Gadd, Christopher Andrew; (2003) The relationship of the neurokinin-1 receptor to reward and learning and memory behaviours in the mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mice lacking the neurokinin-1 (NK1) receptor, the preferred receptor for the neurotransmitter substance P, appear to be insensitive to the rewarding properties of morphine, suggesting a role for this system in opiate abuse. The primary aim of this work was to extend these findings in the mouse. Following confirmation that the distribution of the NK1 receptor in the mouse brain was similar to that in the rat, the reduction in sensitivity of NK1 receptor knockout (NK1-/-) mice to morphine reward was verified. Using the locomotor sensitisation model, it was further demonstrated that mice lacking NK1 receptors do not exhibit the behaviours associated with the adaptive changes in response to repeated opiate exposure, suggesting that the NK1 receptor is crucial for the development of opiate addiction. Subsequently, two approaches were used to attempt to identify the locus for these effects. Firstly, c-Fos immunohistochemistry was used to 'map' regions of the brain differentially activated by morphine in NK1-/- mice. Perturbations in c-Fos expression were observed in the basolateral nucleus of the amygdala, the dentate gyrus and cortical areas in response to the morphine conditioned place preference task. Secondly, using the specific neurotoxin substance P-saporin, mice with bilateral ablation of neurones expressing the NK1 receptor in the amygdala, but not in the nucleus accumbens, showed similar reductions in morphine reward-related behaviours to NK1-/- mice. The amygdala is therefore an important area for the NK1 receptor's effects in mediating behaviours related to morphine reward in mice. Finally, the behaviour of NK1-/- mice was assessed in a range of learning and memory tasks. Despite having higher levels of hippocampal neurogenesis and brain-derived neurotrophic factor, NK1-/- mice displayed very similar behaviours to wild type mice, suggesting that the NK1 receptor and these hippocampal adaptations have only a weak influence on learning behaviour and memory.

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