Temporal Rewiring of Striatal Circuits Initiated by Nicotine

Abstract

Drug addiction has been conceptualized as maladaptive recruitment of integrative circuits coursing through the striatum, facilitating drug-seeking and drug-taking behavior. The aim of this study was to define temporal neuroadaptations in striatal subregions initiated by 3 weeks of intermittent nicotine exposure followed by protracted abstinence. Enhanced rearing activity was assessed in motor activity boxes as a measurement of behavioral change induced by nicotine (0.36 mg/kg), whereas electrophysiological field potential recordings were performed to evaluate treatment effects on neuronal activity. Dopamine receptor mRNA expression was quantified by qPCR, and nicotine-induced dopamine release was measured in striatal subregions using in vivo microdialysis. Golgi staining was performed to assess nicotine-induced changes in spine density of medium spiny neurons. The data presented here show that a brief period of nicotine exposure followed by abstinence leads to temporal changes in synaptic efficacy, dopamine receptor expression, and spine density in a subregion-specific manner. Nicotine may thus initiate a reorganization of striatal circuits that continues to develop despite protracted abstinence. We also show that the response to nicotine is modulated in previously exposed rats even after 6 months of abstinence. The data presented here suggests that, even though not self-administered, nicotine may produce progressive neuronal alterations in brain regions associated with goal-directed and habitual performance, which might contribute to the development of compulsive drug seeking and the increased vulnerability to relapse, which are hallmarks of drug addiction.

Figure 1

Long-lasting changes in locomotion and progressive changes in striatal neurotransmission following nicotine exposure. Rats received 15 injections of either vehicle or nicotine over a 3-week period (hatched area) and locomotor activity in response to vehicle or nicotine injection was assessed in different batches of animals after 6, 12, 18, and 24 weeks of abstinence (n=6–12 per group). (a and b) Repeated administration of nicotine significantly enhance horizontal activity and suppressed corner time in a manner that was sustained even after 6 months of nicotine abstinence. (c) Nicotine initially depressed rearing activity, whereas repeated administration enhanced vertical beam breaks for up to 6 weeks after the last administration. (d) Previous exposure to nicotine significantly depressed the response amplitude in the DMS for up to 1 month. (e) In the dorsolateral striatum (DLS), a decline in input/output function developed over time and was significant following 3 months of nicotine abstinence. (f and g) Five injections of nicotine were sufficient to enhance horizontal activity and rearing. Time-course figure shows beam breaks during the 5th administration of vehicle/nicotine (n=10 per group). (h) Input/output function was significantly depressed in the DMS of rats receiving five injections of nicotine as compared with vehicle-treated control. (i) This treatment paradigm, however, was not sufficient to produce a long-lasting decline in population spikes (PS) amplitude during nicotine abstinence. *Significant effect by treatment (*P<0.05, **P<0.01, and ***P<0.001).

Figure 2

Nicotine abstinence produces temporal neuroadaptations in specific subregions. (a and b) Following 1 month of withdrawal, spine density and paired-pulse ratio (PPR) was enhanced in the dorsomedial striatum (DMS) of nicotine-treated rats, indicative of a decrease in probability for transmitter release but increase in the number of synapses in this treatment group. (c) In addition, both dopamine D1 and D2 receptor mRNA expressions were enhanced in nicotine-treated rats. (d–f) After 2 additional months of abstinence, treatment effects on spine density, PPR, and mRNA expression were reversed in the DMS. (g–l) In the dorsolateral striatum (DLS), spine density, PPR, or mRNA expression were not significantly modulated following neither 1 nor 3 months of abstinence. *Significant effect by treatment (*P<0.05, **P<0.01, and ***P<0.001).

Figure 3

Nicotine enhances extracellular dopamine levels in a subregion-specific manner. (a) Administration of nicotine selectively enhanced the extracellular concentration of dopamine in the nucleus accumbens (nAc) of nicotine-naïve rats. (b) The subregion-specific release of dopamine remained in rats subjected to 3 weeks of intermittent nicotine administration. Arrow marks time point for nicotine administration (0.36 mg/kg, subcutaneously). (c) Schematic drawing describing the areas of microdialysis probe placement in the different subregions of the striatum: (A) DLS, (B) DMS, and (C) nAc.

Figure 4

Changes in responsiveness to nicotine after 6 months of nicotine abstinence. After 6 months of nicotine abstinence, vehicle- (vehicle+6) and nicotine-treated (nicotine+6) rats received 6 days of nicotine administration. (a) Horizontal activity and rearing activity were significantly enhanced in response to the first nicotine injection in rats previously exposed to nicotine as compared with vehicle-treated control rats housed in parallel. (b) Micrographs showing representative Golgi staining of dendritic spines in the dorsomedial striatum (DMS); vehicle (I), vehicle receiving nicotine (vehicle+6) (II), nicotine (III), and nicotine receiving nicotine (nicotine+6) (IV). (c) Input/output function was restored in the DMS after 6 months of nicotine abstinence. (d) Re-exposure to nicotine did not depress population spikes (PS) amplitude in the DMS of rats previously exposed to nicotine. (e) Paired-pulse ratio (PPR) was not significantly modulated by treatment in the DMS. (f) Spine density was enhanced by nicotine in the DMS of rats previously exposed to nicotine (nicotine+6). (g) Example traces showing evoked PS amplitudes in the DMS of slices from vehicle (A), nicotine (B), and nicotine+6-treated rats (C). (h) Input/output function was not modulated in the dorsolateral striatum (DLS) following 6 months of abstinence. (i) Six additional days of nicotine treatment significantly depressed input/output function in rats previously treated with nicotine (nicotine+6). (j) PPR was not modulated by treatment in the DLS. (k) Nicotine exposure significantly enhanced DLS spine density in re-exposed rats. (l) Example traces showing evoked PS amplitudes in the DLS of slices from vehicle (A), nicotine (B), and nicotine+6-treated rats (C). Calibration is 0.15 mV, 0.2 ms. *Significant effect by previous treatment (*P<0.05 and **P<0.01). ^#Significant effect compared with vehicle (^#P<0.05 and ^##P<0.01).