No abstract

Background: While (±)-3,4-methylenedioxymethamphetamine (MDMA) primarily induces serotonin release, it also affects dopamine and noradrenaline transmission. It is, however, unclear what role each of these neurotransmitters play in the behavioural profile of MDMA. Methods: In this study we used the drug discrimination (DD) and the acoustic startle (ASR) paradigms to examine the behaviour of rats with and without a genetic deletion of the serotonin transporter SERT (SERT−/− and SERT+/+ rats). In DD, rats were trained to respond on different levers following an injection of 1.5 mg/kg MDMA, or saline. After acquisition, they were given a challenge dose of 0.5 mg/kg amphetamine (AMPH). In the ASR paradigm, SERT+/+ and SERT−/− rats were given 0, 5 or 10 mg/kg MDMA. Results: In DD, significantly fewer SERT−/− rats acquired MDMA discrimination. When the acquirers were challenged with AMPH, SERT+/+ showed partial, while SERT−/− rats showed full generalisation to MDMA. In the ASR paradigm, MDMA significantly reduced prepulse inhibition and startle habituation in SERT+/+ rats, while having no effect in SERT−/− rats. Conclusion: Together these data suggest that in wildtype rats the interoceptive cues of MDMA are primarily mediated by serotonin and to a lesser extent by dopamine and noradrenaline, while the effects in the startle paradigm are almost exclusively mediated via serotonin. Together, these data contribute to our understanding of the complex pharmacodynamics of MDMA.

<p>Rationale: Given the high prevalence and large burden of psychiatric disorders it is imperative to determine the underling etiology in order for better understanding and treatment. The neurotransmitter serotonin (5-HT) has been associated with mental disorders in humans both pharmacologically and genetically. Individuals with the short-allele of a prominent polymorphism within the 5-HT transporter (SERT) show increased incidence of mood disorders and drug dependence. However, whether or not dysregulation in the 5-HT system causes, or is just associated with, psychiatric disorders is impossible to determine from human studies alone. Consequently, it is imperative to employ an animal model of down-regulated SERT function. To better understand the role of 5-HT in drug dependence, the rat’s behavioural response to the psychostimulant (±) 3, 4-methylenedioxymethamphetamine (MDMA), a preferentially serotonergically mediated drug, was assessed. Finally, the ability to rescue the anxiety-like phenotype in the SERT-/- rat by altering extracellular 5-HT during early development was also evaluated.  Objective: The primary objective of the current thesis was to determine whether dysregulation of 5-HT is directly linked to the occurrence of psychiatric disorders, particularly drug dependence and anxiety.  Methods: A model of down-regulated SERT function, the SERT knock-out (SERT-/-) rat, was used for all experiments in order to determine a causal relationship between 5-HT dysregulation and psychiatric disorders. In Chapter 2, the response of the SERT-/- rats to various tasks usually disrupted by MDMA was assessed. In Chapter 3, the sensitivity of the SERT-/- rats to the reinforcing effects of MDMA was determined using the self-administration paradigm. Finally, in Chapter 4, whether the anxiety-like behaviour of the SERT-/- rat could be rescued through normalising excessive extracellular 5-HT neonatally was assessed. An attempt was also made to determine a mechanism by which 5-HT dysregulation could alter behaviour. To this end, gene expression previously found to be up- or down-regulated in the SERT-/- rat was assessed in the neonatally treated rats.  Results: The results of Chapter 2 indicated the SERT is necessary for MDMA’s disruption of startle habituation but not its psychomotor effects. Moreover, for those rats that could discriminate low dose MDMA from saline, genetic removal of the SERT resulted in the inability to discriminate MDMA from amphetamine, implying that, in these rats, MDMA was now subjectively indistinguishable from amphetamine. Indeed, this alteration also resulted in enhanced sensitivity to the reinforcing properties of MDMA, giving MDMA the qualities of a traditional psychostimulant in SERT-/- rats (Chapter 3). Finally, lowering the excessive 5-HT during neonatal development in SERT-/- rats led to a rescue of mild, but not high, anxiety-like behaviour in males. However, mRNA levels of long 3’NTR BDNF and 5-HT1a, genes associated with neurodevelopment, remained unchanged across genotypes and treatment groups (Chapter 4).  Conclusions: Genetic removal of the 5-HT transporter results in an altered behavioural response to MDMA, in particular an increased sensitivity to its reinforcing properties. However, while the genetic removal of the SERT results in enhanced extracellular 5-HT, the pathological phenotypes present in this rat are likely due to this increase occurring in early development, not its continued presence in adulthood. Overall, these findings contribute to the growing body of literature indicating that enhanced brain 5-HT during early development can lead to pathological behaviour in adulthood.</p>

No abstract

<p>Rationale: Given the high prevalence and large burden of psychiatric disorders it is imperative to determine the underling etiology in order for better understanding and treatment. The neurotransmitter serotonin (5-HT) has been associated with mental disorders in humans both pharmacologically and genetically. Individuals with the short-allele of a prominent polymorphism within the 5-HT transporter (SERT) show increased incidence of mood disorders and drug dependence. However, whether or not dysregulation in the 5-HT system causes, or is just associated with, psychiatric disorders is impossible to determine from human studies alone. Consequently, it is imperative to employ an animal model of down-regulated SERT function. To better understand the role of 5-HT in drug dependence, the rat’s behavioural response to the psychostimulant (±) 3, 4-methylenedioxymethamphetamine (MDMA), a preferentially serotonergically mediated drug, was assessed. Finally, the ability to rescue the anxiety-like phenotype in the SERT-/- rat by altering extracellular 5-HT during early development was also evaluated.  Objective: The primary objective of the current thesis was to determine whether dysregulation of 5-HT is directly linked to the occurrence of psychiatric disorders, particularly drug dependence and anxiety.  Methods: A model of down-regulated SERT function, the SERT knock-out (SERT-/-) rat, was used for all experiments in order to determine a causal relationship between 5-HT dysregulation and psychiatric disorders. In Chapter 2, the response of the SERT-/- rats to various tasks usually disrupted by MDMA was assessed. In Chapter 3, the sensitivity of the SERT-/- rats to the reinforcing effects of MDMA was determined using the self-administration paradigm. Finally, in Chapter 4, whether the anxiety-like behaviour of the SERT-/- rat could be rescued through normalising excessive extracellular 5-HT neonatally was assessed. An attempt was also made to determine a mechanism by which 5-HT dysregulation could alter behaviour. To this end, gene expression previously found to be up- or down-regulated in the SERT-/- rat was assessed in the neonatally treated rats.  Results: The results of Chapter 2 indicated the SERT is necessary for MDMA’s disruption of startle habituation but not its psychomotor effects. Moreover, for those rats that could discriminate low dose MDMA from saline, genetic removal of the SERT resulted in the inability to discriminate MDMA from amphetamine, implying that, in these rats, MDMA was now subjectively indistinguishable from amphetamine. Indeed, this alteration also resulted in enhanced sensitivity to the reinforcing properties of MDMA, giving MDMA the qualities of a traditional psychostimulant in SERT-/- rats (Chapter 3). Finally, lowering the excessive 5-HT during neonatal development in SERT-/- rats led to a rescue of mild, but not high, anxiety-like behaviour in males. However, mRNA levels of long 3’NTR BDNF and 5-HT1a, genes associated with neurodevelopment, remained unchanged across genotypes and treatment groups (Chapter 4).  Conclusions: Genetic removal of the 5-HT transporter results in an altered behavioural response to MDMA, in particular an increased sensitivity to its reinforcing properties. However, while the genetic removal of the SERT results in enhanced extracellular 5-HT, the pathological phenotypes present in this rat are likely due to this increase occurring in early development, not its continued presence in adulthood. Overall, these findings contribute to the growing body of literature indicating that enhanced brain 5-HT during early development can lead to pathological behaviour in adulthood.</p>