Time course of spontaneous nicotine somatic withdrawal. (a) Somatic withdrawal signs were recorded in mice at 30 min, 4, 8, 12, 24, and 48 h after minipump removal. After 13 days of nicotine minipumps (7 mg/kg/day (n=6) and 1.4 mg/kg/day (n=6)), an abstinence syndrome compared with saline-treated mice (n=6) was observed that peaked at 8 h after pump removal (^*p<0.05). D₂ (−/−) mice treated with 7 mg/kg/day nicotine (n=6) observed for abstinence signs 8 h after pump removal showed a somatic withdrawal syndrome that did not differ from wild-type mice. (b) Somatic withdrawal signs were recorded in rats at 30 min, 4, 8, 12, 16, 24, 36 and 48 h after minipump removal. After 7 days of nicotine minipumps (1 mg/kg/day (n=8) and 3.16 mg/kg/day (n=8)), an abstinence syndrome compared with saline-treated rats (n=8) was observed that peaked at 16 h after pump removal (^*p<0.05). Rats treated with 0.1 mg/kg α-flupenthixol (α-flu) (n=6) observed for abstinence signs 16 h after pump removal showed a somatic withdrawal syndrome that differed from saline-treated rats (^*p<0.05). (c) Mice were trained in the W procedure at 4, 8, and 12 h after pump removal at the 7 mg/kg/day chronic nicotine dose. A significant motivational effect was observed in chronic nicotine-treated mice only at the 8-h time point (^*p<0.05). Data represent means±SEM.

Dopaminergic signaling differentially mediates the opponent motivational process after acute and chronic nicotine. (a) Mice chronically treated with nicotine (7 mg/kg/day) and pretreated with saline (n=8) show a conditioned place aversion to the withdrawal-paired environment in the B procedure. α-flu (0.08 mg/kg, i.p.) given 1 h before conditioning during chronic nicotine administration (no delay; n=11) did not prevent the aversive response from occurring. However, α-flu given before conditioning after 8 h of abstinence from chronic nicotine (delay) blocked the aversive response from occurring (^*p<0.05 vs saline). (b) Previously drug naive mice given acute nicotine (1.75 mg/kg, s.c.), pretreated with saline (n=14), and conditioned after 8 h of abstinence from nicotine show a preference for the acute withdrawal-paired environment. α-flu (0.08 mg/kg, i.p.) administered before acute nicotine (no delay; n=12) prevented the rewarding response from occurring (^*p<0.05 vs saline). However, α-flu given before conditioning after 8 h of abstinence from acute nicotine (delay; n=16) did not prevent the occurrence of the rewarding response. Data represent means±SEM.

(a) The opponent process theory of motivation. Solomon and Corbit (1974) postulated that any stimulus would trigger an initial a-process that will closely follow the stimulus and will be fast to occur and fast to end. The a-process can be rewarding or aversive and will be followed by a later occurring b-process that is longer lasting, slower to end and is opposite in direction to the a-process. At the dose used in the present experiments, acute nicotine is aversive and the a-process is therefore negative. The acute nicotine b-process will be later occurring and positive or rewarding. We postulate that chronic nicotine elicits a rewarding a-process in dependent animals and the aversion to nicotine withdrawal is the conditioned opponent b-process. (b) The B, N, and W procedures. In procedure B, each animal experienced the effects of nicotine in one environment (Nic) and the lack of nicotine (or the effects of withdrawal) in the other environment (WD). Procedure B measures both the rewarding value of the drug itself and the aversiveness associated with drug withdrawal. In procedure N, each animal was conditioned only while experiencing the effects of chronic nicotine. On the alternate day, the animals experienced withdrawal in their home cage. Procedure N measures the rewarding value of the drug itself. In procedure W, conditioning took place only while the animals experienced withdrawal from nicotine. On the alternate day, the animal was confined to its home cage during chronic nicotine exposure. Procedure W measures only the aversive motivational effects of drug withdrawal, separate from the rewarding value of the drug itself.

The opponent processes of chronic and acute nicotine and the effect of dopamine (DA) antagonism. (a) Separation of the rewarding effects of chronic nicotine from the aversive effects of withdrawal in nicotine-dependent mice, as revealed by a modified place conditioning paradigm for assessing the rewarding effects of nicotine only (Nicotine procedure; n=11), the aversive effects of nicotine withdrawal (Withdrawal procedure; n=14), or both the rewarding effects of nicotine and the aversive effects of withdrawal (Both procedure; n=15). Nicotine-dependent mice conditioned in all three procedures showed a significant motivational response as compared with saline-treated animals (^*p<0.05). (b) α-flu (0.08 mg/kg, i.p.) pretreatment attenuated the motivational response in each of the B (n=16), N (n=12), and W (n=14) procedures, and had no motivational effect in saline-treated mice. (c) Separation of the rewarding effects of chronic nicotine from the aversive effects of withdrawal in nicotine-dependent rats. Significant effects were observed in the Both (n=8) and Withdrawal (n=10) procedures, but not in the Nicotine (n=10) procedure (^*p<0.05) as compared with saline. (d) α-flu (0.1 mg/kg) pretreatment attenuated the Both (n=8) and Withdrawal (n=4) effects. (e) Previously drug naive mice (n=13) administered a single dose of nicotine (1.75 mg/kg, s.c.) and conditioned immediately (0 h) in the B procedure showed a significant conditioned place aversion for the nicotine-paired environment (^*p<0.05). Mice (n=14) conditioned 8 h after acute nicotine administration showed a significant preference for the nicotine-paired environment (^*p<0.05). Mice conditioned 4 or 12 h after nicotine administration showed no significant effect. Data represent means±SEM.

The DA D₂ receptor mediates the aversive response to chronic nicotine withdrawal. Wild-type mice (D₂ (+/+); n=10) conditioned in procedure N showed a preference for chronic nicotine that was not present in D₂ (−/−) mice (n=7; ^*p<0.05). D₂ (−/−) mice (n=13) conditioned in procedure W did not show nicotine aversions whereas D₂ (+/+) mice (n=14) showed normal aversions to chronic nicotine withdrawal (^*p<0.05). Data represent means±SEM.