Nicotine and amphetamine acutely cross-potentiate their behavioral and neurochemical responses in female Holtzman rats

Abstract

Rationale: Psychostimulants are often used in close temporal proximity to nicotine and have been reported to enhance acutely nicotine's desirability in humans.

Objective: To investigate the acute associations between amphetamine and nicotine, we examined the potentiative interactions between clinically relevant, low doses of these drugs on locomotor activity, and dopamine overflow in the rat.

Materials and methods: Locomotor activity was measured by telemetry in the home cage environment, and dopamine overflow was evaluated in striatal slice preparations from female Holtzman rats.

Results: When administered simultaneously, nicotine and amphetamine produced a predominantly additive effect on locomotor behavior. However amphetamine, when given 2-4 h before nicotine, strongly potentiated nicotine-induced locomotor activity. Correspondingly, nicotine given 1-4 h before amphetamine robustly enhanced amphetamine-stimulated locomotor activity even when the effects of the nicotine pretreatment dissipated. Acute nicotine pretreatment similarly potentiated the effects of dopamine transporter ligands, cocaine, nomifensine, and methamphetamine but not a direct dopamine receptor agonist. Consistent with the behavioral studies, in vivo nicotine pretreatment exaggerated amphetamine-induced dopamine efflux from rat striatal slices. Likewise, in vivo pretreatment of rats with amphetamine potentiated nicotine-induced dopamine efflux from striatal slices. Direct pretreatment of striatal tissue by nicotine also potentiated subsequent amphetamine-stimulated dopamine overflow, further suggesting that the nicotine-amphetamine interaction occurs at the level of the dopamine terminal.

Conclusion: Overall, the present data demonstrate that acute interactions of nicotine and other psychomotor stimulants produce potentiative effects and that these transient interactions may play a role in the frequent co-use and abuse of nicotine and other stimulants.

Figure 1.

Simultaneous administration of amphetamine and nicotine. Rats were administered (i.p.) either saline, 0.32 mg/kg amphetamine, 0.32 mg/kg nicotine, or a combination of 0.32 mg/kg amphetamine with 0.32 mg/kg nicotine. The injections occurred at time 0.

Figure 2.

Acute interactions between amphetamine and nicotine. (a,c,e,f) Nicotine (0.32 mg/kg) or amphetamine (0.32 mg/kg) pretreatments were administered 2 h prior to an acute challenge with either nicotine (0.32 mg/kg) or amphetamine (0.32 mg/kg). The combination of pretreatment and challenge is designated by “pretreatment + challenge” on each graph. The pretreatment injection occurred at time 0, and the challenge injection occurred at 120 min as indicated by the break in the x-axis. (b,d,f,h) The locomotor activity counts were summed from 120 to 210 min in order to obtain the total activity counts produced by each challenge condition. * p<0.05 as compared with saline-pretreated rats.

Figure 3.

Activity counts stimulated by amphetamine challenge (0.32 mg/kg) following nicotine pretreatments (a) 4 h or (b) 8 h prior to challenge injection. Only one nicotine dose (0.32 mg/kg) was administered as a 8 h pretreatment to amphetamine challenge. Activity counts stimulated by nicotine challenge (0.32 mg/kg) following amphetamine pretreatments (c) 4 h or (d) 8 h prior to challenge injection. Only one amphetamine dose (0.32 mg/kg) was administered as an 8 h pretreatment to nicotine challenge.

Figure 4.

(a) The effects of in vivo saline (●) or nicotine (○) pretreatment on amphetamine-stimulated dopamine overflow from striatal slices. Rats were injected with saline or 0.32 mg/kg nicotine (i.p.) 4 h prior to sacrifice. Striatal slices were collected and washed for 75 min, then exposed to 10 μM amphetamine for 5 min at fraction 5 to stimulate dopamine release. (b) The effects of in vitro saline (●) or nicotine (○) pretreatment on amphetamine-stimulated dopamine overflow from striatal slices. Striatal slice from naïve rats were collected and washed for 60 min. Slices were exposed to 10 μM nicotine for 15 min prior to the start of fraction collection. Dopamine overflow was stimulated by 10 μM amphetamine. Dopamine overflow is reported as pmol/mg wet weight of striatum. (c) The effects of in vivo saline (●) or amphetamine (○) pretreatment on nicotine-stimulated dopamine overflow from rat striatal slices. Rats were injected with saline or 0.32 mg/kg amphetamine (i.p.) 4 h prior to sacrifice. Striatal slices were collected and washed for 75 min and then exposed to 30 μM nicotine for 5 min at fraction 6 only. In all graphs, the arrow indicates when the challenge was administered. * p<0.05, ** p<0.01, *** p<0.001 as determined by Bonferroni’s post hoc test.

Figure 5.

The nonselective nicotinic receptor antagonist mecamylamine was administered before nicotine pretreatment in order to determine of the nicotinic receptor mediated the nicotine-induced enhancement of amphetamine. Rats were injected with saline (●, ○) or mecamylamine (▾) 1 h prior to the pretreatment (saline (●) or 0.32 mg/kg nicotine (○)), and the amphetamine challenge (0.32 mg/kg) was administered 4 h later. These data show the data collected following the amphetamine challenge in terms of (a) time course or (b) total activity counts for 90 min following challenge injection. ** p<0.01 as compared with sal + sal pretreatment, ## p<0.01 as compared with sal + nic pretreatment.

Figure 6.

The effects of nicotine pretreatment on locomotor activity induced by other psychomotor stimulants: (a) cocaine, (b) nomifensine, (c) methamphetamine, or (d) the direct dopamine D1 agonist SKF81297. Saline or 0.32 mg/kg nicotine (i.p.) was administered 2 h prior to 3.2 mg/kg cocaine, 1.0 mg/kg nomifensine, 0.56 mg/kg methamphetamine, 0.32 mg/kg SKF81297, or 1.0 mg/kg SKF81297. For comparison, saline alone stimulates approximately 200 counts of activity. Data are expressed as total locomotor activity counts for 90 min following the challenge injection ± sem. * p<0.05 as compared with saline pretreatment.