Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Abstract

Stimulatory actions of nicotine on mesocorticolimbic dopamine transmission are partly mediated by nicotine-induced glutamate release acting on ionotropic and metabotropic glutamate (mGlu) receptors. Because both presynaptic inhibitory mGlu2/3 and postsynaptic excitatory mGlu5 receptors provide potential targets for treatment of aspects of nicotine dependence, we examined interacting effects of mGlu5 (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and mGlu2/3 (LY341495) receptor antagonists on nicotine self-administration and brain reward threshold elevations associated with spontaneous nicotine withdrawal in rats. We hypothesized that increasing glutamate transmission by blocking presynaptic inhibitory mGlu2/3 autoreceptors would antagonize MPEP-induced decreases in nicotine self-administration. We also hypothesized that blocking postsynaptic actions of glutamate on mGlu5 receptors would exacerbate nicotine withdrawal-induced reward deficits, and that this effect would be attenuated by co-administration of the mGlu2/3 receptor antagonist LY341495. MPEP selectively decreased nicotine, but not food, self-administration in rats. LY341495 slightly decreased both nicotine and food self-administration. Co-administration of LY341495 with MPEP attenuated the effectiveness of MPEP in decreasing nicotine intake, although MPEP was still effective. Spontaneous nicotine withdrawal induced somatic signs of withdrawal and reward threshold elevations indicating reward deficits. MPEP increased somatic signs and reward deficits in both nicotine- and saline-withdrawing rats. Thus, while mGlu5 receptor antagonists may be therapeutically useful in decreasing tobacco smoking, they worsen nicotine withdrawal. Co-administration of LY341495 reduced MPEP-induced reward deficits in both nicotine- and saline-withdrawing rats. Thus, increasing glutamate transmission via mGlu2/3 autoreceptor blockade reduces the effects of mGlu5 receptor blockade on nicotine self-administration and MPEP-induced exacerbation of brain reward deficits associated with nicotine withdrawal.

Figure 1

The effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine- and food-maintained responding in rats (n=10 for each of the four MPEP doses for the nicotine groups, n=5 for each of four MPEP doses for the food groups). MPEP alone significantly reduced nicotine self-administration (A) but not food-maintained responding (B). LY341495 alone reduced nicotine self-administration (A) and food self-administration (B). Interestingly, LY341495 attenuated the decreases in nicotine self-administration seen after administration of 6 or 9 mg/kg MPEP (A), as demonstrated by a significant LY341495 × MPEP dose interaction (# for P<0.01; see text for details). Data are expressed as mean±S.E.M. percent of baseline (mean of last three days of baseline nicotine or food responding). Asterisks indicate significant differences from the corresponding vehicle condition (Dunnett's tests: * P<0.05, ** P<0.01, *** P<0.001).

Figure 2

The effects of repeated injections of the mGlu5 receptor antagonist MPEP on intracranial self-stimulation threshold elevations (A) and somatic signs (B) associated with spontaneous nicotine withdrawal. Rats received MPEP injections (3 mg/kg) or vehicle 30 min before testing at the 24-168 h time points, as indicated by vertical lines over the time-points when injections were administered. A: Intracranial self-stimulation thresholds were tested 6, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 240 h after pump removal. There was a significant elevation in intracranial self-stimulation thresholds in the nicotine-withdrawing rats compared to control rats [Pump content × Time interaction: F(10,250)=5.12; P<0.001]. Treatment with MPEP elevated intracranial self-stimulation thresholds in both nicotine- and saline withdrawing rats [Drug × Time interaction: F(10,250)=2.02, P<0.05]. Asterisks indicate significant difference from the corresponding saline-vehicle control condition (Dunnett's tests: * P<0.05, *** P<0.001). Data are expressed as mean±S.E.M. percentage change from baseline thresholds prior to removal of nicotine- or saline-containing osmotic mini-pumps. B: Somatic signs were assessed immediately following the intracranial self-stimulation test sessions 6, 24, 48, 72, 96, 168, 192 and 240 h after pump removal. Data are expressed as mean±S.E.M. of total number of somatic signs observed during the 10 min observation periods. Somatic signs were increased in nicotine-treated compared to saline-treated animals [Pump × Time interaction: F(7,175)=7.30; P<0.001]. MPEP increased somatic signs in both nicotine- and saline-treated rats [MPEP × Time interaction: F(7,175)=2.18; P<0.05]. Asterisks (Dunnett's test: * P<0.05) indicate significant difference from the vehicle-treated control group.

Figure 3

The effects of co-administration of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on intracranial self-stimulation threshold elevations associated with spontaneous nicotine withdrawal. Intracranial self-stimulation thresholds were assessed 6, 12, 24, 48, 72, 96 and 120 h after pump removal. Rats received a single co-administration of MPEP (3 mg/kg) and LY341495 (1 mg/kg) or vehicle 30 min before testing at the 12-h time point (indicated by a vertical line). There was a significant elevation in intracranial self-stimulation thresholds in the nicotine-withdrawing rats compared to control rats [Pump content × Time interaction: F(6,300)=7.93; P<0.001]. The combined treatment with MPEP and LY341495 had no effect on intracranial self-stimulation elevations induced by the removal of the nicotine-containing pumps and did not affect intracranial self-stimulation thresholds in the control rats. Asterisks (Dunnett's tests: * P<0.05, ** P<0.01) indicate significant difference from the vehicle-treated control group. Data are expressed as mean±S.E.M. percentage change from baseline thresholds prior to removal of nicotine-or saline-containing osmotic minipumps.

Figure 4

Comparison of the effects of the first MPEP administration and of co-administration of MPEP and LY341495 on intracranial self-stimulation thresholds in nicotine- and saline withdrawing rats. A. At the 24 h time point, the first MPEP injection similarly elevated intracranial self-stimulation thresholds in both nicotine- and saline withdrawing rats [main effect of MPEP: F(1,25)=6.44; # P<0.05, main effect of Nicotine: F(1,25)=5.05; P<0.05, no Nicotine × MPEP interaction]. B. At the 12 h time point, co-administration of MPEP and LY341495 had no effect in either nicotine or saline withdrawing rats [no main effect of MPEP/LY341495, NS for non-significant, main effect of Nicotine: F(1,51)=9.72; P<0.01, no MPEP/LY341495 × Nicotine interaction]. Data are expressed as mean±S.E.M. percentage change from baseline thresholds prior to removal of nicotine- or saline-containing osmotic minipumps. Data are represent measurements shown in Figures 2A (24 h time-point) and Figure 3 (12 h time-point).