Effect of Orexin A antagonist (SB-334867) infusion into the nucleus accumbens on consummatory behavior and alcohol preference in Wistar rats

Abstract

Objective:Nucleus accumbens (NAcc) has a role in addiction and ingestive behavior. In order to assess orexinergic system involved in this, we infused Orexin A antagonist and assessed the effect on food intake fluid intake and alcohol preference in Wistar rats.Materials and Methods:Inbred Wistar rats (n = 54) were divided into control and experimental groups (low dose and high dose). Using stereotaxic method, guide cannula was set in place bilaterally to reach NAcc. Low dose (3 ng) and high dose (6 ng) of Orexin A antagonist (SB-334867) was infused, and the food consumption, water intake and alcohol intake, and two bottle free choice preference test for alcohol were carried out in the experimental group. The control group received saline infusion and rest of the methods followed were same. The measurements were carried out immediately after the infusion, at 1 h, 2 h, 4 h, and for the whole day and represented in the figure and tables.Results:A decrease in water intake observed immediately after the infusion in 1st h (P < 0.05) and 2nd h (P < 0.01), which was more in high dose group compared to low dose and controls. Alcohol intake was also following the same pattern. In two bottle free choice, rats did not show any specific preference to alcohol.Conclusion:There was dose dependent reduction in intake of food and fluids in treated rats. This suggested a possible role for orexinergic system in ingestive behavior. However, Orexin A may not have a role in modulation of alcohol addiction by the rewarding center NAcc.

Identification of discrete, intermingled hypocretin neuronal populations

“…The role of Hcrt neurons in promoting reward seeking behaviors and cue-induced reinstatement has been established for a variety of drugs of abuse including cocaine (Borgland, Taha, Sarti, Fields, & Bonci, 2006; Boutrel et al, 2005; Harris, Wimmer, & Aston-Jones, 2005; Smith, See, & Aston-Jones, 2009; Smith, Tahsili-Fahadan, & Aston-Jones, 2010), ethanol (Mayannavar, Rashmi, Rao, Yadav, & Ganaraja, 2014, 2016; Shoblock et al, 2011; Srinivasan et al, 2012), nicotine (Dehkordi et al, 2017; Hollander, Lu, Cameron, Kamenecka, & Kenny, 2008; LeSage, Perry, Kotz, Shelley, & Corrigall, 2010; Plaza-Zabala, Martin-Garcia, de Lecea, Maldonado, & Berrendero, 2010), morphine (Georgescu et al, 2003; Harris et al, 2005; Harris, Wimmer, Randall-Thompson, & Aston-Jones, 2007; Narita et al, 2006; Sharf, Guarnieri, Taylor, & DiLeone, 2010; Sharf, Sarhan, & Dileone, 2008; Zarepour, Fatahi, Sarihi, & Haghparast, 2014), and heroin (Smith & Aston-Jones, 2012). These effects are thought to be mediated by direct projections to both components of the mesolimbic reward circuit, the ventral tegmental area (VTA) (Baimel & Borgland, 2015; Borgland, Storm, & Bonci, 2008; Borgland et al, 2006; España, Melchior, Roberts, & Jones, 2011; España et al, 2010; Hrabovszky et al, 2013; Muschamp et al, 2014; Srinivasan et al, 2012; Taslimi et al, 2012; Zarepour et al, 2014) and the nucleus accumbens (NAc) (Mayannavar et al, 2014, 2016; Mori, Kim, & Sasaki, 2011; Mukai et al, 2009; Sharf et al, 2008; Thorpe & Kotz, 2005).…”

Habitual behaviour associated with exposure to high-calorie diet is prevented by an orexin-receptor-1 antagonist

“…The current study demonstrates that motivation for food (as indicated by lever response rates) occurs outside of the SNc, in a circuit independent of that which regulates habitual actions. Prior studies show that SB-334867 administered into the nucleus accumbens or ventral tegmental area reduces food intake [ 44 , 67 , 75 ], making the ventral, rather than dorsal, striatal circuit a possible site for these effects when SB-334867 was systemically administered in the current study [ 3 ].…”

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“… 36,178 Orexin‐B, which predominantly stimulates OX2‐R, has only minor response on feeding, supporting the key role of OX1‐R in these physiological processes. Indeed, under various conditions, the selective blockade of OX1‐R with the 1‐SORA SB‐334867 inhibits consummatory behavior, after IP at high dose 31,184 or central injections 185,186 . SB‐334867 , however, is not fully devoid of off‐target effects, thus experiments with this compound have to be regarded with caution 187,188 .…”

“…Indeed, under various conditions, the selective blockade of OX1-R with the 1-SORA SB-334867 inhibits consummatory behavior, after IP at high dose 31,184 or central injections. 185,186 SB-334867, however, is not fully devoid of off-target effects, thus experiments with this compound have to be regarded with caution. 187,188 The identification of many other physiological responses connected with the orexinergic signaling, including motivation to obtain food and reward-related factors, like palatable food, prompted the investigation of the role of OX-Rs in compulsive and dysregulated eating behaviors, such as binge-eating.…”