The effects of nicotine in the neonatal quinpirole rodent model of psychosis: Neural plasticity mechanisms and nicotinic receptor changes

Abstract

Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 receptor sensitivity persistent throughout the animal's lifetime. In Experiment 1, we analyzed the role of α7 and α4β2 nicotinic receptors (nAChRs) in nicotine behavioral sensitization and on the brain-derived neurotrophic factor (BDNF) response to nicotine in NQ- and neonatally saline (NS)-treated rats. In Experiment 2, we analyzed changes in α7 and α4β2 nAChR density in the nucleus accumbens (NAcc) and dorsal striatum in NQ and NS animals sensitized to nicotine. Male and female Sprague-Dawley rats were neonatally treated with quinpirole (1mg/kg) or saline from postnatal days (P)1-21. Animals were given ip injections of either saline or nicotine (0.5mg/kg free base) every second day from P33 to P49 and tested on behavioral sensitization. Before each injection, animals were ip administered the α7 nAChR antagonist methyllycaconitine (MLA; 2 or 4mg/kg) or the α4β2 nAChR antagonist dihydro beta erythroidine (DhβE; 1 or 3mg/kg). Results revealed NQ enhanced nicotine sensitization that was blocked by DhβE. MLA blocked the enhanced nicotine sensitization in NQ animals, but did not block nicotine sensitization. NQ enhanced the NAcc BDNF response to nicotine which was blocked by both antagonists. In Experiment 2, NQ enhanced nicotine sensitization and enhanced α4β2, but not α7, nAChR upregulation in the NAcc. These results suggest a relationship between accumbal BDNF and α4β2 nAChRs and their role in the behavioral response to nicotine in the NQ model which has relevance to schizophrenia, a behavioral disorder with high rates of tobacco smoking.

Keywords: Adolescence; Brain-derived neurotrophic factor (BDNF); Dopamine D2 receptor; Nicotine sensitization; α4β2 nicotinic receptor; α7 nicotinic receptor.

Fig. 1

The difference in distance traveled is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) for behavioral sensitization in Experiment 1. Group NQ administered SN demonstrated significantly higher distance traveled during behavioral sensitization than all other groups (indicated by **, p < 0.05). All groups given nicotine with the exception of the NS groups administered 3 mg/kg DN and both NQ DN groups demonstrated significantly greater distance traveled during behavioral sensitization than controls (Group NS administered SS; indicated by *, p < 0.05).

Fig. 2

NAcc BDNF (pg/mg) protein is presented as a function neonatal drug treatment (x-axis) and adolescent drug treatment (legend). Group NQ administered SN demonstrated significantly higher BDNF protein levels in the NAcc than all other groups (indicated by **, p < 0.05). Group NS administered SN demonstrated significantly higher BDNF protein levels in the NAcc than controls (Group NS and NQ administered SS) and all groups given an antagonist (indicated by *, p < 0.05). All antagonist groups demonstrated significantly lower NAcc BDNF protein levels than controls (indicated by #, p < 0.05).

Fig. 3

The difference in distance traveled is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) for behavioral sensitization in Experiment 2. Group NQ administered SN demonstrated significantly higher distance traveled than all other groups (indicated by **, p < 0.05). NS Group administered SN demonstrated significantly higher distance traveled than controls (Group NS and Group NQ administered SS; indicated by *, p < 0.05).

Fig. 4

The density of binding (nCi/mg) is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) α7 nAChR binding in the NAcc (A) and dorsal striatum (B). In the NAcc, NS administered SN demonstrated significantly higher α7 nAChR binding than all other groups (indicated by *, p < 0.05). In the dorsal striatum, Group NS and Group NQ administered SS were equivalent and demonstrated significantly higher BDNF protein levels than the other groups (indicated by *, p < 0.05).

Fig. 5

The density of binding (nCi/mg) is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) α4β2 nAChR binding in the NAcc (A) and dorsal striatum (B). In the NAcc, NQ administered SN demonstrated significantly higher α4β2 nAChR binding than all other groups (indicated by **, p < 0.05). Group NS administered SN demonstrated significantly higher α4β2 nAChR binding than controls administered SS (indicated by *, p < 0.05). In the dorsal striatum, there were no significant differences between groups.