The present studies showed that administration of the GABAB receptor allosteric positive modulators CGP7930, GS39783, or BHF177 attenuated the reinforcing effects of nicotine. Administration of GS39783 increased the attenuating effect of a sub-effective dose of the GABAB receptor agonist CGP44532 on nicotine reinforcement, thereby selectively decreasing nicotine- but not food-maintained responding. In addition, administration of BHF177 attenuated the motivation to seek nicotine, assessed via a progressive-ratio schedule of reinforcement, while having limited effects on food-maintained responding under either fixed- or progressive-ratio schedules of reinforcement. Furthermore, administration of either BHF177 or the GABAB receptor agonist CGP44532 blocked the reward-enhancing effects of noncontingent nicotine, although these effects are likely to be nonspecific because these compounds elevated thresholds on their own (indicated by the lack of statistically significant interactions).
Data obtained from fixed-ratio schedules of reinforcement provide a measure of drug intake and reinforcer efficacy. Nicotine self-administration exhibits a relatively flat dose-response curve under a fixed-ratio schedule of reinforcement that is shifted downward after administration of nicotinic acetylcholine receptor antagonists. This decrease in nicotine self-administration is seen at all unit doses of nicotine tested (e.g., Donny et al., 1999
; Watkins et al., 1999
; but see Fattore et al., 2002
). Therefore, the decreased nicotine self-administration observed after pretreatment with any one of the three GABAB
receptor positive modulators in the present studies can be unambiguously interpreted as a decrease in the reinforcing effects of nicotine. Although the effects of the GABAB
receptor positive modulator CGP7930 were not assessed on responding for a non-nicotine reinforcer, administration of either GS39783 or BHF177 decreased nicotine intake at doses that had no effect on responding for food under a fixed-ratio schedule. Administration of the GABAB
receptor agonist CGP44532 selectively decreased nicotine vs.
food self-administration on the fixed-ratio schedule of reinforcement, and co-administration of both GS39783 and CGP44532 had additive effects in decreasing nicotine self-administration. Only co-administration of the two highest doses of the two compounds (40 mg/kg of GS39783 + 0.25 mg/kg of CGP44532) decreased food-maintained responding in addition to decreasing nicotine self-administration.
Data obtained from progressive-ratio schedules of reinforcement provide a measure of the motivation to obtain a reinforcer (Arnold and Roberts, 1997
). The present studies indicated that administration of intermediate doses of the GABAB
receptor positive modulator BHF177 attenuated the motivational properties of nicotine without decreasing breakpoints for food. Nonetheless, the highest dose of BHF177 (40 mg/kg) significantly decreased breakpoints for both nicotine and food. The same dose of BHF177 selectively decreased nicotine but not food-maintained responding under a fixed-ratio schedule of reinforcement, perhaps indicating greater sensitivity of the motivational effects of nicotine to enhanced GABAergic tone, although this difference also may be explained by the increased response requirements under the progressive-compared to the fixed-ratio schedule.
The selective nature of the effects of GABAB
receptor positive modulators contrasts with the nonselective suppressant effects of the GABAB
receptor agonist compounds baclofen or CGP44532 on nicotine or cocaine self-administration compared with food-maintained responding when administered either acutely (Roberts et al., 1996
; Paterson et al., 2004
) or chronically (Paterson et al., 2005b
). Nevertheless, the GABAB
receptor agonist CGP44532 also selectively decreased breakpoints for cocaine but not food under a progressive-ratio schedule of reinforcement (Brebner et al., 1999
). Corrigall and colleagues (2000)
suggested that the different degrees of selectivity for cocaine- or nicotine- vs.
food-maintained responding may be related to greater recruitment of GABAergic negative feedback from the nucleus accumbens to the ventral tegmental area after cocaine vs.
Interestingly, the nonselective effects of the highest BHF177 dose on the motivational properties of nicotine also were seen clearly in the ICSS procedure, where 30 mg/kg BHF177 significantly elevated ICSS thresholds when administered alone. The intermediate doses of BHF177 (7.5 and 15 mg/kg) blocked the ICSS threshold-lowering effect of noncontingent nicotine while nonsignificantly elevating brain reward thresholds. These doses of BHF177 are in the same range as the doses of BHF177 (10 and 20 mg/kg) that selectively decreased nicotine- but not food-maintained responding under fixed- and progressive-ratio schedules of reinforcement. As indicated above, the ICSS threshold-lowering effect of acute nicotine is hypothesized to reflect the reward-enhancing effect of nicotine (Harrison et al., 2002
; Kenny and Markou, 2006
). Thus, administration of the GABAB
positive receptor modulator BHF177 attenuated the reinforcing, reward-enhancing, and motivational properties of nicotine. In contrast to the effects of BHF177, only the highest dose of CGP44532 blocked the threshold-lowering effect of nicotine at a dose that significantly impaired brain reward function when administered alone (0.5 mg/kg). A lower dose of CGP44532 (0.25 mg/kg) that elevated ICSS thresholds when administered alone but did not block the reward-enhancing effect of nicotine, decreased nicotine self-administration under the fixed-ratio schedule.
As indicated previously, GABAB
receptor agonists exert unwanted locomotor side-effects, in contrast to the GABAB
receptor positive modulators that are mostly free of such undesirable side-effects (Cryan et al., 2004
). Consistent with a lack of locomotor suppression by the GABAB
receptor positive modulator GS39783 (Cryan et al., 2004
), the present self-administration studies found no effect of administration of any of the positive modulators on inactive lever responding, unlike the GABAB
receptor agonist CGP44532. In the ICSS experiments, although BHF177 was found to increase response latencies, CGP44532 had no such effect. Finally, the selective effects of GS39783 and BHF177 on nicotine vs.
food-maintained responding suggest the absence of motor-suppressant effects because behaviors emitted at higher rates (such as food-maintained responding in the present studies) tend to be more sensitive to locomotor-suppressant effects of drug pretreatments. Taken together, these results clearly indicate that the effects of GABAB
receptor positive modulators on the behaviors reported here are highly unlikely to be attributable to motor suppressant effects of these compounds.
The behavioral effects of the GABAB
receptor positive modulators in the present study are consistent with GS39783-induced blockade of the rewarding effects of nicotine measured with the conditioned place preference procedure in rats (Mombereau et al., 2007
). Administration of GS39783 also prevented nicotine-induced accumulation of δFosB in the nucleus accumbens (Mombereau et al., 2007
). Beyond nicotine, the GABAB
receptor positive modulators GS39783 and CGP7930 decreased ethanol intake in alcohol-preferring rats (Orru et al., 2005
), with no effect on responding for water in the case of CGP7930 (Liang et al., 2006
). Interestingly, co-administration of subeffective doses of the GABAB
receptor agonist baclofen and CGP7930 decreased ethanol self-administration (Liang et al., 2006
), similar to the effects of co-administration of CGP44532 and GS39783 in the present study. Previously, the GABAB
receptor positive modulators GS39783 and CGP7930 decreased cocaine self-administration under both fixed- and progressive-ratio schedules (Smith et al., 2004
). More recently, CGP7930 selectively decreased cocaine, but not food, self-administration (Filip et al., 2007
) and attenuated cocaine- and cue-induced reinstatement of cocaine-seeking behavior, but not food-induced reinstatement of food-seeking behavior (Filip and Frankowska, 2007
). Furthermore, consistent with the present data, the GABAB
receptor positive modulator GS39783 selectively attenuated cocaine-induced lowering of ICSS thresholds, unlike baclofen that blocked cocaine-induced reward facilitation at doses that elevated ICSS thresholds when administered alone (Slattery et al., 2005
). Finally, GS39783 partially attenuated cocaine-induced δFosB induction in the dorsal striatum and blocked cocaine-induced CREB (cyclic adenosine monophosphate [cAMP] response-element binding protein) activation and DARPP-32 (dopamine and cAMP-regulated phosphoprotein with relative molecular weight of 32 kDa) accumulation in the nucleus accumbens in the mouse (Lhuillier et al., 2006
). Thus, GABAB
receptor allosteric positive modulators attenuate the reinforcing and motivational properties of ethanol, cocaine, cocaine-associated conditioned reinforcers, and the molecular correlates of psychostimulant exposure.
In summary, accumulating evidence suggests that GABAB
receptor allosteric positive modulators may be useful in attenuating the reinforcing, motivational, and reward-facilitating effects of nicotine (present studies) and in preventing nicotine-induced δFosB accumulation (Mombereau et al., 2007
). Thus, the currently available data indicate that GABAB
receptor positive modulators deserve further investigation as potential treatments for nicotine dependence.