Critical role of nitric oxide on nicotine-induced hyperactivation of dopaminergic nigrostriatal system: Electrophysiological and neurochemical evidence in rats

Abstract

Nicotine, the main psychoactive ingredient in tobacco, stimulates dopamine (DA) function, increasing DA neuronal activity and DA release. DA is involved in both motor control and in the rewarding and reinforcing effects of nicotine; however, the complete understanding of its molecular mechanisms is yet to be attained. Substantial evidence indicates that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the nitric oxide (NO) system, which may act by modulating central dopaminergic function. In this study, using single cell recordings in vivo coupled with microiontophoresis and microdialysis in freely moving animals, the role of NO signaling on the hyperactivation elicited by nicotine of the nigrostriatal system was investigated in rats. Nicotine induced a dose-dependent increase of the firing activity of the substantia nigra pars compacta (SNc) DA neurons and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the striatum. Pharmacological manipulation of the NO system did not produce any change under basal condition in terms of neuronal discharge and DA release. In contrast, pretreatments with two NO synthase (NOS) inhibitors, N-omega-nitro-l-arginine methyl ester (l-NAME) and 7-nitroindazole (7-NI) were both capable of blocking the nicotine-induced increase of SNc DA neuron activity and DA striatal levels. The effects of nicotine in l-NAME and 7-NI-pretreated rats were partially restored when rats were pretreated with the NO donor molsidomine. These results further support the evidence of an important role played by NO on modulation of dopaminergic function and drug addiction, thus revealing new pharmacological possibilities in the treatment of nicotine dependence and other DA dysfunctions.

Figure 1

Effect of systemic and local manipulation of NO signaling on the firing rate of dopaminergic SNc neurons. Representative rate histograms showing the effects elicited by i.p. administration (at arrows) of l‐NAME (50 mg/kg) (A), 7‐NI (50 mg/kg) (B), MOL (50 mg/kg) (C). APO, apomorphine administration (10 μg/kg i.v., at arrow). (D) Cumulative dose–response curve showing the mean percentage change (± SEM) in firing rate after vehicle, 7‐NI (50 mg/kg), l‐NAME (50 mg/kg), MOL (50 mg/kg) and l‐ARG (50 mg/kg).

Figure 2

Blockade by 7‐NI and l‐NAME of the excitatory actions of nicotine on the firing rate of SNc neurons. (A) Representative rate histogram showing that i.v. effect of nicotine (25, 50, 100, 200, and 400 μg/kg, at arrows). (B,C) Representative rate histograms showing that pretreatment with 7‐NI and l‐NAME (50 mg/kg, i.p.) prevents the excitatory effect of nicotine. (D) Cumulative dose–response curve showing the mean percentage change (± SEM) in firing rate after nicotine, vehicle, 7‐NI + nicotine, l‐NAME + nicotine, 7‐NI + nicotine + MOL, and l‐NAME + nicotine +MOL. Statistical analysis revealed a significant effect of nicotine (one‐way ANOVA; P < 0.01; n = 7) compared with vehicle group (n = 10). Pretreatment with 7‐NI or l‐NAME (50 mg/kg, i.p.), prevented nicotine‐induced increase in DA firing rate (two‐way ANOVA; nicotine vs. vehicle *P < 0.05; **P < 0.01 and NOS inhibitors vs. nicotine #P < 0.05; ##P < 0.01 by Tukey‐Kramer post hoc test).

Figure 3

(A) Time course of the effect of acute nicotine (1 mg/kg, i.p.) administration on extracellular levels of DA in the corpus striatum (n = 5). All the drugs and vehicle were injected at the time indicated by vertical arrow. Each data point represents mean ± SEM absolute levels of DA, without considering probe recovery. Statistical analysis shows a significant effect of nicotine (one‐way ANOVA; P < 0.01) as compared with the control group. 7‐NI (50 mg/kg), l‐NAME (50 mg/kg), MOL (50 mg/kg), and l‐ARG (50 mg/kg) did not modify at any time the DA levels. (B) Time course of the blockade by 7‐NI and l‐NAME of the excitatory actions of nicotine (1 mg/kg, i.p.) administration on extracellular levels of DA in the corpus striatum. The dose of 50 mg/kg i.p. 7‐NI and l‐NAME completely prevented nicotine‐induced increase in DA release (two‐way ANOVA; #P < 0.05, ##P < 0.01 by Tukey‐Kramer post hoc test).

Figure 4

(A) Time course of the effect of acute nicotine (1 mg/kg, i.p.) administration on extracellular levels of DOPAC in the corpus striatum (n = 5). All the drugs and vehicle were injected at the time indicated by vertical arrow. Each data point represents mean ± SEM absolute levels of DA, without considering probe recovery. Statistical analysis shows a significant effect of nicotine and 7‐NI (one‐way ANOVA; P < 0.01) as compared with the control group. l‐NAME (50 mg/kg), MOL (50 mg/kg), and l‐ARG (50 mg/kg) did not modify at any time the DOPAC levels. (B) Time course of the blockade by 7‐NI and l‐NAME of the excitatory actions of nicotine (1 mg/kg, i.p.) administration on extracellular levels of DOPAC in the corpus striatum. The dose of 50 mg/kg i.p. 7‐NI and l‐NAME completely prevented nicotine‐induced increase in DOPAC release (two‐way ANOVA; #P < 0.05, ##P < 0.01 by Tukey‐Kramer post hoc test).