Florey Department of Neuroscience and Mental Health - Theses
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ItemPrefrontal dopaminergic mechanisms of adolescent cue extinction learning( 2016)Addiction and anxiety disorders represent the most prevalent mental illnesses in young people worldwide. Unfortunately, adolescents attain poorer outcomes following extinction-based treatment for these disorders compared to adults. Cue extinction learning involves dopamine signaling via the dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) in the medial prefrontal cortex. In particular, the infralimbic cortex, a subregion of the medial prefrontal cortex, has been implicated in extinction learning in both adolescent and adult rodents. The prefrontal dopamine system changes dramatically during adolescence. However, the role of prefrontal dopamine in adolescent cue extinction learning is poorly understood. Therefore, this thesis aimed to elucidate the role of prefrontal dopamine in adolescent cue extinction, using cocaine self-administration and fear conditioning in rats. My first study examined cocaine self-administration and cocaine-associated cue extinction in adolescent versus adult rats. Adolescents displayed a deficit in cocaine-cue extinction learning compared to adults (postnatal day [P]53 and P88 on cue extinction day, respectively). A single infusion of the full D2R agonist quinpirole into the infralimbic cortex prior to extinction enhanced adolescent cue extinction to reduce relapse-like behavior the next day. This effect was recapitulated by a systemic injection of the partial D2R agonist aripiprazole, an FDA-approved drug for the treatment of psychosis with strong translational potential. My second study examined fear conditioning and extinction in adolescent and adult rats. I first aimed to optimize behavior in late adolescent (P53) and adult (P88) rats during the dark phase of their 12-hour light-dark cycle, to remain consistent with conditions of the previous chapter. However, this produced unreliable behavioral results. In contrast, adolescent rats (P35) consistently display a deficit in long-term fear extinction compared to adults (P88) during the light phase. Infusion of the D1R agonist SKF-81297 into the infralimbic cortex prior to fear extinction had no effect for either age group. However, infusion of quinpirole into the infralimbic cortex significantly enhanced long-term fear extinction in adolescents, whereas it delayed within-session extinction in adults. Interestingly, an acute systemic injection of aripiprazole improved long-term fear extinction in adults. My final experiments measured prefrontal gene expression for D1R, D2R, and D1R relative to D2R (D1R/D2R ratio) in naïve rats across adolescent development, or following cocaine-cue, or fear extinction. There were no significant differences in prefrontal dopamine receptor gene expression across naïve rats age P35, P53, and P88. Following cocaine-cue extinction, prefrontal D1R gene expression was upregulated in adults but not adolescents. By comparison, following fear conditioning, adolescents showed higher D1R and D1R/D2R ratio gene expression compared to adults. D1R/D2R ratio was modulated in opposite directions following fear extinction learning during adolescence versus adulthood. These findings show that adolescents are impaired in extinction of emotionally salient cues across both appetitive (drug) and aversive (fear) learning domains. Functional and molecular data provide novel evidence for divergent involvement of prefrontal dopamine in cue extinction learning across adolescent development. Results not only extend understandings of extinction learning in general, but represent an exciting step towards finding new therapeutic targets to facilitate exposure-based therapy in the clinic.
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ItemRelaxin-3/RXFP3 system in alcohol self-administration and relapse( 2016)Alcoholism is a chronic relapsing disorder, accounting for 10% of disability-adjusted life years lost in industrialized countries. Our understanding of the neurobiology of addiction is far from complete and due to high relapse rates, there is a need to identify new therapeutic targets to assist the development of better treatments. In early studies, the neuropeptide relaxin-3 was implicated in the regulation of stress responses and arousal/motivational behaviours such as feeding, as well as spatial memory. Relaxin-3 is primarily expressed in large GABAergic neurons of the nucleus incertus (NI) in the hindbrain that project topographically to forebrain regions containing neurons expressing the native relaxin-3 G-protein-coupled receptor, RXFP3, several of which are implicated in the control of drug-seeking behaviour. Therefore, the present study directly investigated the role of the central relaxin-3/RXFP3 signalling system in alcohol- and sucrose-seeking in alcohol-preferring (iP) and Wistar rats. Firstly, the effect of central antagonism of RXFP3 using a receptor-selective relaxin-3 analogue peptide on self-administration of alcohol and sucrose was investigated; and then the effect of the same antagonist treatment on cue- and stress-induced reinstatement of both sucrose- and alcohol-seeking was studied. Thereafter, the impact of RXFP3 antagonism within the stress-related bed nucleus of stria terminalis (BNST) on stress-induced reinstatement of alcohol-seeking was also examined. Central antagonism of RXFP3 reduced cue- and stress-induced reinstatement of alcohol-seeking, but did not markedly alter sucrose-seeking in either paradigm, suggesting a specific effect on alcohol-related behaviour(s). Alcohol consumption and stress-induced reinstatement were also both attenuated by local RXFP3 antagonism within the BNST. These data are the first identifying a role for relaxin-3/RXFP3 signalling in alcohol use and seeking. In light of these initial findings and the enrichment of RXFP3 in other stress-related brain areas, the ability of RXFP3 antagonism within the central amygdala (CeA) to modulate alcohol self-administration and stress-induced reinstatement of alcohol-seeking was also examined. Indeed, RXFP3 antagonism in CeA also reduced alcohol self-administration and stress-induced reinstatement of alcohol-seeking, further indicating an involvement of native relaxin-3/RXFP3 signalling in stress-induced reinstatement and potential interactions with other major peptide transmitter systems implicated in these behaviours, such as corticotropin-releasing factor (CRF) and orexin. NI relaxin-3 neurons express the CRF type 1 receptor (CRF1) and are activated by CRF; likewise there is anatomical evidence for the expression of orexin-1 (OX1) and orexin-2 (OX2) receptors in the NI. Accordingly, the effect of bilateral NI infusions of the CRF1receptor antagonist (CP376395), the OX1 receptor antagonist (SB-334867) and the OX2 receptor antagonist (TCS-OX2-29) on stress-induced reinstatement of alcohol-seeking was examined. CP376395 and TCS-OX2-29 reduced stress-induced reinstatement of alcohol-seeking, whereas SB-334867 was ineffective. These data suggest that CRF- and orexin-mediated activation of NI neurons occurs during stress-induced reinstatement, via CRF1 and OX2 receptor signalling events. Together, these data demonstrate that the relaxin-3/RXFP3 system can modulate stress-induced reinstatement of alcohol-seeking via both forebrain sites and a potential CRF- and orexin-primed activation of the NI during stress exposure. These findings have added significantly to our knowledge of the neurocircuitry that underpins stress-induced relapse-like behaviour and to our general understanding of addictive behaviours, with implications for the development of better treatment strategies and the identification of potential drug targets for treating alcoholism and other stress-related addictions.