Insular hypocretin transmission regulates nicotine reward

Abstract

Damage to the insular cortex can profoundly disrupt tobacco addiction in human smokers, reflected in spontaneous cessation of the tobacco habit and persistently decreased urge to smoke. Little is known concerning the neurobiological mechanisms through which the insula may control the maintenance of the tobacco habit. Emerging evidence suggests that hypocretin (orexin) transmission may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoke, remains largely unexplored. Here we show that blockade of hypocretin transmission at hypocretin-1 (Hcrt-1; orexin-1) receptors decreases i.v. nicotine self-administration in rats and the motivation to obtain the drug. Blockade of Hcrt-1 receptors also abolished the stimulatory effects of nicotine on brain reward circuitries, as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds. In addition, we show that hypocretin-containing fibers innervate the insula, Hcrt-1 receptors are located on insular cells, and blockade of Hcrt-1 receptors in the insula but not in the adjacent somatosensory cortex decreases nicotine self-administration. These data demonstrate that insular hypocretin transmission plays a permissive role in the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary for maintaining tobacco addiction in human smokers.craving ͉ orexin ͉ self-administration ͉ intracranial self-stimulation C igarette smoking is one of the largest preventable causes of death and disease in developed countries, and accounts for approximately 440,000 deaths and $160 billion in health-related costs annually in the United States (1). Despite the well known negative health consequences of the tobacco smoking habit, only approximately 10% of smokers who attempt to quit annually remain abstinent after 1 year, highlighting the persistence of the smoking habit. The insula is a cortical brain region involved in processing interoceptive information related to emotional and motivational states to facilitate maintenance of physiological homeostasis (2). This brain region may also regulate the experience of conscious urges and cravings (2-4). It was recently reported that damage to the insula in human smokers resulted in a profound disruption of tobacco addiction characterized by spontaneous cessation of the smoking habit and a low urge to smoke thereafter (3). Conversely, abstinence-induced cigarette craving in smokers is highly correlated with activation of the insular cortex (5). The neurobiological mechanisms through which the insula regulates the persistence of the tobacco habit remain unclear.Nicotine is a major reinforcing constituent of tobacco responsible for the smoking habit in humans (6). In common with other major drugs of abuse, nicotine can directly stimulate reward circuitries in the brain (7), and obtaining the reward-enhancing effects of nicotine may contribute to the persistence of the tobacco ...

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

“…These data confirm and extend the previous findings that OX 1 R plays a role in reward processing and precipitation of drug-seeking behavior (Boutrel et al, 2005;Lawrence et al, 2006;Hollander et al, 2008;Smith et al, 2010). Thus, further work will be needed to evaluate whether the suppressive effect on BE evoked by OX 1 R antagonists is related to their influence on stress or reward mechanisms, or on both.…”

“…Thus, blockade of OX 1 R decreases ethanol (Lawrence et al, 2006) and nicotine self-administration (Hollander et al, 2008), inhibits cue-induced reinstatement of ethanol- (Lawrence et al, 2006), cocaine- , and morphine-seeking (Harris et al, 2005), and attenuates stress-induced reinstatement of cocaine- (Boutrel et al, 2005) and ethanol-seeking (Richards et al, 2008). Moreover, recent evidence also linked OX 2 R-selective mechanisms to alcohol reward and seeking behavior (Shoblock et al, 2011).…”

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

“…Vulnerability to addiction is markedly increased in impulsive individuals, and cocaine-induced increases in impulsivity are hypothesized to contribute to the emergence of addiction (23,27). Moreover, orexin transmission and dynorphin transmission have been independently implicated in regulating the rewarding effects of cocaine and other drugs of abuse (28)(29)(30)(31)(32). We hypothesized that interactions between orexin and dynorphin transmission may directly control drug taking.…”

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

“…properties (22) results, Hcrtr-1 signaling has also been reported to modulate the reinforcing effects of opioids (23,24), nicotine (25) and alcohol (26,27). However, the involvement of the hypocretin system in the rewarding properties of cocaine has mainly been revealed under conditions that require greater degrees of effort and motivation to obtain the drug (28,29).…”