An analysis of the rewarding and aversive associative properties of nicotine in the neonatal quinpirole model: Effects on glial cell line-derived neurotrophic factor (GDNF)

Abstract

This study analyzed the associative properties of nicotine in a conditioned place preference (CPP) paradigm in adolescent rats neonatally treated with quinpirole (NQ) or saline (NS). NQ produces dopamine D₂ receptor supersensitivity that persists throughout the animal's lifetime, and therefore has relevance towards schizophrenia. In two experiments, rats were ip administered quinpirole (1mg/kg) or saline from postnatal day (P)1-21. After an initial preference test at P42-43, animals were conditioned for eight consecutive days with saline or nicotine (0.6mg/kg free base) in Experiment 1 or saline or nicotine (1.8mg/kg free base) in Experiment 2. In addition, there were NQ and NS groups in each experiment given the antipsychotic haloperidol (0.05mg/kg) or clozapine (2.5mg/kg) before nicotine conditioning. A drug free post-conditioning test was administered at P52. At P53, the nucleus accumbens (NAc) was analyzed for glial cell-line derived neurotrophic factor (GDNF). Results revealed that NQ enhanced nicotine CPP, but blunted the aversive properties of nicotine. Haloperidol was more effective than clozapine at blocking nicotine CPP in Experiment 1, but neither antipsychotic affected nicotine conditioned place aversion in Experiment 2. NQ increased accumbal GDNF which was sensitized in NQ rats conditioned to nicotine in Experiment 1, but the aversive dose of nicotine reduced GDNF in NQ animals in Experiment 2. Both antipsychotics in combination with the aversive dose of nicotine decreased accumbal GDNF. In sum, increased D₂ receptor sensitivity influenced the associative properties and GDNF response to nicotine which has implications towards pharmacological targets for smoking cessation in schizophrenia.

Keywords: Adolescence; Antipsychotics; Conditioned place preference; Dopamine D2 receptor; Nicotine; Schizophrenia.

Figure 1

Group codes: NQ=neonatal quinpirole; NS=neonatal saline; SS=adolescent saline/saline; SN=adolescent saline/nicotine; CN=adolescent clozapine/nicotine; HN=adolescent haloperidol/nicotine. Dose of nicotine administered = 0.6 mg/kg (base). (a). The difference in time spent in the paired context on the pre- and post-conditioning preference test is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) in Experiment 1. NQ-SN demonstrated a significant increased preference for the paired context on the post-conditioning test (CPP) compared to all other groups (indicated by **, p<.05). Groups NS-SN and NS-CN were statistically equivalent and demonstrated a significant increase preference for the paired context on the post-conditioning test compared to NS-SS (indicated by *, p<.05). (b) Accumbal GDNF (pg/ml) is presented as a function of neonatal drug treatment and adolescent drug treatment. NQ-SN demonstrated a significant increase of accumbal GDNF compared to all other groups (indicated by **, p<.05). NQ-SS demonstrated significantly greater GDNF than NS-SS (indicated by #, p<.05; as analyzed by independent groups t-test comparison). NQ-SS and NQ-HN were statistically equivalent and significantly greater than NQ-CN (indicated by *, p<.05). Likewise, Groups NS-SS, NS-SN, and NS-HN were all statistically equivalent and significantly greater NS-CN (indicated by *, p<.05).

Figure 2

Group codes: NQ=neonatal quinpirole; NS=neonatal saline; SS=adolescent saline/saline; SN=adolescent saline/nicotine; CN=adolescent clozapine/nicotine; HN=adolescent haloperidol/nicotine. Dose of nicotine administered = 1.8 mg/kg (base). (a). The difference in time spent in the paired context on the pre- and post-conditioning preference test is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) in Experiment 2. NS-SS, NQ-SS and NQ-SA were all statistically equivalent and demonstrated a significant increased preference for the paired context than all other groups (indicated by *, p<.05). (b). Accumbal GDNF (pg/ml) is presented as a function of neonatal drug treatment and adolescent drug treatment. NQ-SS demonstrated significantly greater accumbal GDNF than all other groups (indicated by **, p<.05). Groups NS-SS and NS-SA were statistically equivalent and significantly greater than NS-HA and NS-CA (indicated by *, p<.05). In addition, NQ-SA and NQ-CA were statistically equivalent and significantly greater than NQ-HA.