Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens of rats

Abstract

Nicotine and methamphetamine (METH) cause addiction by triggering neuroplastic changes in brain reward pathways though they each engage distinct molecular targets (nicotine receptors and dopamine transporters respectively). Addiction to both drugs is very prevalent, with the vast majority of METH users also being smokers of cigarettes. This co-morbid occurrence thus raised questions about potential synergistic rewarding effects of the drugs. However, few studies have investigated the chronic neurobiological changes associated with co-morbid nicotine and METH addiction. Here we investigated the effects of these two drugs alone and in combination on the expression of several immediate early genes (IEGs) that are sensitive to drug exposures. Chronic exposure to either nicotine or METH caused significant decreases in the expression of fosb, fra1, and fra2 in the nucleus accumbens (NAc) but not in the dorsal striatum whereas the drug combination increased fra2 expression in both structures. Except for junB mRNA levels that were decreased by the three drug treatments in the NAc, there were no significant changes in the Jun family members. Of the Egr family members, NAc egr2 expression was decreased after nicotine and the drug combination whereas NAc egr3 was decreased after METH and the drug combination. The drug combination also increased striatal egr3 expression. The Nr4a family member, nr4a2/nurr1, showed increased striatal expression after all three drug treatments, while striatal nr4a3/nor-1 expression was increased by the drug combination whereas NAc nr4a1/nurr77 was decreased by nicotine and the drug combination. These observations suggest that, when given in combination, the two drugs exert distinct effects on the expression of IEGs in dopaminergic projection areas from those elicited by each drug alone. The significance of these changes in IEG expression and in other molecular markers in fostering co-morbid METH and nicotine abuse needs to be further evaluated.

Figure 1

Effects of chronic nicotine, chronic METH and their combination on mRNA levels of Fos IEG family in the rat dorsal striatum. Rats were treated as described in the text. Results are presented as fold-changes SEM. The data were analyzed by one-way ANOVA followed by Fisher’s protected least significant difference (PLSD) post-hoc test. Key to statistics: * compared to SS; # compared to NS; ! compared to SM. Symbol guide: single symbol, p< 0.05; double symbol, p< 0.01, and triple symbol, p<0.001. n=7–8 rats per groups.

Figure 2

Effects of chronic nicotine, chronic METH and their combination on mRNA levels of Fos IEG family in the rat NAc. Treatment is as described in the text. Results are presented as fold-changes ± SEM. The results were analyzed by one-way ANOVA followed by Fisher’s PLSD post-hoc test. Key to statistics: * compared to SS; # compared to NS; ! compared to SM. Symbol guide: single symbol, p< 0.05; double symbol, p< 0.01, and triple symbol, p<0.001. n=4–7 rats per groups.

Figure 3

Effects of chronic nicotine, METH, and their combination on mRNA levels of mRNA levels of Jun IEG family members in the rat dorsal striatum. Treatment is as described in the text. Results are presented as described in figure 1. Key to statistics: !, p< 0.05, in comparison to the SM group. n=6–8 rats per groups

Figure 4

Effects of chronic nicotine, METH and their combination on the expression of Jun IEG family in the rat NAc. Results are presented as described in figure 1. Key to statistics: * compared to SS; # compared to NS. Symbol guide: single symbol, p< 0.05 and triple symbol, p<0.001. n=4–8 rats per groups.

Figure 5

Effects of chronic nicotine, METH and their combination on mRNA levels of Egr IEG family members in the rat dorsal striatum. Results are presented as in figure 1. Key to statistics: * compared to SS; # compared to NS; ! compared to SM. Symbol guide: double symbol, p< 0.01. n=6–8 rats per groups.

Figure 6

Effects of chronic nicotine, METH and their combination on the NAc expression of Egr IEG family members. Treatment is as described in the text. Key to statistics: * compared to SS; # compared to NS; ! compared to SM. Symbol guide: single symbol, p< 0.05; double symbol, p< 0.01, and triple symbol, p<0.001. n=4–8 rats per groups.

Figure 7

Effects of chronic nicotine, METH and their combination on mRNA levels of Nr4a IEG family members in the rat dorsal striatum. Treatment is as described in the text. Results are presented as above. Key to statistics: * compared to SS; # compared to NS; ! compared to SM. Symbol guide: single symbol, p< 0.05; double symbol, p< 0.01, and triple symbol, p <0.001. n=6–8 rats per groups.

Figure 8

Effects of chronic nicotine, METH and their combination on the NAc expression of Nr4a IEG family members. Key to statistics: * compared to SS; # compared to NS. Symbol guide: double symbol, p< 0.01, and triple symbol, p<0.001. n=4–8 rats per groups.