Research reportNicotine sensitization increases dendritic length and spine density in the nucleus accumbens and cingulate cortex
Introduction
Nicotine is a psychostimulant that is present in tobacco and is believed to be the primary culprit of addiction to tobacco products. Tobacco addiction has become a major health problem primarily due to the fact that cigarette smoking has been accepted as a major factor that increases the risk of coronary disease, peripheral vascular disease, stroke, and lung cancer [16], [20], [43]. Cigarette smoking alone accounts for more than 400 000 deaths yearly and 30% of all cancer deaths [14], [31]. Because of the severity of the health problems associated with tobacco use, there has been a large research focus on the physiological mechanisms that may underlie nicotine addiction.
One of the primary factors that has been identified in nicotine addiction is that chronic exposure to nicotine results in an increase in density of nicotinic receptors. This receptor upregulation has been shown in the brains of mice [30], rats [39], and humans [4]. The increase in receptor density produced by nicotine has been found in several brain areas [2], [29], [30] and it has been hypothesized that experience-dependent changes in behavior observed with nicotine is due to these changes in receptor density. However, one problem with this hypothesis is that receptor upregulation is transient. Receptor upregulation observed in animals that have received chronic nicotine administration dissipates to control levels within as rapidly as 1 week to as long as 4 weeks, depending on the dose and the type of administration [11], [33], [42].
In two recent studies, Robinson and Kolb [36], [37] have shown that chronic administration of two other psychostimulants, amphetamine and cocaine, can produce persistent structural modifications in the nucleus accumbens and cingulate cortex, two brain areas that have been implicated in not only the reinforcing effects of these drugs but also in drug craving behavior [35]. In these two studies, results showed sensitization to either drug produced significant increases in dendritic length and spine density in the nucleus accumbens and cingulate cortex. These findings indicate that sensitization to amphetamine or cocaine produces fundamental alterations in the pattern and number of synaptic connections on neurons of both the nucleus accumbens and prefrontal cortex.
The purpose of this experiment was to analyze whether nicotine would produce the same type of dendritic structural modifications as observed with amphetamine and cocaine. Similar to nicotine, both amphetamine and cocaine are psychostimulants, very reinforcing drugs, and all three of these drugs have been shown to have very strong addictive properties. In the present study, animals were sensitized to nicotine over 5 weeks and given a challenge after a 2-week abstinence period. After animals’ brains were removed, Golgi-stained material was used to quantify dendritic length as measured by Sholl analysis [41], and spine density was quantified in three brain areas: the nucleus accumbens (NA), cingulate cortex (Zilles’ area Cg3; [45]) and parietal cortex (Zilles’ area Par 1). Due to nicotine’s effects on the cholinergic system, the Par 1 area was included to analyze whether nicotine’s effects on dendritic morphology might include other areas of the cerebral cortex that receive significant cholinergic projections but not receive significant dopaminergic projections.
Section snippets
Materials and methods
Sixteen male Long–Evans hooded rats weighing 350–400 g were group housed in a climate-controlled vivarium with a 12 h on/12 h off light cycle. Food and water was available ad libitum. Rats were divided into two groups of eight animals each, with one group sensitized to nicotine (0.7 mg/kg free base) and the other group was given the vehicle. Nicotine was derived from the liquid free base form and mixed into peanut oil, which served as the vehicle. All injections were in the volume of 1 ml/kg
Results
Fig. 1 shows locomotor activity for the nicotine and saline groups. Each of the five time points along the x-axis represent a mean of 3 days of activity (e.g. 1 week of injections), ‘C’ represents the challenge injection given after a 2-week abstinence period and the asterisk represents the time points at which the nicotine group demonstrated significantly higher activity than the saline group. Before drug administration began, animals were given 3 days of habituation to the locomotor box, and
Discussion
This study demonstrated that repeated injections of nicotine produced behavioral sensitization and produced changes in dendritic morphology in the nucleus accumbens and prefrontal cortex. The morphological changes produced by nicotine in the nucleus accumbens were especially dramatic, including an increase of 35% in dendritic length. These dendritic changes produced by nicotine have implications relative to the underlying physiological mechanisms of nicotine addiction and it’s cognitive
Acknowledgements
The first author would like to graciously thank Grazyna Gorny for microscopy training and the patience that was required to teach the first author to trace cells. This work was supported by an Alberta Heritage Foundation for Medical Research postdoctoral fellowship to R.W. Brown and a National Science and Engineering Research Council of Canada to B. Kolb.
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