Hypocretin -dopamine interactions: Implications for behavior and cognition

• Main Author: Vittoz, Nicole M
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2006
• Subjects: Neurology; Neurosciences; Psychobiology
• ISBN: 0542879603; 9780542879609

The neuropeptide hypocretin/orexin exerts robust behavioral arousal-promoting effects, in part via its actions on a broad array of neuromodulatory systems. In addition, dopamine is implicated in the modulation of behavioral state and state-dependent processes, particularly under high-arousal appetitive and aversive conditions. Given recent evidence suggesting the particular involvement of hypocretin in appetitive and aversive high-arousal states, the actions of hypocretin on dopamine systems are of particular interest. When applied in vitro, hypocretin activates dopamine neurons within the ventral tegmental area. To date, however, little is known about the actions of hypocretin on dopamine neurotransmission in vivo . The first study presented here found that hypocretin administration increases dopamine levels preferentially within the prefrontal cortex and not within the core division of the nucleus accumbens. It is unclear whether these observations reflect the selective activation of prefrontal cortex-projecting dopamine neurons within the ventral tegmmental area. To address this question, the second study presented here examined the topographical location and projection targets of hypocretin-activated dopamine neurons. These studies provide support for the hypothesis that hypocretin selectively activates a subpopulation of prefrontal cortex-projecting dopamine neurons located in the caudomedial portion of the ventral tegmental area. The prefrontal cortex is critically involved a variety of higher cognitive and affective processes. Moreover, hypocretin fibers and receptors are located in the prefrontal cortex. Thus, the hypocretin system is well-situated to influence prefrontal cortex-dependent function, via both direct actions and via indirect actions on neuromodulatory (e.g. dopamine) systems. To better understand the impact of hypocretin on prefrontal cortex-dependent cognition, the third study examined the effects of hypocretin on spatial working memory in the rat. This study demonstrated that centrally administered hypocretin produces a stress-like impairment in working memory. Altogether, the current studies provide evidence for prominent actions of hypocretin on prefrontal cortical dopamine neurotransmission as well as prefrontal cortex-dependent cognition. These observations further implicate the dysregulation of hypocretin neurotransmission in cognitive and affective deficits associated with a variety of neuropsychiatric disorders.