The Role of Serotonin in the Development of Psychiatric Disorders: Studies on Drug Dependence and Anxiety-like Behaviour Following the Genetic Reduction of the Serotonin Transporter

2021 ◽  
Author(s):  
◽  
Alana Oakly
Keyword(s):  
Psychiatric Disorders ◽  
Early Development ◽  
Drug Dependence ◽  
Primary Objective ◽  
Behavioural Response ◽  
Mrna Levels ◽  
Self Administration ◽  
Knock Out ◽  
Enhanced Sensitivity

<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>

The Role of Serotonin in the Development of Psychiatric Disorders: Studies on Drug Dependence and Anxiety-like Behaviour Following the Genetic Reduction of the Serotonin Transporter

2021 ◽  
Author(s):  
◽  
Alana Oakly
Keyword(s):  
Psychiatric Disorders ◽  
Early Development ◽  
Drug Dependence ◽  
Primary Objective ◽  
Behavioural Response ◽  
Mrna Levels ◽  
Self Administration ◽  
Knock Out ◽  
Enhanced Sensitivity

<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>

The Role of Psychiatric Disorders in Predicting Drug Dependence Treatment Outcomes

2003 ◽  
Vol 160 (5) ◽  
pp. 890-895 ◽  
Author(s):  
Wilson M. Compton III ◽  
Linda B. Cottler ◽  
Jacqueline L. Jacobs ◽  
Arbi Ben-Abdallah ◽  
Edward L. Spitznagel
Keyword(s):  
Psychiatric Disorders ◽  
Treatment Outcomes ◽  
Drug Dependence ◽  
Drug Dependence Treatment

scholarly journals The Role of Serotonin in MDMA Self-administration in Rats

2021 ◽  
Author(s):  
◽  
Sarah Bradbury
Keyword(s):  
Negative Impact ◽  
Primary Objective ◽  
Repeated Exposure ◽  
Lesion Group ◽  
Control Group ◽  
Self Administration ◽  
Initial Exposure ◽  
Abstinence Period

<p>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.</p>

scholarly journals The Role of Serotonin in MDMA Self-administration in Rats

2021 ◽  
Author(s):  
◽  
Sarah Bradbury
Keyword(s):  
Negative Impact ◽  
Primary Objective ◽  
Repeated Exposure ◽  
Lesion Group ◽  
Control Group ◽  
Self Administration ◽  
Initial Exposure ◽  
Abstinence Period

<p>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.</p>

Collection of Ego-Centered Network Data with Computer-Assisted Interviews

Methodology ◽  
2006 ◽  
Vol 2 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Joachim Gerich ◽  
Roland Lehner
Keyword(s):  
Survey Methods ◽  
A Priori ◽  
Dynamic Structure ◽  
Computer Assisted ◽  
Network Data ◽  
Great Effort ◽  
Self Administration ◽  
Face To Face ◽  
Full Network

Although ego-centered network data provide information that is limited in various ways as compared with full network data, an ego-centered design can be used without the need for a priori and researcher-defined network borders. Moreover, ego-centered network data can be obtained with traditional survey methods. However, due to the dynamic structure of the questionnaires involved, a great effort is required on the part of either respondents (with self-administration) or interviewers (with face-to-face interviews). As an alternative, we will show the advantages of using CASI (computer-assisted self-administered interview) methods for the collection of ego-centered network data as applied in a study on the role of social networks in substance use among college students.

scholarly journals Decision Making from the Experience of Orthognathic Surgery Patients: A Grounded Theory Approach

2021 ◽  
pp. 238008442110144
Author(s):  
N.R. Paul ◽  
S.R. Baker ◽  
B.J. Gibson
Keyword(s):  
Decision Making ◽  
Grounded Theory ◽  
Treatment Options ◽  
Study Data ◽  
Primary Objective ◽  
Major Surgery ◽  
Future Research ◽  
Decision Making Process ◽  
Theory Approach

Introduction: Patients’ decisions to undergo major surgery such as orthognathic treatment are not just about how the decision is made but what influences the decision. Objectives: The primary objective of the study was to identify the key processes involved in patients’ experience of decision making for orthognathic treatment. Methods: This study reports some of the findings of a larger grounded theory study. Data were collected through face-to-face interviews of patients who were seen for orthognathic treatment at a teaching hospital in the United Kingdom. Twenty-two participants were recruited (age range 18–66 y), of whom 12 (male = 2, female = 10) were 6 to 8 wk postsurgery, 6 (male = 2, female = 4) were in the decision-making stage, and 4 (male = 0, female = 4) were 1 to 2 y postsurgery. Additional data were also collected from online blogs and forums on jaw surgery. The data analysis stages of grounded theory methodology were undertaken, including open and selective coding. Results: The study identified the central role of dental care professionals (DCPs) in several underlying processes associated with decision making, including legitimating, mediating, scheduling, projecting, and supporting patients’ decisions. Six categories were related to key aspects of decision making. These were awareness about their underlying dentofacial problems and treatment options available, the information available about the treatment, the temporality of when surgery would be undertaken, the motivations and expectation of patients, social support, and fear of the surgery, hospitalization, and potentially disliking their new face. Conclusion: The decision-making process for orthognathic treatment is complex, multifactorial, and heavily influenced by the role of DCPs in patient care. Understanding the magnitude of this role will enable DCPs to more clearly participate in improving patients’ decision-making process. The findings of this study can inform future quantitative studies. Knowledge Transfer Statement: The results of this study can be used both for informing clinical practice around enabling decision making for orthognathic treatment and also for designing future research. The findings can better inform clinicians about the importance of their role in the patients’ decision-making process for orthognathic treatment and the means to improve the patient experience. It is suggested that further research could be conducted to measure some of the key constructs identified within our grounded theory and assess how these change during the treatment process.

Sign in / Sign up

Export Citation Format

Share Document