The hypothalamic neuropeptide orexin mediates arousal, sleep, and naturally rewarding behaviors, including food intake. Male sexual behavior is altered by orexin receptor-1 agonists or antagonists, suggesting a role for orexin-A in this naturally rewarding behavior. However, the specific role of endogenous orexin-A or B in different elements of male sexual behavior is currently unclear. Therefore, the current studies utilized markers for neural activation and orexin cell-specific lesions to test the hypothesis that orexin is critical for sexual motivation and performance in male rats. First, cFos expression in orexin neurons was demonstrated following presentation of a receptive or non-receptive female without further activation by different elements of mating. Next, the functional role of orexin was tested utilizing orexin-B conjugated saporin, resulting in orexin cell body lesions in the hypothalamus. Lesions were conducted in sexually naive males and subsequent sexual behavior was recorded during four mating trials. Lesion males showed shortened latencies to mount and intromit during the first, but not subsequent mating trials, suggesting lesions facilitated initiation of sexual behavior in sexually naive, but not experienced males. Likewise, lesions did not affect sexual motivation in experienced males, determined by runway tests. Finally, elevated plus maze tests demonstrated reduced anxiety-like behaviors in lesioned males, supporting a role for orexin in anxiety associated with initial exposure to the female in naive animals. Overall, these findings show that orexin is not critical for male sexual performance or motivation, but may play a role in arousal and anxiety related to sexual behavior in naive animals.
Orexin, also known as hypocretin, is a hypothalamic neuropeptide critical for feeding behavior (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, 2007, Furlong and Carrive, 2007, Furlong et al., 2009 and Carter et al., 2009). Orexin neurons are localized to the lateral hypothalamic area (LHA) and perifornical dorsomedial hypothalamus (PFA-DMH) and produce two neuropeptides, orexin-A and B (de Lecea et al., 1998 and Sakurai et al., 1998). Orexin neurons have been shown to project to brain structures involved in mediation of arousal including the locus coeruleus, tuberomammillary nucleus and peduculopontine tegmental nucleus (Peyron et al., 1998, Hagan et al., 1999, Horvath et al., 1999 and Baldo et al., 2003). Orexin has also been implicated in reward and motivation, specifically related to food and drugs of abuse (Aston-Jones et al., 2009a and Aston-Jones et al., 2009b) and orexin neurons have been shown to project to reward-related brain structures in the mesolimbic system including the ventral tegmental area (VTA) and nucleus accumbens (NAc) (Peyron et al., 1998, Fadel and Deutch, 2002, Martin et al., 2002 and Baldo et al., 2003). Orexin neurons are activated by conditioned contextual cues associated with food and drug reward (Harris et al., 2005, de Lecea et al., 2006 and Choi et al., 2010) and have been shown to play a role in reward-based feeding behavior (Choi et al., 2010). Moreover, intracerebroventricular (ICV) or intraperitoneal administration of an orexin receptor 1 (ORX1) antagonist results in reduced motivation for palatable food (Thorpe et al., 2005 and Nair et al., 2008), whereas ICV orexin-A administration can reinstate this motivation (Boutrel et al., 2005).
The role of orexin in other rewarding behaviors is currently unclear, although several studies have implicated a role for orexin in control of sexual behavior in male rats. It has previously been shown that orexin neurons are activated by copulation in male rats (Muschamp et al., 2007). In addition, administration of orexin-A into the medial preoptic area (mPOA) resulted in enhanced sexual performance evidenced by reduced latencies to mount and intromit, and increased frequencies of mounts and intromission (Gulia et al., 2003). In contrast, ICV administration of orexin-A attenuated sexual motivation by reducing female preference, although only in highly sexually motivated males (Bai et al., 2009). Studies using ORX1 antagonists have also demonstrated contradictory data, as systemic administration of ORX1 antagonist slightly impaired sexual performance by increasing latency to intromit without affecting other parameters of sexual behavior (Muschamp et al., 2007), while ICV administration of ORX1 antagonist had no effect on sexual motivation (Bai et al., 2009). Together these studies suggest that administration of exogenous orexin-A affects sexual performance and motivation; however, endogenous orexin may not play an important role in mediating sexual behavior (Bai et al., 2009). Therefore, the goal of the present study was to determine if endogenous orexin is essential for male rat sexual motivation and performance.
First, it was determined when during sexual behavior orexin neurons are activated, testing the hypothesis that orexin neurons are activated upon introduction of the rewarding stimulus. Moreover, as it has been shown that sexual experience influences sexual performance (Dewsbury, 1969) and the rewarding properties of sexual behavior (Tenk et al., 2009), it was determined whether sexual experience influences orexin neuron activation during mating. Finally, it was tested whether orexin plays a critical role in sexual motivation and performance using cell body specific lesions of orexin neurons.
