The hypothalamic neuropeptide orexin (hypocretin) mediates reward related to drugs of abuse and food intake. However, a role for orexin in sexual reward has yet to be investigated. Orexin neurons are activated by sexual behavior, but endogenous orexin does not appear to be essential for sexual performance and motivation in male rats. Therefore, the goal of the current study was to test the hypothesis that orexin is critically involved in processing of sexual reward in male rats. First, it was demonstrated following exposure to conditioned contextual cues associated with sexual behavior in a conditioned place preference paradigm that cFos expression is induced in orexin neurons, indicating activation of orexin neurons by cues predicting sexual reward. Next, orexin-cell specific lesions were utilized to determine the functional role of orexin in sexual reward processing. Hypothalami of adult male rats were infused with orexin-B-conjugated saporin, resulting in greater than 80% loss of orexin neurons in the perifornical–dorsomedial and lateral hypothalamus. Orexin lesions did not affect expression of sexual behavior, but prevented formation of conditioned place preference for a sexual behavior paired chamber. In contrast, intact sham-treated males or males with partial lesions developed a conditioned place preference for mating. Orexin lesioned males maintained the ability to form a conditioned place aversion to lithium chloride-induced visceral illness, indicating that orexin lesions did not disrupt associative contextual memory. Overall, these findings suggest that orexin is not essential for sexual performance or motivation, but is critical for reward processing and conditioned cue-induced seeking of sexual behavior.
The hypothalamic neuropeptide orexin (hypocretin) is found exclusively in the lateral hypothalamic area (LHA) and the perifornical–dorsomedial hypothalamus (PFA-DMH) and consists of two active peptides, orexin-A and orexin-B (de Lecea et al., 1998 and Sakurai et al., 1998). Orexin is critical for food intake (de Lecea et al., 1998, Sakurai et al., 1998, Sakurai, 2006 and Benoit et al., 2008), arousal and sleep (Chemelli et al., 1999, Lin et al., 1999, Sakurai, 2007a, Sakurai, 2007b and Carter et al., 2009). Recent studies have shown that orexin also plays a critical role in mediation of reward (DiLeone et al., 2003, Aston-Jones et al., 2009 and Aston-Jones et al., 2010) and orexin cells have extensive projections throughout the brain, including to reward associated brain areas such as the nucleus accumbens (NAc) and ventral tegmental area (VTA) (Peyron et al., 1998, Fadel & Deutch, 2002 and Martin et al., 2002).
Orexin neurons are activated by conditioned contextual cues associated with food and drug reward in a conditioned place preference (CPP) paradigm (de Lecea et al., 2006), a standard paradigm used to determine reward seeking behavior (Tzschentke, 2007). Moreover, excitotoxic lesions of orexin neurons in the LHA or orexin receptor-1 antagonists in the VTA significantly reduce morphine preference in a CPP paradigm (Harris et al., 2007). In addition, LHA orexin neuronal stimulation, and intra-VTA orexin-A administration reinstate morphine CPP following extinction (Harris et al., 2005). Orexin-A administration into the LHA increases self-administration of palatable food (Thorpe et al., 2005) while orexin receptor-1 antagonists block self-administration of food (Nair et al., 2008), ethanol (Lawrence et al., 2006) and nicotine (Hollander et al., 2008). Thus, there is ample evidence that orexin plays a role in reward processing related to food intake and drugs of abuse.
Orexin neurons are activated by sexual behavior in male rats (Muschamp et al., 2007 and Di Sebastiano et al., 2010). In addition, exogenous orexin-A administration into the medial preoptic area enhances copulatory performance in male rates, evidenced by shortened latencies to mount and intromission, and increased frequency of mounts and intromissions (Gulia et al., 2003). However, a critical role for endogenous orexin in sexual behavior is not supported by findings that orexin cell-specific lesions do not disrupt sexual motivation or performance (Di Sebastiano et al., 2010), that intracerebroventricular (ICV) administration of an orexin receptor-1 antagonist does not disrupt sexual motivation (Bai et al., 2009), and that systemic administration of antagonist only slightly inhibits sexual performance (Muschamp et al., 2007). However, a role for endogenous orexin in mediation of sexual reward has yet to be elucidated. Therefore, the goal of the current study was to test the hypothesis that orexin plays a critical role in processing of sexual reward. First, it was determined whether orexin neurons are activated by conditioned cues predicting sexual reward by exposing male rats to an environment associated with prior sexual behavior. Next, orexin cell-specific lesions were utilized to determine a specific role for orexin in sexual reward processing using a CPP paradigm (Agmo & Gomez, 1993 and Tenk et al., 2009).
