Acute nicotine administration increases BOLD fMRI signal in brain regions involved in reward signaling and compulsive drug intake in rats

Abstract

Background: Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine.

Methods: Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03-0.6 mg/kg) on the BOLD signal was investigated for 10 min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated.

Results: A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal.

Conclusions: These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function.

Keywords: addiction; compulsive behavior; nicotine; pharmacological fMRI; rats; reward..

Figure 1.

Nicotine-induced increase in the BOLD signal. Composite maps depict the effect of the acute administration of nicotine (0.03–0.6mg/kg, iv) on the BOLD signal. Voxels on the 2D atlases showing red-to-yellow color gradation represents localized changes in the BOLD signal relative to the 5 minute baseline (within-subject) with a minimum threshold p value of 0.05, false discovery rate–corrected. N = 8–9 per group.

Figure 2.

Temporal BOLD response to nicotine. Arrow indicates the time of drug administration (nicotine, 0.03–0.60mg/kg, iv). N = 8–9 per group. Data expressed as means ± SEM.

Figure 3.

Three-dimensional composite maps of nicotine-induced BOLD activity. (A) Regions of interest that were analyzed for time-dependent increases in BOLD. (B) Three-dimensional segmentation of BOLD activation in neocortical areas. Maps are shown for voxels that are activated (show increase BOLD signal) at 1.5 minutes after nicotine treatment and at 5 minutes. (C) BOLD response to 0.3mg/kg of nicotine at 1.5 and 5 minutes for the extended amygdala (amygdala proper, periamygdaloid areas, and bed nucleus of stria terminalis), dorsal striatum, and ventral striatum (which included data from the prelimbic region). (D) BOLD response to 0.6mg/kg of nicotine at 1.5 and 5 minutes for the same regions a shown in C. Red-colored sections depict the localization of activated voxels relative to the 5minute baseline. N = 8–9 per group.

Figure 4.

Effect of mecamylamine on nicotine-induced BOLD activity. Composite maps of the rat brain are shown for saline, mecamylamine, nicotine, and mecamylamine followed by nicotine. Voxels on the 2D atlases showing red-to-yellow color gradation represent localized changes in BOLD signal relative to the 5 minute baseline (within-subject), with a minimum threshold p value of 0.05, false discovery rate–corrected. N = 8–9 per group.

Figure 5.

Mecamylamine diminishes the temporal BOLD response to nicotine. Saline (sc) and mecamylamine (sc) were administered 15minutes before the administration of nicotine (iv). Doses are expressed in mg/kg of body weight. Arrow depicts the time point that nicotine was administered. N = 8–9 per group. Data expressed as means ± SEM.