Role of insular cortex D₁ and D₂ dopamine receptors in nicotine self-administration in rats

Highlights

• Acute insular infusion of a D1 antagonist reduced nicotine self-administration.

• Chronic insular infusion of a D1 antagonist reduced nicotine self-administration.

• Acute insular infusion of a D2 antagonist was not found to reduce nicotine self-administration.

Abstract

The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D₁ and D₂ receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D₁ and D₂ antagonists (SCH-23390 and haloperidol). Acute local infusions of the D₁ antagonist SCH-23390 into the insula (1–2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D₂ antagonist haloperidol 0.5–2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D₁ systems in the insula for nicotine reward.

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.