Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers

There is growing evidence that neuropeptides, including neuropeptide Y (NPY), act as
neuronal messengers in the brain and have diverse neurobehavioral functions. Their
therapeutic application for psychiatric disorders has been limited, however, by difficult
and unreliable penetration of the blood-brain barrier (BBB). The BBB has prevented the use
of many therapeutic agents for treating central nervous system (CNS) disorders. Several
molecules have successfully been administered through intranasal delivery, however, thanks
to the unique connection that the nerves involved in sensing odors and chemicals provide
between the CNS and its environment.

NPY, the most abundant peptide in the mammalian brain, is co-localized with norepinephrine
in sympathetic nerve fibers and has been of longstanding interest to our research group
(Morgan et al., 2002; Morgan et al., 2003; Morgan et al., 2001; Morgan et al., 2000;
Rasmusson et al., 2000; Rasmusson et al., 1998) because of its potential role in modulating
mood and anxiety. NPY has been implicated as factor in the adaptive stress response
(Thorsell et al., 1999), and has been shown to impact the consolidation of fear-related
memories after shock (Flood et al., 1989). Clinically, lower plasma NPY levels have been
correlated with greater psychological distress, increased symptoms of dissociation, and
poorer performance among active duty military personnel. Acute stress in humans has been
found to elicit NPY release, in a manner parallel to the changes in cortisol and
norepinephrine that are usually seen, with a blunting of the plasma NPY response in response
to yohimbine (Morgan et al., 2002). Baseline NPY levels in combat veterans with PTSD are
reduced compared to healthy non-traumatized individuals (Rasmusson et al., 2000). Another
study found that repeated exposure to traumatic stress, rather than the presence of PTSD or
PTSD-type symptoms, is associated with a reduction in baseline plasma NPY (Morgan et al.,
2003). A recent report found deceased CSF concentrations of NPY in patients with treatment
resistant unipolar major depression (Heilig et al 2004). In summary, there has been
suggestion from studies in patients with anxiety and mood disorders as well as healthy
volunteers of an abnormal regulation of this peptide.

In this study, we will evaluate intranasal administration of NPY in healthy male volunteers
ages 25-45 using a specialized delivery device. Pending the initial feasibility and
tolerability in healthy volunteers, future protocols will examine the effect of intranasal
NPY administration in patients with disorders such as PTSD, major depression, panic
disorder, and social anxiety disorder.