The 27 amino acid peptide, pituitary adenylate cyclase‐activating polypeptide (PACAP‐27), and its 38 amino acid analogue, PACAP‐38, stimulate serotonin‐N‐acetyltransferase (NAT) activity and N‐acetylserotonin (NAS) and melatonin content of pineal glands from adult rats. Maximal stimulation of rat pineal NAT by PACAP‐38 is not increased further significantly by concurrent stimulation with the two related peptides, vasoactive intestinal polypeptide (VIP) and/or peptide N‐terminal histidine C‐terminal isoleucine (PHI). Isoproterenol was a more potent inducer of NAT activity than any of these peptides alone or in combination. PACAP‐38 also stimulates melatonin production by chicken pineal cells in culture as does VIP. Stimulation by both was not greater than after either alone. Prior stimulation of rat pineal NAT activity with VIP, PHI, or PACAP‐38 reduces the magnitude of subsequent stimulation with PACAP‐38 or forskolin. Concurrent stimulation of α‐receptors or treatment with active phorbol ester augments rat pineal response to PACAP‐38 stimulation just as it increases the response to VIP, PHI, and β‐receptor stimulation. Pineals from newborn rats respond to PACAP‐38 with an increase in NAT activity and the increase is augmented by concomitant α1‐adrenergic stimulation. The putative PACAP inhibitor PACAP (6–38) and the putative VIP inhibitor (Ac‐Tyr,d‐Phe)‐GRF 1–29 amide, in 100–1,000‐fold excess, did not affect the stimulatory activity of any of the peptides. Pineal melatonin concentration parallels changes in pineal NAT activity.

Exposure of adult rat pineal glands in organ culture to the polypeptides vasoactive intestinal polypeptide (VIP), and peptide N-terminal histidine C-terminal isoleucine (PHI) increases pineal serotonin N-acetyltransferase (NAT) activity and melatonin synthesis. The following research results are taken to indicate that VIP and PHI share common components of the NAT induction system: (1) The effects of the two peptides are additive at concentrations of 10 nM VIP and 100 nM PHI but not at higher peptide concentrations. (2) Pineals from newborns also respond to PHI with a dose dependent increase in NAT activity. NAT responses are additive at the same concentrations as seen with the adult pineals. (3) Light exposure affects the sensitivity of pineals to VIP and PHI stimulation in a similar manner; pineals taken after 3 hr of light are much less sensitive to PHI or VIP than those taken after 13 hr of light. (4) Pineals exposed for 48 hr to either PHI or VIP have a reduced NAT response to either agonist, which is reversible by culture in agonist-free media. (5) Neither VIP nor PHI stimulation of NAT activity is affected by concentrations of the VIP antagonists (N-Ac-Tyr1,D-Phe2)-GRF(1-29)-NH2 (NAcTDGRF), L-8-K, VIP-Neurotensin Hybrid (VIPNET), or (4Cl-D-Phe6, Leu17)-VIP (4C1PLVIP), which affect VIP binding or function in other tissues.

Probenecid inhibits the transport of the small monocarboxylic acids lactate and propionate from blood to brain but does not affect the transport of 5HIAA or HVA. Neither lactate, 5HIAA, HVA, nor probenecid itself inhibits probenecid uptake into brain from blood and neither lactate nor 5HIAA itself inhibits 5HIAA uptake. These results indicate first that probenecid inhibits the lactate carrier but is itself not transported by that carrier and second that 5HIAA and probenecid are independently transported from blood to brain by a low affinity system, probably by diffusion. Preloading animals with both tryptophan and probenecid increased the apparent transport of lactate, probenecid and 5HIAA but not the transport of glucose. This indicates that the transport of 5HIAA, lactate and probenecid from brain to blood involves a common, saturable carrier. These two sets of data indicate that either the brain capillary transport system is asymmetric or that probenecid-inhibited transport of monoamine catabolites from brain occurs at sites other than the capillary transport system of the blood-brain barrier.