-derived KOPr agonists as prospective therapeutics for cocaine abuse.</p>
Relapse to drug seeking after prolonged abstinence is a major problem in the clinical treatment of drug addiction. The use of pharmacological interventions to disrupt established drug reward memories is a promising strategy for the treatment of drug addiction. A growth hormone secretagogue receptor 1 A antagonist, JMV2959, has been shown to reduce morphine-induced conditioned place preference (CPP) in rats within hours of intervention; thus, JMV2959 is a potential candidate for drug addiction treatment. However, the effect of JMV2959 on reconsolidation to disrupt drug seeking remains unknown. In this study, we assessed the effect of JMV2959 on morphine induced memory reconsolidation to inhibit drug seeking after drug withdrawal. Our results showed that the administration of JMV2959 (6 mg/kg) significantly reduced environmental cue induced CPP, which suggested a preventive effect of JMV2959 on morphine induced memory reconsolidation. Additionally, JMV2959 administration significantly altered the locomotor activity and food and water intake but did not significantly alter the natural reward preference. We concluded that JMV2959 may be an effective candidate to treat drug addiction.
Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.
<p><b>Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.</b></p> <p>Methods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined. Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function. Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.</p>
<p>Background: Drug addiction is a chronic, relapsing disorder with great socioeconomic and morbidity costs. An estimated 27 million people worldwide suffer from drug dependence, with over 180,000 drug abuse-related deaths reported annually (UNODC, 2015). Currently, there are no FDA-approved pharmacotherapies for psychostimulant addiction, limiting the efficacy of treatment for cocaine and amphetamine abuse. Kappa-opioid receptor (KOPr) agonists can act as inhibitors of reward, and have been investigated in pre-clinical models of drug abuse for potential anti-addictive properties, but display undesirable side-effects such as dysphoria and sedation. A naturally-occurring KOPr agonist, Salvinorin A (SalA), has been explored as a lead for new KOPr-based anti-addictive medications. SalA is a short-acting but potent non-nitrogenous KOPr agonist with known anti-cocaine effects, and chemical alterations to this structure have produced novel agonists with comparable or greater potency at the KOPr. This thesis compares two novel SalA analogues, 16-ethynyl Salvinorin A (Ethy-SalA) and 16-methyl Salvinorin A (Me-SalA), in pre-clinical models of addiction and side-effect tests. Methods: Sprague-Dawley rats were used to model the behavioural effects of acute KOPr treatment upon cocaine self-administration and drug-seeking behaviour, natural reward-seeking, cocaine-induced and spontaneous locomotion, and pro-depressive forced-swim testing. Transiently co-transfected HEK-293 cells were used to model the influence of KOPr activation upon dopamine transporter (DAT) function in an in vitro model of dopamine uptake, using confocal microscopy to detect internalisation of the fluorescent DAT substrate ASP+. Results: Acute pre-treatments of Ethy-SalA significantly attenuated cocaine-reinstatement of drug-seeking behaviour (at 0.1 and 0.3 mg/kg) and progressive ratio (PR) self-administration of cocaine (at 2.0 mg/kg). The less potent agonist Me-SalA did not attenuate cocaine-reinstatement or PR self-administration at the doses tested (0.3-2.0 mg/kg). Despite apparent anti-cocaine effects, Ethy-SalA (0.3 mg/kg) was not found to effectively reduce cocaine-induced locomotor hyperactivity or sensitisation in rats. Side-effect screens were carried out on the novel compounds using the doses tested in cocaine-primed reinstatement. Ethy-SalA (0.3 mg/kg) and Me-SalA (1.0 mg/kg) did not significantly affect spontaneous locomotor behaviour 0.3 mg/kg, or reduce self-administration of the natural reward sucrose at a dose of 0.3 mg/kg in rats. Depression-like effects caused by acute Ethy-SalA treatment (0.3 mg/kg) were also not detected in the Forced Swim Test. Treatment with Ethy-SalA (10 µM) significantly increased uptake of the fluorescent ASP+ in co-transfected DAT/KOPr HEK-293 cells. Conclusions: A single treatment of the novel KOPr agonist Ethy-SalA, but not the novel agonist Me-SalA, was found to attenuate drug-seeking behaviours in models of cocaine administration with greater potency than SalA, and without detectable sedative or depression-like effects at a dose of 0.3 mg/kg. The cellular mechanism-of-action by which Ethy-SalA depresses cocaine reward is at least in part due to positive regulation of DAT, which would act to reduce extracellular dopamine within the brain. The lack of significant side-effects and the apparent improved potency of the compound support further exploration of Ethy-SalA as a lead for the development of an anti-addictive pharmacotherapy.</p>
<p><b>Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.</b></p> <p>Methods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined. Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function. Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.</p>
<p>Background: Drug addiction is a chronic, relapsing disorder with great socioeconomic and morbidity costs. An estimated 27 million people worldwide suffer from drug dependence, with over 180,000 drug abuse-related deaths reported annually (UNODC, 2015). Currently, there are no FDA-approved pharmacotherapies for psychostimulant addiction, limiting the efficacy of treatment for cocaine and amphetamine abuse. Kappa-opioid receptor (KOPr) agonists can act as inhibitors of reward, and have been investigated in pre-clinical models of drug abuse for potential anti-addictive properties, but display undesirable side-effects such as dysphoria and sedation. A naturally-occurring KOPr agonist, Salvinorin A (SalA), has been explored as a lead for new KOPr-based anti-addictive medications. SalA is a short-acting but potent non-nitrogenous KOPr agonist with known anti-cocaine effects, and chemical alterations to this structure have produced novel agonists with comparable or greater potency at the KOPr. This thesis compares two novel SalA analogues, 16-ethynyl Salvinorin A (Ethy-SalA) and 16-methyl Salvinorin A (Me-SalA), in pre-clinical models of addiction and side-effect tests. Methods: Sprague-Dawley rats were used to model the behavioural effects of acute KOPr treatment upon cocaine self-administration and drug-seeking behaviour, natural reward-seeking, cocaine-induced and spontaneous locomotion, and pro-depressive forced-swim testing. Transiently co-transfected HEK-293 cells were used to model the influence of KOPr activation upon dopamine transporter (DAT) function in an in vitro model of dopamine uptake, using confocal microscopy to detect internalisation of the fluorescent DAT substrate ASP+. Results: Acute pre-treatments of Ethy-SalA significantly attenuated cocaine-reinstatement of drug-seeking behaviour (at 0.1 and 0.3 mg/kg) and progressive ratio (PR) self-administration of cocaine (at 2.0 mg/kg). The less potent agonist Me-SalA did not attenuate cocaine-reinstatement or PR self-administration at the doses tested (0.3-2.0 mg/kg). Despite apparent anti-cocaine effects, Ethy-SalA (0.3 mg/kg) was not found to effectively reduce cocaine-induced locomotor hyperactivity or sensitisation in rats. Side-effect screens were carried out on the novel compounds using the doses tested in cocaine-primed reinstatement. Ethy-SalA (0.3 mg/kg) and Me-SalA (1.0 mg/kg) did not significantly affect spontaneous locomotor behaviour 0.3 mg/kg, or reduce self-administration of the natural reward sucrose at a dose of 0.3 mg/kg in rats. Depression-like effects caused by acute Ethy-SalA treatment (0.3 mg/kg) were also not detected in the Forced Swim Test. Treatment with Ethy-SalA (10 µM) significantly increased uptake of the fluorescent ASP+ in co-transfected DAT/KOPr HEK-293 cells. Conclusions: A single treatment of the novel KOPr agonist Ethy-SalA, but not the novel agonist Me-SalA, was found to attenuate drug-seeking behaviours in models of cocaine administration with greater potency than SalA, and without detectable sedative or depression-like effects at a dose of 0.3 mg/kg. The cellular mechanism-of-action by which Ethy-SalA depresses cocaine reward is at least in part due to positive regulation of DAT, which would act to reduce extracellular dopamine within the brain. The lack of significant side-effects and the apparent improved potency of the compound support further exploration of Ethy-SalA as a lead for the development of an anti-addictive pharmacotherapy.</p>
<p>It has been suggested that the response to novelty and impulsivity predict the latency to acquisition and maintenance of drug self-administration, respectively. The aim of this thesis was to examine the relationship between these two traits and (1) the latency to acquisition and (2) maintenance (drug seeking) of 3,4-methylenedioxymethamphetamine (MDMA) self–administration. Impulsivity, measured as premature responding on the 5-choice serial reaction time task (5-CSRTT), and novelty seeking, measured as the locomotor response in a novel environment, were measured prior to self-administration. Due to characteristics of the rat strain and test equipment the 5-CSRTT was configurated in the first part of this study and modified from the standard version. Following training in this task animals were implanted with a siliastic catheter and were subsequently screened for their response to a novel environment prior to MDMA self-administration. Latency to acquisition was determined as the number of test sessions required to self-administer an initial criterion of 90 infusions of 1.0 mg/kg/infusion as well as an additional 150 infusions of 0.5 mg/kg/infusion MDMA. For some rats, the ability of MDMA (0, 5.0 or 10.0 mg/kg, IP) to produce drug seeking was subsequently measured and for others, impulsivity was again measured following self-administration. Novelty seeking predicted cocaine self-administration but was not significantly correlated with either the acquisition or drug-seeking measures of MDMA self-administration. Impulsivity was not significantly correlated with the latency to acquire self-administration of MDMA but was significantly and positively correlated with the magnitude of MDMA produced drug-seeking. Furthermore, MDMA self-administration produced a number of notable, but transient, deficits in the 5-CSRTT; there was an increase in omission rate and a delayed increase in premature responses in particular. These findings suggest that impulsivity, but not sensation seeking, might be a risk factor for the development of compulsive drug-seeking following withdrawal from MDMA self-administration. A surprising finding from this study was a high acquisition rate amongst rats that acquired the 5-CSRTT prior to self-administration. This difference was examined in a separate set of experiments. This effect could not be explained by an effect of handling, food restriction, or exposure to sweetened condensed milk and might possibly be due to differences in instrumental learning.</p>
<p>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.</p>
