The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on behavioural responses to nicotine

Abstract

Rationale: Previous studies have shown that blockade of metabotropic glutamate 5 receptors (mGluR5) results in inhibition of nicotine self-administration in experimental animals. However, these studies have not established the behavioural mechanisms which mediate these effects or the extent to which the effects of mGluR5 antagonism on nicotine self-administration reflect a selective attenuation of nicotine reinforcement.

Objectives: To investigate the effects of antagonising mGluR5 receptors on psychopharmacological responses to nicotine measured using conditioned and unconditioned behaviours.

Results: 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) significantly (P < 0.01) reduced nicotine self-administration and attenuated (P < 0.01) the ability of non-contingent nicotine to enhance the reinforcing properties of a weak reinforcer (extinguishing the house light in an operant chamber). It also attenuated (P < 0.05) the much lower levels of responding for this reinforcer measured in control animals treated with saline. MPEP did not attenuate the increase in locomotor activity induced by acute and repeated nicotine in animals habituated on the test day to the test environment. Furthermore, it had no significant effects on responding for a palatable food reward. By contrast, MPEP significantly reduced (P < 0.001) conditioned locomotor stimulation evoked by pairing nicotine with a specific environment.

Conclusion: The results are consistent with the hypothesis that mGluR5 receptors play an important role in mediating the effects of contextual cues in conditioned behavioural responses to nicotine.

Fig. 1

The effects of intravenous MPEP on operant responding for nicotine. Rats were trained to lever-press for nicotine on an FR3 schedule of reinforcement with a 20-s timeout. The figure shows mean responding on the active lever (open columns) and the inactive lever (filled columns) for rats pretreated with saline or MPEP (N = 8 for 2.5 mg/kg; N = 4 for 5.0 mg/kg) prior to the session. Data for the day after the MPEP session are also presented. The data are reported as means ± SEM. Significantly different from rats pretreated with saline *P < 0.05; **P < 0.01

Fig. 2

The influence of contingency on the response-enhancing effects of nicotine. Groups of rats (N = 8 in each group) were treated with daily injections of saline (open bars) or nicotine (0.4 mg/kg, s.c.; filled bars) and trained in an operant task reinforced by stimulus light above the active lever and extinguishing the house light. The bars represent the means ± SEM of the lever presses on the active and inactive levers when responding was reinforced using contingencies which increased from FR1:TO20 to FR5:TO20. Significantly different from rats injected with saline *P < 0.05; **P < 0.01

Fig. 3

The effects of MPEP on the response-enhancing effects of nicotine. Saline and nicotine (0.4 mg/kg, s.c.) treated rats (N = 8 in each group) were trained in an operant task (FR2:TO20) reinforced by a stimulus light above the active lever and extinguishing the house light. The bars represent means ± SEM for the lever-pressing responses on the active lever (panel A) and the inactive lever (panel B)

Fig. 4

The effects of lever reversal on operant responding reinforced by extinguishing the house light. Saline and nicotine (0.4 mg/kg, s.c.) treated rats (N = 8 in each group) were trained (FR2:TO20) to extinguish the house light by pressing either the left or the right lever of a two-lever operant chamber. The data are expressed as means ± SEM and show responding on the lever used during training (open bars) and the non-training lever (filled bars). The data for day 0 represent the results for the last day on which responding was reinforced by the lever used during training. The data for day 14 represent the results for the 14th day on which the reinforcer was delivered when the rats pressed the alternate lever

Fig. 5

The effects of nicotine and MPEP on activity in a cross maze. Groups of rats (N = 6 in each group) were treated with daily injections (s.c.) with saline or nicotine (0.4 mg/kg) for 8 days. Prior to the injection on day 1, the rats were placed in a cross maze for 30 min before being given an i.p injection of MPEP (5.0 mg/kg; filled columns) or saline (open columns). Thirty minutes after the injection, the rats were given a second s.c. injection of saline or nicotine (0.4 mg/kg), and entries into the arms of the cross maze counted for 20 min starting immediately after the second injection (acute treatment). The procedure was repeated on day 10 (repeated treatment). The data are expressed as means ± SEM. Significantly different from rats treated with s.c. saline ***P < 0.001; significantly different from rats tested after acute nicotine +P < 0.05

Fig. 6

The effects of repeated nicotine on activity in a cross maze. Groups of rats (N = 6 per group) were given daily s.c. injections of saline (open circles) or nicotine (0.4 mg/kg; filled triangles) and placed in the maze after each injection for 15 min. The results are expressed as mean ± SEM and represent the data for the days on which activity was recorded. Significantly different from saline-treated rats *P < 0.05; ***P < 0.001

Fig. 7

Effects of conditioning on locomotor responses to nicotine in a cross maze. One group of rats were pretreated with daily injections (s.c.) of saline or nicotine (0.4 mg/kg) for 16 days (chronic treatment) and returned to their home cages after each injection (non pre-exposed rats). On test days, the rats (N = 6 per group) were pretreated with MPEP (5.0 mg/kg, i.p. filled columns) or its saline vehicle (open columns), using a counter-balanced experimental design, 30 min before they were given a second s.c. injection (test treatment) of saline or nicotine. The same experimental design on the test days was used for a second group of rats which were pre-exposed to the maze by testing them for 15 min per day after each of their chronic injections. The data are expressed as means ± SEM. Significantly different from habituated to the maze with saline **P < 0.01. Significantly different from rats given i.p. saline on the test day ++P < 0.01