'Nicotine deprivation effect' in rats with intermittent 23-hour access to intravenous nicotine self-administration

Abstract

Our previous work demonstrates that rats allowed extended 23-hour access to intravenous nicotine self-administration (IVSA) display voluntary, dose-related levels of nicotine intake (i.e., higher doses result in higher intake) that remain stable across 40 days. This study examined whether an escalating dose regimen with intermittent abstinence periods produces different levels of nicotine intake relative to those observed during continuous access to a fixed unit dose. Rats were trained to nose-poke for food and water in 23-hour sessions prior to and after recovery from surgical implantation of jugular catheters. Animals (n=12) then were given access to nicotine IVSA in 4-day cycles, each separated by three intervening days of abstinence in their home cage. The unit dose available for nicotine IVSA was increased between cycles as follows: 0.015, 0.03, 0.06, 0.09 mg/kg/0.1 ml infusion/1 s, fixed ratio 1. Control rats (n=6) were given access to saline for five 4-day IVSA periods. Nicotine dependence was assessed by examining physical signs of withdrawal following an injection of the nicotinic antagonist mecamylamine (1.5 mg/kg, i.p.). Nicotine intake dose-dependently increased between cycles. Within each cycle, nicotine intake was highest on the first day after abstinence and decreased over the next 3 days of continuous access. Mecamylamine produced a significant increase in overt signs of withdrawal in the 23-hour access animals comparable to that observed in previous studies of nicotine dependence. Our findings suggest that abstinence from nicotine may produce a "deprivation effect" in nicotine-dependent rats. In addition, intermittent access to increasing unit doses appears to produce higher levels of nicotine intake than continuous access to a constant unit nicotine dose.

Fig 1

Nicotine intake (solid circles; mean mg/kg ± SEM) and saline intake (open circles; mean ml/kg ± SEM) during the entire 23 h session in rats allowed 23 h access to saline or escalating doses of nicotine (0.015, 0.03, 0.06, or 0.09 mg/kg/0.1 ml infusion) for 4-day repeated cycles of access. Rats receiving intermittent access to nicotine displayed a dose-dependent increase in nicotine intake (main effect of dose; F_2,22 = 117.1, p < 0.001). Asterisks (*) denote that higher levels of nicotine intake were observed across time in rats receiving the 0.09 dose relative to the 0.06 and 0.03 doses of nicotine (p < 0.001). Daggers (†) denote that higher levels of nicotine intake were observed in rats receiving the 0.06 dose relative to the 0.03 dose of nicotine (p < 0.001). Plus signs (+) denote that lower levels of nicotine intake were observed in rats receiving the 0.03 dose relative to the 0.06 and 0.09 doses of nicotine (p < 0.001). The pattern of intake was the same the first and second time the rats received the same dose of nicotine. There were no changes in saline intake across time.

Fig 2

Nicotine intake (solid circles; mean mg/kg ± SEM) and saline intake (open circles; mean ml/kg ± SEM) during the first hour of nicotine access (11 AM– 12 PM) in rats allowed 23 h access to saline or escalating doses of nicotine (0.015, 0.03, 0.06, or 0.09 mg/kg/0.1 ml infusion) for repeated 4-day cycles of access. The pattern of nicotine intake in the first hour of access was similar to the pattern of intake observed across 23 h. A dose-dependent increase in nicotine intake was observed (main effect of dose; F_2,22 = 75.4, p < 0.001). Asterisks (*) denote that higher levels of nicotine intake were observed across time in rats receiving the 0.09 dose relative to the 0.06 and 0.03 doses of nicotine (p < 0.001). Daggers (†) denote that higher levels of nicotine intake were observed in rats receiving the 0.06 dose relative to the 0.03 dose of nicotine (p < 0.001). Plus signs (+) denote that lower levels of nicotine intake were observed in rats receiving the 0.03 dose relative to the 0.06 and 0.09 doses of nicotine (p < 0.001).

Fig 3

Total food intake in rats allowed 23 h access to escalating doses of nicotine (0.015, 0.03, 0.06, or 0.09 mg/kg/0.1 ml infusion) for seven 4-day cycles of nicotine IVSA (solid circles) or in saline control rats (open circles) given five 4-day cycles of saline IVSA. A dose-dependent decrease in food intake was observed (main effect of dose; F_2,22 = 127.5, p < 0.001). Asterisks (*) denote that lower levels of food intake were observed across time in rats receiving the 0.09 dose of nicotine relative to the 0.06 and 0.03 doses (p < 0.001). Daggers (†) denote that lower levels of nicotine intake were observed in rats receiving the 0.06 dose relative to the 0.03 dose of nicotine (p < 0.001). Plus signs (+) denote that higher levels of nicotine intake were observed in rats receiving the 0.03 dose relative to the 0.06 and 0.09 doses of nicotine (p < 0.001). The pattern of food intake was the same across all doses of nicotine, with rats responding less for food on the first day of nicotine access and then stabilizing their intake across the next 3 days. This likely reflects the fact that on the first day the rats had just received 2 days of free-access to food and water in their home cages. This pattern was different in saline control rats that displayed higher levels of food intake overall and did not show the initial decrease in food intake on the first day of the 4-day cycle.