A nose-brain pathway for psychotropic peptides: evidence from a brain evoked potential study with cholecystokinin

Abstract

The access of substances to the brain is of particular relevance for the etiology and treatment of psychiatric and neurologic diseases. This study provides functional evidence for a direct access of peptides to the human brain after intranasal administration. Effects were compared of intranasal (IN, 10 micrograms) and intravenous (i.v., 0.25 and 2.5 micrograms) administered cholecystokinin-8 (CCK) on the auditory event related potential (AERP) in 20 healthy subjects. Also, plasma concentration of cortisol and ACTH were monitored. The study was designed as a placebo-controlled, double-blind within-subject cross-over comparison. AERPs were recorded while the subject performed on an attention task (oddball task). Plasma CCK concentrations after IN administration of CCK were comparable to those after i.v. administration of 0.25 microgram CCK, but were substantially lower than those after 2.5 micrograms CCK. The P3 complex of the AERP was markedly increased following the IN administration of CCK (p < .01) compared to placebo and to the i.v. administration of 0.25 microgram. This pattern was more obvious in women than men. Increases in plasma ACTH concentrations after CCK reached significance selectively following the IN mode of administration (p < .01).

Is nose-to-brain transport of drugs in man a reality?

“…Furthermore, plasma concentrations of vasopressin during task performance were enhanced more after the intravenous administration of AVP than after nasal administration. Similar results were obtained by the same group after nasal and intravenous administration of cholecystokinin-8 (Pietrowsky et al 1996b) and performance of an auditory attention task (oddball task) in 20 volunteers in a double blind cross-over study recording the auditory event-related brain potentials. Further studies confirmed the results (Pietrowsky et al 2001).…”

Delivery of Nerve Growth Factor to the Brain via the Olfactory Pathway

“…In more recent studies, direct transport of the peptides arginine-vasopressin and cholecystokinin-8 from the nose to the brain has been reported in humans, providing encouraging evidence that use of drug delivery via the olfactory pathway may be possible in patients with a variety of brain disorders (22,23).…”

“…A variety of substances, including the antibiotic cephalexin (24), the steroid hormone progesterone (16), the peptides vasopressin (22) and cholecystokinin (23) and the protein horseradish peroxidase (HRP) (2), have all been proposed to undergo extraneuronal transport from the nasal cavity to the CNS. For instance, following unilateral intranasal administration, HRP (40 kDa) has been found within 45-90 min in intercellular openings of the olfactory epithelium as well as on the pial surface and nerve fiber layer of the olfactory bulb bilaterally in both rats and monkeys (2).…”

“…This finding provides further evidence for a direct connection between the nose and the brain. A variety of substances, including metals (5,8), dyes (30), viruses (21), peptides (22,23), proteins (1,2,28) and drugs (4,24), have been reported to reach the brain from the nasal cavity, without having to cross the BBB.…”

Oxytocin, vasopressin, and human social behavior

“…Recent neuropharmacological research has shown that neuropeptides gain access to the human brain after intranasal administration [18, 41,66,129], providing a useful method for studying the central nervous effects of OT and AVP in humans [68]. In particular, a potential clinical use is dependent on a more direct and secure pathway to the human brain.…”