Understanding how memory, learning and reward work in unison to form adaptive and sometime maladaptive behaviour is at the forefront of modern neuroscience. The largest unmet need in treating maladaptive reward learning behaviours such as addiction is maintaining long-term abstinence and preventing relapse after re-exposure to drug-associated cues. Nicotinic acetylcholine receptors (nAChR) have been implicated in responses to drugs of abuse other than nicotine (Rahman et al., 2015) and the aim of this work was to characterise the role of α7 nAChRs in morphine reward learning using conditioned place preference (CPP). The α7 nAChR antagonist methyllycaconitine (MLA) was used to determine if these receptors contribute to specific stages of drug-paired learning, namely acquisition, expression, reconsolidation or reinstatement of morphine-CPP. In 7-8week old C57BL/6J mice MLA (4mg/kg, s.c), given 20 minutes prior to a conditioning dose of morphine (10mg/kg, i.p) or post-test trial, had no effect on the acquisition, reconsolidation or expression of morphine-CPP. However, when given 20 minutes prior to a priming dose of morphine (5mg/kg, i.p), MLA (4mg/kg, s.c) significantly inhibited drug-induced reinstatement. The mechanisms of this effect were investigated using glutamate receptor autoradiography. Changes in 2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) and N-methyl-D-aspartate (NMDA) binding were examined in mice treated with either saline or MLA at morphine reinstatement. There were no significant changes in NMDA receptor binding (using [3H]MK-801) but morphine reinstatement significantly increased [3H]AMPA binding in the CA1/2 of the ventral but not dorsal hippocampus, or in any other brain regions examined (including mPFC, nucleus accumbens, amygdala and VTA). The selective increase in the hippocampus was partially antagonised by MLA, linking α7 nAChR activation to glutamatergic synaptic plasticity in the hippocampus. Intracranial infusions of MLA into the ventral but not the dorsal hippocampus or medial prefrontal cortex blocked reinstatement to morphine-CPP in male Wistar rats.
|Date of Award
|11 Dec 2015
|Sue Wonnacott (Supervisor), Chris Bailey (Supervisor) & David Heal (Supervisor)
- Conditioned Place Preference
- in vivo