Adolescent nicotine-induced dendrite remodeling in the nucleus accumbens is rapid, persistent, and D1-dopamine receptor dependent

Abstract

Chronic nicotine exposure during adolescence induces dendritic remodeling of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) shell. While nicotine-induced dendritic remodeling has frequently been described as persistent, the trajectory of dendrite remodeling is unknown. Specifically, no study to date has characterized the structural plasticity of dendrites in the NAcc immediately following chronic nicotine, leaving open the possibility that dendrite remodeling emerges gradually over time. Further, the neuropharmacological mechanisms through which nicotine induces dendrite remodeling are not well understood. To address these questions, rats were co-administered chronic nicotine (0.5 mg/kg) and the D1-dopamine receptor (D1DR) antagonist SCH-23390 (0.05 mg/kg) subcutaneously every other day during adolescence. Brains were then processed for Golgi-Cox staining either 1 day or 21 days following drug exposure and dendrites from MSNs in the NAcc shell digitally reconstructed in 3D. Spine density was also measured at both time points. Our morphometric results show (1) the formation of new dendritic branches and spines 1 day following nicotine exposure, (2) new dendritic branches, but not spine density, remains relatively stable for at least 21 days, (3) the co-administration of SCH-23390 completely blocked nicotine-induced dendritic remodeling of MSNs at both early and late time points, suggesting the formation of new dendritic branches in response to nicotine is D1DR-dependent, and (4) SCH-23390 failed to block nicotine-induced increases in spine density. Overall this study provides new insight into how nicotine influences the normal trajectory of adolescent brain development and demonstrates a persistent form of nicotine-induced neuroplasticity in the NAcc shell that develops rapidly and is D1DR dependent.

Adolescent nicotine induces persisting changes in development of neural connectivity

“…Overall, these papers were the first to convincingly demonstrate nicotine-induced age-related modifications of MSN dendritic morphology in the NAcc, a brain region critical for processing the reinforcing properties of drugs of abuse. Ehlinger et al (2015) recently confirmed the finding that adolescent nicotine stimulates MSN dendritic growth, found that this growth occurs after a more limited dosing period (3X weekly IP injection, 0.5 mg/kg, P28-42), and showed that the elaboration is evident immediately upon the conclusion of dosing; it does not require a prolonged postdosing incubation period. The rapidly developing proliferation is also persistent, and remains at three weeks postdosing.…”

“…While changes in dendritic branching don't provide direct confirmation of synaptic changes, we earlier noted that all branches of NAcc MSNs in nicotine-dosed animals were densely spined ; this by definition includes the new branches induced by nicotine, although we cannot identify new branches separately in Golgi-stained tissue. Ehlinger et al (2015) recently found transient increases in spine density on MSN dendrites, and persisting increase in spine number (density × total branch length), after adolescent nicotine. We (Ehlinger et al, 2012b) also reported that, while spine density was not increased in dentate after adolescent nicotine, the estimate of total number of spines was similarly increased by increased total dendrite length.…”

Adolescent nicotine alters dendritic morphology in the bed nucleus of the stria terminalis

“…The pattern of adolescent nicotine-induced dendritic remodeling observed in the BNST in the present study is similar to results in the NAcc shell [12,6], and basolateral amygdala [2], in which the formation of new dendritic branches occurs primarily on the portion of the dendritic arbor distal to the soma. However, the 49% increase in total branch length of BNST neurons represents a more robust response than has been observed in other structures examined to date.…”

“…The pattern of dendritic remodeling observed in the BNST, in which elaboration occurs on the distal dendritic arbor, may suggest that similar mechanisms regulate nicotine-induced dendritic remodeling in each of these brain regions. Recently, [6] found that adolescent nicotine-induced dendrite remodeling in the NAcc shell is dependent on D1 dopamine receptor activity during the time of drug-exposure, that remodeling occurs rapidly following nicotine administration, and is persistent through an extended withdrawal period. Neurons within the BNST are similar to those in the NAcc in that the majority are GABAergic and classified as medium spiny neurons (MSNs) [11].…”

“…Dendritic remodeling in response to adolescent nicotine exposure has been demonstrated in several brain regions associated with nicotine dependence and anxiety-like behavior, including the nucleus accumbens (NAcc) shell [12,13,6] and the basolateral amygdala [2]. These observed changes came in the form of increased dendritic branching and ଝ Support: Virginia Foundation for Healthy Youth.…”