Effect of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide on Acquisition and Expression of Nicotine-Induced Behavioral Sensitization and Striatal Adenosine Levels

Abstract

Introduction: Behavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release.

Objective: The aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization.

Methods: In the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV.

Results: Taken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum.

Conclusion: The behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS.

Keywords: 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS); HPLC; adenosine; drug addiction; locomotor activity; nicotine sensitization; pharmacotherapy.

Figure 1

Effect of nicotine administration (0.5 mg/kg i.p.) on the induction of behavioral sensitization. BALB/c mice (n=6/group) were used for a seven days protocol with a nicotine challenge dose on day 11. One-way ANOVA followed by Tukey’s test revealed a significant difference **p<0.01, ***p<0.001, on days 7 and 11 between normal saline and nicotine-treated groups, which confirmed the development of the behavioral sensitization model group.

Figure 2

Effect of 4-FBS 20, 40, 60mg/kg p.o. on the acquisition of nicotine-induced behavioral sensitization. BALB/c mice (n=6/group) were used in this protocol. On day 1, one-way ANOVA followed by Tukey’s test showed no significance between nicotine and 4-FBS-treated groups while on day 7, only 40mg/kg showed significant result *p < 0.05 compared to nicotine. After 3 days of abstinence, all three doses, ie, 20, 40, 60mg/kg showed significant reduction in locomotion **p<0.01, ***P<0.001 compared to nicotine. No significant difference was observed between saline and 4-FBS 20, 40 and, 60mg/kg on days 7 and 11.

Figure 3

Effect of 4-FBS 20, 40, 60mg/kg p.o administration on the expression of nicotine-induced behavioral sensitization. BALB/c mice (n=6/group) were used in seven days protocol followed by a nicotine challenge dose on day 11. One-way ANOVA followed by Tukey’s test on day 11 showed that 4-FBS 40mg and 60mg have significant **p<0.01 ***p<0.001 reductions in locomotion as compared to nicotine. No significant difference was observed between saline and 4-FBS 20, 40 and, 60mg/kg on day 11.

Figure 4

Effect of nicotine sensitization on Adenosine turnover in the striatum. BALB/c mice (n=6/group) striatum were used for this protocol. Adenosine levels were significantly increased (**p<0.001) in the nicotine group in comparison to the saline group. No significant difference was observed between 4-FBS at 20, 40, and 60mg/kg and nicotine treated group. One-way ANOVA followed by Tukey’s multiple comparison tests was used for this analysis.

Figure 5

Effect of nicotine sensitization and 4-FBS on Adenosine turnover in the striatum. BALB/c mice (n=6/group) striatum were used for this protocol. Adenosine levels were significantly increased (***p<0.001) in the nicotine group compared to the saline group. 4-FBS at the dose of 60mg/kg significantly reduces adenosine (*p<0.05). Other doses 20, 40, mg/kg) have no significant difference over nicotine treated group. One-way ANOVA followed by Tukey’s multiple comparison tests was used for this analysis.