Trait differences in response to chronic nicotine and nicotine withdrawal in rats.

INTRODUCTION: Understanding an individual's vulnerability to drug addiction has important implications for the development of effective personal treatment plans. Although theories acknowledge impulsive behaviour as a key component of drug addiction, little is known about the influence of trait impulsivity on an individual's susceptibility to the effects of psychostimulants on impulsivity at critical phases of the addiction cycle. METHODS: This study investigated the short and longer-term effects of chronic nicotine administration on impulsive choice in rats selected for high (HI) and low impulsivity (LI) on a delay discounting task. Rats prepared with subcutaneously osmotic mini-pumps received either nicotine (3.16 mg/kg/day [freebase]) or saline for 7 days. Performance was assessed during chronic treatment, early and late withdrawal, and in response to acute nicotine challenges following prolonged abstinence. RESULTS: Chronic nicotine increased impulsive choice in LI but not HI animals. Spontaneous withdrawal was associated with a nicotine abstinence syndrome, the early stages of which were characterised by opposing effects on impulsive choice in HI and LI animals. A transient decrease in impulsivity was observed in HI animals whilst the LI group remained more impulsive for up to 1 week following drug termination. Following normalisation of behaviour, acute nicotine challenges (0.125, 0.25, 0.5 mg/kg, SC) markedly increased impulsive choice regardless of trait impulsivity and drug history. CONCLUSION: The results indicate that only LI individuals are vulnerable to chronic drug- and withdrawal-induced impairments in self-control which may increase the likelihood of the transition to, and maintenance of, nicotine dependence.

Effects of chronic nicotine, nicotine withdrawal and subsequent nicotine challenges on behavioural inhibition in rats.

RATIONALE: Drug addiction is a chronically relapsing disorder characterised by compulsive drug use and loss of control over drug intake. Although several theories propose impulsivity as a key component of addiction, the precise nature of this relationship remains unclear. OBJECTIVES: This study aims to investigate the short- and longer-term effects of chronic nicotine administration on behavioural inhibition. METHODS: Rats were trained on a symmetrically reinforced go/no-go task, following which they were subcutaneously prepared with osmotic minipumps delivering either nicotine (3.16 mg kg(-1) day(-1) (freebase)) or saline for 7 days. Performance was assessed daily during chronic treatment, in early and late abstinence, and in response to acute nicotine challenges following prolonged abstinence. RESULTS: Chronic nicotine resulted in a transient reduction in inhibitory control. Spontaneous withdrawal was associated with a nicotine abstinence syndrome, the early stages of which were characterised by a significant increase in inhibitory control. This was, however, short-lived with a decrease in inhibition observed in the second week of abstinence. Whilst performance returned to baseline by the end of the third week, acute challenges (0.125, 0.25, 0.5 mg/kg, SC) revealed that nicotine exposure had sensitised animals to the disinhibitory effects of the compound. CONCLUSIONS: Drug-induced loss of inhibitory control may be critically involved both in the initial and later stages of addiction. Neuroadaptations occurring during chronic exposure to and/or withdrawal from nicotine render animals more sensitive to the disinhibitory effects of the drug. Longer-term changes in behaviour may play an important role in the increased susceptibility to relapse in those with a history of nicotine abuse.

The NK1 receptor antagonist NKP608 lacks anxiolytic-like activity in Swiss-Webster mice exposed to the elevated plus-maze.

The selective non-peptide NK(1) receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC(50) values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003-10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15 mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001-10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK(1) receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK(1) receptor antagonists to their potency at NK(1) receptors.