Research reportRole of insular cortex D1 and D2 dopamine receptors in nicotine self-administration in rats
Introduction
Nicotinic acetylcholine receptors (nAChRs) are considered to be the primary therapeutic targets in the treatment of tobacco addiction. However, nicotinic receptor systems interact with a variety of other neural systems, which are also important components of reinforcement circuitry and are key to the development and maintenance of addiction. In particular, dopamine receptor systems have been found to play important roles for the rewarding properties of nicotine. For example, Corrigall and Coen [1] examined the effects of subcutaneous injections of the selective D1 dopamine antagonist SCH-23390 and D2 dopamine antagonists spiperone and haloperidol on nicotine self-administration, food-maintained responding, and locomotor activity in rats. Results showed that all three dopaminergic antagonists reduced both nicotine self-administration and locomotor activity. Furthermore, O’Neill et al. [2] found that nicotine induced hyperactivity is reduced with the systemic injections of the SCH-23390, as well as the D2 antagonist raclopride, and D1/D2 antagonist fluphenzine. Specifically, the DA activity in the NAc was found to play an important role in the processing of reward salience (e.g. [3], [4]). Dopaminergic innervation of the NAc has also long been known to be key for the reinforcing effects of a variety of addictive drugs including nicotine (see [5] for a review). For instance, several studies [6] showed that both systemic and local injections of nicotine into the NAc increased extracellular DA levels. Furthermore, dopaminergic neurons in the NAc are populated with nAChRs, which cause DA release when nicotine is injected into the NAc. Fu et al. [7] showed that blocking a subtype of nAChRs (α7-nAChRs) also blocks the DA release in response to nicotine administration.
Other brain areas have also been found to play important roles in tobacco addiction. Ischemic damage to the insular cortex, which plays an important role in monitoring and preserving physiological homeostasis, encoding the incentive value of the taste of foods [8] and other rewards [9] has been associated with decreased desire to smoke [10]. Studies have linked the insula with incentive learning [8], conditioned taste-aversion [11] and disgust [12]. According to Naqvi and Bechera [13], along with the ventromedial prefrontal cortex, anterior cingulate cortex, NAc, and amygdala, the insula is a part of the network which is responsible for the conscious pleasure from drugs and urge for drug taking as well as relapse of this behavior. Specifically, the insula processes interoceptive information about the drugs received from a thalamocortical pathway and relays this information to the prefrontal regions and the amygdala which evoke pleasure related effects of the drugs through dopaminergic activation in the ventral tegmental area (VTA). Similarly, the model suggests that the insula contributes to the urge of drug taking by integrating the internal representation of the drug effects received from the ventromedial prefrontal cortex and the information about the environmental cues received from the anterior cingulate cortex. Finally, this information is fed into the NAc and gives rise to the motivational elements of drug taking behavior.
The insula consists of three main subregions: posterior granular insula, intermediate dysgranular, and anterior agranular insula. The granular insula receives projections from a thalamocortical pathway including the thalamus, parietal, occipital, and temporal association cortices and it is responsible for processing of the interoceptive information and of somatosensory, vestibular, and motor integration. This subregion of the insula also plays an important role in the addictive behavior. For example, Forget et al. [14] demonstrated that inactivation of the granular insula by using the GABAergic agonist Muscimol decreased nicotine self-administration in rats. Moreover, the agranular insula was found to mediate cocaine self-administration. The agranular insula, on the other hand, is responsible for the emotional and motivational integration of visceral information and has reciprocal connections with the limbic areas responsible for reward-processing such as the anterior cingulate cortex, the ventromedial prefrontal cortex, the amygdala, and the ventral striatum [13], [15], [16]. In line with its role in motivation, the agranular insula contains a high density of dopaminergic D1 receptors [17] as well as μ-opioid receptors which play a role in pain modulation and the rewarding effects of drugs [18]. These receptors make the agranular insula a natural target for the studies of reward and addiction. Di Pietro et al. [19], demonstrated that when dopaminergic activity in the prefrontal dorsal agranular insula was blocked with the D1-like receptor antagonist SCH 23390, the cocaine self-administration was reduced. However neural system interactions within the insula that are responsible for this effect are not well understood.
The current studies were conducted to determine the role of dopaminergic D1 and D2 receptors in the agranular insular cortex for the control of IV nicotine self-administration. It was hypothesized that dopaminergic innervation of the agranular insular cortex plays an important role in controlling nicotine self-administration. Furthermore, we expect to find similar effects of D1 and D2 antagonists on nicotine self-administration.
Section snippets
Subjects
Young adult female Sprague-Dawley rats (Taconic Lab, Germantown, NY, USA) were used in the present study. Animals were individually housed in a temperature controlled vivarium room located adjacent to the nicotine self-administration testing room. Animals were maintained on a 12:12 reverse light–dark cycle so that experimental sessions occurred during the active part of the rats’ diurnal cycle. Animals were given ad lib. access to water at all times excluding experimental sessions, and were fed
Histological localization
Only those rats with both of the bilateral infusion cannulae within the agranular insular cortex were used for statistical analysis of the effects of local insular infusion of dopamine antagonists on nicotine self-administration.
SCH-23390 higher dose-effect function
The main effect of the D1 antagonist SCH-23390 was significant (F(3,36) = 3.94, p < 0.025). Paired comparisons of each dose with control showed that doses, 2 (p < 0.025) and 4 μg/side (p < 0.005) caused significant decreases in nicotine self-administration (Fig. 3).
SCH-23390 lower dose-effect function
To determine
Discussion
The insular cortex was found in previous studies to be significantly associated with the loss of desire to smoke in people with stroke damage to this area as compared with damage to other brain regions [10]. Our results showed that while 2 and 4 μg/side doses of the D1 antagonist SCH-23390 decrease nicotine self-administration in rats, neither the 1 μg/side dose nor the lower doses (0.125, 0.250, and 0.5 μg/side) of the drug affected the self-administration behavior. Our results suggest that the
Acknowledgement
This research was supported by a grant from the National Institute on Drug Abuse of the National Institutes of Health (P50 Center grant DA027840).
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