Nicotine and methamphetamine share discriminative stimulus effects

Abstract

Background: Nicotine and methamphetamine are both abused in similar settings, sometimes together. Because there are known interactions between central nicotinic acetylcholine receptors and dopamine receptors, it is of interest to characterize the nature of the interaction of these two compounds in vivo.

Methods: The purpose of this study was to characterize the extent to which these two compounds produce similar discriminative stimulus effects and to identify pharmacological mechanisms for their interaction. Male Sprague-Dawley rats were trained to discriminate methamphetamine or nicotine from saline. First, the ability of methamphetamine and nicotine to cross-substitute in rats trained to the other compound was tested. Subsequently, the ability of a dopamine antagonist (haloperidol) and a centrally acting nicotinic antagonist (mecamylamine) to block the discriminative stimulus effects of methamphetamine and nicotine were also tested.

Results: Nicotine fully substituted in methamphetamine-trained rats, but methamphetamine only partially substituted in nicotine-trained rats. In nicotine-trained rats, mecamylamine fully antagonized the discriminative stimulus effects of nicotine, but haloperidol had no effect. The partial substitution of methamphetamine was partially attenuated by haloperidol, but not altered by mecamylamine. In methamphetamine-trained rats, mecamylamine failed to antagonize the discriminative stimulus effects of methamphetamine, but haloperidol fully blocked the methamphetamine cue. Mecamylamine blocked the ability of nicotine to substitute for methamphetamine, but haloperidol had no effect.

Conclusions: These results indicate that nicotine and methamphetamine share discriminative stimulus effects in some subjects and that the two compounds do not act at the same site, but produce their interaction indirectly. These findings suggest that these two compounds might be at least partially interchangeable in human users, and that there are potentially interesting pharmacological reasons for the commonly observed co-administration of nicotine and methamphetamine.

Figure 1. Substitution and blockade of the discriminative stimulus effects of nicotine (0.4 mg/kg, i.p.)

Top panels show percent nicotine-lever appropriate responding. Bottom panels show rate of responding (r/s). Nicotine and methamphetamine fully substituted for the discriminative stimulus effects of nicotine (left panels). Nicotine increased response rates, whereas methamphetamine decreased rates. Asterisks show response rates different from vehicle control (p<0.05). Mecamylamine fully blocked the discriminative stimulus effects of nicotine, whereas haloperidol had no effect (right panels). Mecamylamine did not change response rates, whereas haloperidol dose-dependently decreased rates. N=10 except where shown. Asterisks indicate response rates different from nicotine control (p<0.05). Nic=nicotine; Meth=methamphetamine. Hal= haloperidol; Mec=mecamylamine. Ctrl=control.

Figure 2. Substitution and blockade of the discriminative stimulus effects of methamphetamine (1 mg/kg, i.p.)

Top panels show percent methamphetamine-lever appropriate responding. Bottom panels show rate of responding (r/s). Methamphetamine fully substituted for the discriminative stimulus effects of methamphetamine, but nicotine produced only partial substitution (left panels). Methamphetamine did not alter response rates at the doses tested. Nicotine dose-dependently decreased response rates. Asterisks show response rates different from vehicle control (p<0.05). Haloperidol fully blocked the discriminative stimulus effects of methamphetamine, whereas mecamylamine produced only a small attenuation of drug-appropriate responding (right panels). Haloperidol did not change response rates, whereas mecamylamine decreased rates. N=10 except where shown. Asterisks indicate response rates different from nicotine control (p<0.05). Nic=nicotine; Meth=methamphetamine. Hal= haloperidol; Mec=mecamylamine. Ctrl=control.

Figure 3. Antagonism of cross-substitution

Left panels show the effects of nicotine (0.25 mg/kg, s.c.) alone and in combination with mecamylamine and haloperidol in methamphetamine-trained rats. Nicotine partially substituted in methamphetamine-trained rats. The top panel shows haloperidol did not alter the effects of nicotine, whereas the bottom panel shows mecamylamine (0.1 and 0.5 mg/kg, i.p.) fully blocked the partial substitution of nicotine for methamphetamine. Right panels show the effects of methamphetamine (1 mg/kg, i.p.) alone and in combination with mecamylamine and haloperidol in nicotine-trained rats. The top panel shows haloperidol modestly attenuated the ability of methamphetamine to partially substitute for nicotine, whereas the bottom panel shows mecamylamine (0.25, 1 and 10 mg/kg, i.p.) did not alter the ability of methamphetamine to partially substitute for nicotine. Nic=nicotine; Meth=methamphetamine. Hal=haloperidol; Mec=mecamylamine.