Evidence for the involvement of ventral hippocampal α7 nicotinic acetylcholine receptors in morphine- primed reinstatement to conditioned place preference

Maintaining long-term abstinence and preventing relapse after re-exposure to drug-associated cues is the main challenge for treating drug addiction. Nicotinic acetylcholine receptors (nAChRs) play a key role in addiction-related behaviours (1). We have shown that the α7 nAChR antagonist methyllycaconitine (MLA) can selectively inhibit reinstatement, but has no effect on the acquisition, expression or reconsolidation of morphine-CPP (2).

To investigate the loci for this effect, intracranial infusions of MLA were conducted in 24 male Wistar rats weighing between 400–450g. All animals underwent acquisition and extinction of morphine-CPP (5mg/kg, s.c.) before the implantation of cannulae (under isoflurane-induced anaesthesia) at coordinates relative to bregma; to target the mPFC: anterior-posterior +3.20, medial-lateral ±0.75, dorsal-ventral -2.8; the dorsal hippocampus: anterior-posterior +3.20, medial-lateral ±2.5, dorsal-ventral -1.8; ventral hippocampus: anterior-posterior -5.3, medial-lateral ±5.2, dorsal-ventral -4.5mm. Methyllycaconitine (MLA, Tocris UK) was administered at a dose of 6.74μg/hemisphere and slowly infused at 2.4μl/hemisphere over a 4-minute period, 20 minutes prior to a morphine reinstatement trial (2.5mg/kg, s.c.).

A one-way ANOVA showed no effect of MLA intra-mPFC (p=0.70, n=8) or intra-dHPC (p=0.82, n=8/treatment group) infusions on the time spent in drug paired side during reinstatement. However there was a significant effect of MLA intra-vHPC infusion (p=0.012, n=8/treatment group). There was no effect of intracranial MLA infusions on locomotion seen in any of the sites (mPFC: p=0.064; dHPC: p=0.24; vHPC: p=0.29) and all cannulae were verified with an infusion of brilliant blue dye.

This finding implicates the ventral hippocampus as an important locus for modulating the α7 nAChR responses to morphine-CPP. To support this finding we used glutamate receptor autoradiography in C57BL/6Jmice following acquisition and extinction of morphine-CPP (5mg/kg, i.p.) followed by morphine-primed reinstatement (2.5mg/kg, i.p.) (2). Reinstatement of morphine-CPP caused an increase in [3H]-AMPA binding in the CA1 (p=0.0016 n=5–6/treatment group) and CA2 (p=0.0159, n=5–6/treatment group) regions of the ventral hippocampus. This increase in [3H]-AMPA binding following morphine-CPP reinstatement was prevented by pre-treating mice with MLA (4mg/kg, s.c) immediately before morphine-primed CPP reinstatement. Morphine-primed CPP reinstatement did not induce changes in [3H]-AMPA binding in other brain regions. These experiments link α7 nAChR in modulating contextual drug induced glutamatergic synaptic plasticity in the ventral hippocampus.

1. Rahman S et al. (2015) Front Neurosci 8: 426.

2. Wright VL et al. (2013) http://www.pA2online.org/abstracts/Vol11Issue3abst030P.pdf