- Title
- The role of cocaine- and amphetamine- regulated transcript (CART) and orexin in drug- seeking and addiction-related behaviours
- Creator
- James, Morgan
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2014
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Over the past decade, two hypothalamic neuropeptides, cocaine- and amphetamine- regulated transcript (CART) and orexin (hypocretin), have been shown to play important roles in regulating addiction-relevant behaviours, including ‘reinstatement’ of drug-seeking, a model of relapse-like behaviour. Interestingly, CART generally opposes the rewarding effects of psychostimulant drugs such as cocaine and negatively regulates reinstatement of drug-seeking. In contrast, orexin generally promotes reinstatement of cocaine seeking. Despite intense interest in CART and orexin as potential novel targets for pharmacotherapies designed to treat cocaine addiction, very little is known as to where in the brain these peptides act to regulate addiction-relevant behaviour. The work presented in this thesis investigated the paraventricular thalamus (PVT) as a potential important site of convergence for CART and orexin signaling in the regulation of reinstatement behaviour. As a first step, I provide evidence that PVT signaling is important for reinstatement behaviour. In Chapter 1, I present data demonstrating that activation of PVT, as gauged by levels of Fos-protein, a marker of neuronal activity, is strongly correlated with cocaine reinstatement elicited by drug-associated cues. In Chapter 2, I show that intra-PVT injections of tetrodotoxin (TTX), a sodium-channel blocker, attenuated drug-primed reinstatement of cocaine seeking. Taken together with evidence implicating the PVT in stress responsivity, these findings point to the PVT as an important substrate that may be common to all forms of reinstatement (cue-, drug- and stress-induced). In Chapter 2 I also show that microinfusions of the CART peptide directly into the PVT attenuated drug-primed reinstatement, suggesting that CART acts in this region to negatively regulate cocaine-seeking behaviour. In contrast, data presented in Chapter 3 suggests that orexin signaling in the PVT is not important for reinstatement behaviour, as intra-PVT injections of the orexin receptor-1 antagonist SB-334867 had no effect on cocaine seeking elicited by drug cues. This Chapter raises the possibility that orexin receptor-2 signaling in the PVT may be more important in reinstatement behaviour. Subsequent studies in Chapter 3 point to the importance of orexin signaling in the ventral tegmental area (VTA) in regulating reinstatement behaviour. Intra-VTA infusions of SB-334867 significantly attenuated cue-induced reinstatement of cocaine seeking without having any effect on spontaneous locomotor activity. These findings are further explored in Chapter 4, where I show that intra-VTA SB-334867 administration altered the activity of key drug-seeking substrates, including the PVT. I also present evidence that intra-VTA SB-334867 treatment does not affect reinstatement responding for a natural reward, suggesting that at low doses, SB-334867 can reduce drug seeking but not affect normal motivated behaviour. This Chapter also summarises the findings from each of the former chapters and discusses the implications of these findings in the context of the existing literature relating to the role of hypothalamic peptides in regulating drug-seeking behaviour. In the final chapter of this thesis, I focus on the orexin system as a possible neurobiological link between addiction and stress-related disorders such as depression and anxiety. In this chapter (Chapter 5), I show that animals exposed to early life stress exhibit hypoactivity of the orexin system following exposure to an additional stressor in adulthood. These findings are consistent with recent clinical evidence of reduced orexin activity in depressed patients. Interestingly, findings in this chapter also demonstrate that access to voluntary wheel running, an intervention known to have beneficial effects for depressive-like symptomology, protected against changes in orexin function and stress-related behaviour in male rats, but not female rats. Whilst these findings represent only the first step in our understanding, they point to the possibility that dysregulated orexin function may represent a neurobiological factor contributing to the high comorbidity of addiction and stress-related disorders.
- Subject
- addiction; orexin; depression; rat; thesis by publication; hypocretin; cocaine- and amphetamine-regulated transcript (CART); cocaine; neuropeptides; paraventricular thalamus; relapse; reinstatement; ventral tegmental area
- Identifier
- http://hdl.handle.net/1959.13/1042341
- Identifier
- uon:14038
- Rights
- Copyright 2014 Morgan James
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 315 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 9 MB | Adobe Acrobat PDF | View Details Download |