Chronic nicotine alters cannabinoid-mediated locomotor activity and receptor density in periadolescent but not adult male rats

Abstract

A significant number of youths use cigarettes, and more than half of the youths who smoke daily also use illicit drugs. The focus of these studies is on how exposure to nicotine affects subsequent responses to both nicotine and cannabinoids in adolescents compared with adults. We have shown previously that chronic treatment with nicotine produces sensitization to its locomotor-activating effects in female and adult rats but not male adolescent rats. To better understand the effects of nicotine on adolescent and adult rats, rats were injected with nicotine or saline for 7 days and, on day 8, either challenged with delta-9-tetrahydrocannabinol (Delta 9-THC) or the cannabinoid agonist CP 55,940 and tested for locomotor activity, or the brains were removed for quantitative autoradiography studies of the cannabinoid(1) receptor. A separate group of rats was treated with nicotine plus the cannabinoid antagonist AM 251 and then challenged with CP 55,940. In adolescent male rats, nicotine administration led to sensitization to the locomotor-decreasing effects of both Delta 9-THC and CP 55,940, but in adult male rats, the response to either drug was unchanged compared to controls. The effect of nicotine on CP 55,940-mediated locomotor activity was blocked by co-administration of AM 251 with the nicotine. Further, cannabinoid receptor density was increased in the prelimbic prefrontal cortex, ventral tegmental area, and select regions of the hippocampus in adolescent male rats pretreated with nicotine compared to vehicle-treated controls. There were no significant changes in cannabinoid receptor binding, however, in any of the brain regions examined in adult males pretreated with nicotine. The prelimbic prefrontal cortex and the hippocampus have been shown previously to be involved in stimulant reinforcement; thus it is possible that these changes contribute to the unique behavioral effects of chronic nicotine and subsequent drug administration in adolescents compared with adults.

Figure 1

Locomotor activity in response to daily injections of nicotine (0.4 mg/kg/day). Activity was measured on the first 2 days (days 1 and 2) and last 2 days of the treatment period (days 6 and 7). Nicotine increased activity in both adolescent (PAM) and adult (ADM) rats, however, only the adult rats developed a significant sensitization to the locomotor-activating effects of nicotine. Data are expressed as % total distance traveled with vehicle injection (baseline) per 60 min test for adult male (ADM, unfilled squares) or periadolescent male (PAM, filled squares) rats. *Significantly different from day 1.

Figure 2

Effect of Δ9-THC on locomotor activity in naïve adult (ADM) and adolescent (PAM) rats. Activity was measured using a cumulative dosing procedure and Δ9-THC decreased activity in both groups of animals. The curves for decreasing locomotor activity were not significantly different in adolescent and adult rats.

Figure 3

Effect of 3.0 mg/kg Δ9-THC after 7 days of administration of nicotine in (A) adolescent or (B) adult rats. Δ9-THC had no effect on locomotor activity after vehicle treatment (compare VEH/VEH to NIC/VEH). However, Δ9-THC significantly decreased activity in adolescent rats after treatment with nicotine compared to vehicle (compare VEH/THC to NIC/VEH), but still had no effect in adult rats. *significant decrease in activity compared with vehicle.

Figure 4

Time course of locomotor activity in response to an acute injection of 0.3 mg/kg CP 55,940 or vehicle in adult male rats. Activity was measured at 5 min intervals. Rats given CP 55,940 exhibited lower levels of activity about 15 min after injection compared with rats given vehicle.

Figure 5

Locomotor activity in response to a CP 55,940 challenge on day 8, one day after a 7-day pretreatment with daily injections of nicotine or vehicle. (A) Periadolescent male rats pretreated with nicotine had significantly decreased activity levels in response to 0.1 and 0.3 mg/kg CP 55,940 compared to periadolescent male rats pretreated with vehicle (p < 0.05). (B) Activity levels were not significantly different in response to CP 55,940 in adult male rats pretreated with nicotine or vehicle. *significant difference compared with vehicle controls (p < 0.05).

Figure 6

(A)Co-administration of AM 251 with nicotine blocked the development of sensitization to CP 55,940 in periadolescent male rats. (B) As with nicotine alone, there were no effects of nicotine + AM 251 on the locomotor-decreasing effects of CP 55,940 in the adult male rats.

Figure 7

Cannabinoid receptor densities in the prefrontal cortex, substantia nigra, ventral tegmental area, and hippocampus on day 8, one day after a 7-day pretreatment with daily injections of nicotine or vehicle. (A) Periadolescent male rats pretreated with nicotine had significantly higher cannabinoid receptor densities in area 1 and area 3 of the cingulate cortex and area 2 of the frontal cortex compared to periadolescent male rats pretreated with vehicle (p < 0.05). (B) There were no significant changes in cannabinoid receptor densities in the prefrontal cortex in adult male rats pretreated with nicotine compared to adult rats pretreated with vehicle. (Cannabinoid receptor densities were measured in four areas of the prefrontal cortex (CG3: area 3 of the cingulate cortex, CG1: area 1 of the cingulate cortex, FR2: area 2 of the frontal cortex, AID: agranular insular cortex, IL: infralimbic area). (C) Periadolescent male rats pretreated with nicotine had significantly higher cannabinoid receptor densities in the ventral tegmental area, dentate gyrus, and the CA3 region of the hippocampus compared to periadolescent male rats pretreated with vehicle (p < 0.05). (D) There were no significant changes in cannabinoid receptor densities in the substantia nigra, ventral tegmental area, and hippocampus in adult male rats pretreated with nicotine compared to adult rats pretreated with vehicle. Cannabinoid receptor densities were measured in two areas of the substantia nigra (SNC: substantia nigra pars compacta, SNR: substantia nigra pars reticulata), the ventral tegmental area, and five areas of the hippocampus (DG: dentate gyrus, CA1, CA2, CA3). *indicates a significant difference from rats pretreated with vehicle, p ≤ 0.05.