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Evidence for in Viva Interactions Between Neuropeptide Y-Related Peptides and CT Receptors in the Mouse Hippocampal Formation

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Evidence for in Viva Interactions Between Neuropeptide Y-Related Peptides and CT Receptors in the Mouse Hippocampal Formation The Journal of Neuroscience, September 1993, K?(9): 39263931 Evidence for in viva Interactions between Neuropeptide Y-related Peptides and CTReceptors in the Mouse Hippocampal Formation Pascale Bouchard,1s2 Yvan Dumont,’ Alain Fournier,4 Serge St.-Pierre,4 and RQmi Quirioni,2,3 ‘Douglas Hospital Research Center, Verdun, Qukbec, Canada H4H lR3, 2Department of Neurology and Neurosurgery and 3Department of Psychiatry, McGill University, Montreal, Qukbec, Canada, and 41nstitut National de la Recherche Scientifique-Sante, Universitk du Qukbec, Pointe-Claire, Qukbec, Canada H9R lG6 Recently, it was proposed that neuropeptide Y (NPY) and Leonard, 1989; Snyder and Largent, 1989; Chavkin, 1990; Mu- peptide YY (PYY) could act as endogenous ligands for sacchio, 1990; Walker et al., 1990; Ferris et al., 199 1; Itzhak u binding sites, as both NPY and PYY competed with high and Stein, 199 la; Su, 199 1). This assumption is mostly based affinity (nanomolar) for 3H-( +)SKF 10,047 binding sites in rat on the fact that high densities of (r binding sites are found in brain membrane homogenates (Roman et al., 1989). How- various limbic structures, including the hippocampus (Gund- ever, various laboratories failed to replicate these in vitro lath et al., 1986; Contreras et al., 1987b; McLean and Weber, findings. In order to clarify this apparent discrepancy and 1988), and to the high affinity of some neuroleptics (e.g., halo- investigate further possible interactions between NPY and peridol and remoxipride, but not sulpiride) for g sites (Su, 1982, (I related sites, we evaluated the effects of NPY, PYY and 199 1; Tam and Cook, 1984; Taylor and Dekleva, 1987). This homologs, as well as nonrelated peptides, on in viva 3H- suggested the possible development of a new class of u-related (+)SKF 10,047 binding parameters in the mouse hippocam- antipsychotic drugs devoid of dopaminergic activity (Su, 1986; pal formation. As expected, haloperidol (2 mg/kg), a pro- Taylor and Dekleva, 1987; Snyder and Largent, 1989). Addi- totypical ~7 receptor ligand, competed for 90% of in viva tional support for this hypothesis came from observations sug- hippocampal labeling observed following a peripheral intra- gesting that certain g drugs such as N-allylnormetazocine (NANM venous injection of 3H-( +)SKF 10,047. Intracerebroventric- or SKF 10,047) induced hallucinations in man (Keats and Tel- ular injections of 300-3000 pmol of either NPY, PYY, NPY,,,, ford, 1964) and delirium in the chronic spinal dog (Martin et or the Y, agonist Leu3’,ProJ4-NPY inhibited significant pro- al., 1976; Vaupel, 1983) although the genuine u nature of these portions (17-35%) of haloperidol-sensitive in viva 3H-( +)SKF effects remains to be fully established (Quirion et al., 1987; 10,047 hippocampal labeling. However, a Y, receptor ago- Walker et al., 1990). nist, NPY,,,,, and nonrelated peptides such as neurotensin The abundance and discrete distribution of u sites in the and vasoactive intestinal polypeptide, as well as adrenalin, mammalian brain may also reveal the possible existence of failed to alter in vivo3H-( +)SKF 10,047 hippocampal binding. endogenous u-related ligands. Early on, few groups (Quirion et It thus appears that NPY, PYY, and a selective Y, agonist al., 1984; Su et al., 1986; Contreras et al., 1987a; Su and Vaupel, can interact in a concentration-dependant manner, with in 1988; Zhang et al., 1988; Connor and Chavkin, 1991, 1992) viva 3H-( +)SKF 10,047 labeling in the mouse hippocampal reported on the possible isolation of such molecules, although formation. This effect demonstrates selectivity as a Y, ag- their purification to homogeneity still remains to be accom- onist, unrelated peptides, and adrenalin failed to alter in viva plished. Thus, the report by Roman et al. (1989) suggesting that c labeling. This in viva interaction may be relevant to some peptides of the pancreatic polypeptide family, namely, neuro- of the respective biological actions of NPY and a-related peptide Y (NPY) and polypeptide YY (PYY), were able to molecules. compete with high affinities for in vitro 3H-(+)SKF 10,047/u [Key words: neuropeptide Y, peptide YY, sigma receptors, binding sites generated tremendous interests. However, it has N -allylnormetazocine (NANM or SKF 10,047), hippocampus, been difficult to replicate these findings using well-established in vivo binding] in vitro membrane binding assays (Quirion et al., 199 1; Tam and Mitchell, 199 1). The existence of sigma (0) receptor binding sites in the brain On the other hand, evidence has recently accumulated sup- has generated much interest over the past few years likely be- porting the existence of interactions between NPY and u-related cause of their possible involvement in psychosis-related behav- systems, in vivo. For example, Monnet et al. (1990a,b, 1992a- iors (for recent reviews, see Deutsch et al., 1988; Junien and c) have shown that both NPY and u agonists, in a haloperidol- sensitive manner, are able to potentiate N-methyl-D-aspartate (NMDA)-induced firing in the pyramidal CA3 subfield of the Received Nov. 2, 1992; revised Feb. 1, 1993; accepted Mar. 23, 1993. hippocampal formation (but see McQuiston and Colmers, 199 I ; This research project is supported by Program Grant 38 from the Medical Connick et al., 1992). Additionally, NPY and a selective u li- Research Council ofcanada, and a studentship award from Jouveinal Laboratories (Fresnes, France) to P.B. R.Q. is a Chercheur-Boursier “mCrite exceptionnel” and gand, JO 1784, can decrease intestinal transport apparently via A.F. is a Chercheur Boursier from the “Fonds de la Recherche en Santi du haloperidol-sensitive c receptors (Riviere et al., 1990). More- QuCbec.” Correspondence should be addressed to Dr. Rkmi Quirion, Douglas Hospital over, it appears that NPY and homologs, as well as various u Research Center, 6875 Boulevard LaSalle, Verdun, Qu&ec, Canada H4H lR3. ligands, are able to potentiate NMDA-induced 3H-noradrena- Copyright 0 I993 Society for Neuroscience 0270-6474/93/133926-06$05.00/O line release in rat hippocampal slices (Monnet et al., 199 1; Ro- The Journal of Neuroscience, September 1993, 13(9) 3927 man et al., 199 1). Accordingly, we decided to investigate further possible interactions between NPY-related peptides and g re- ceptor sites in the mouse hippocampus using an in vivo binding approach; the hippocampal formation was chosen as this region is most enriched with both g- (Gundlach et al., 1986; Contreras et al., 1987b; McLean and Weber, 1988; Weissman et al., 1988, 1990) and NPY (Martel et al., 1986, 1990a; Lynch et al., 1989; Dumont et al., 1990, 1992,1993) receptors. Our results suggest that NPY, PYY, and a selective agonist of the Y, receptor sub- type can interact with a certain proportion of in vivo 3H-( +)SKF 10,047 labeling in the mouse hippocampus. ” TOT HAL NPY (2mglkg) (1500 pmol) Materials and Methods Materials. ‘H-(+)SKF 10,047 (53 Ci/mmol; Comission Energie Ato- Figure 1. 3H-(+)SKF 10,047-related radioactive material present in mique, Saclay, France) was provided by the Institut de Recherches the mouse hippocampal formation following a peripheral intravenous Jouveinal, Fresnes, France. All NPY-related peptides as well as neu- injection (5 &i per 200 ~1,tail vein; total n = 5 1). 3H-(+)SKF 10,047 rotensin and vasoactive intestinal polypeptide (VIP) were synthesized binding is most likely related to (r sites as haloperidol (2 mg/kg, i.p.; in our laboratories as described earlier (St.-Pierre et al., 1981; Martel n = 1 1) almost completely inhibited (90%) labeling in the mouse hip- et al., 1990b). Adrenalin, haloperidol, trizma base (Tris), NaCl, and pocampus.Similarly, although to a lesserextent, intracerebroventricular polyethyleneimine (PEI) were purchased from Sigma Chemicals (St. injections of NPY (1500 pmol; n = 23) significantly inhibited hippo- Louis, MI). MK-801 was from Research Biochemicals Inc. (Natick, campal ‘H-(+)SKF 10,047 labeling. *, p < 0.005; **, p < 0.001. MA), ether and GF/B Whatman filters were obtained from Fisher (Mon- treal, Canada),and Ecolite TM + was purchasedfrom ICN Biochemicals (Montreal, Canada). presence of haloperidol(2 mg/kg, i.p.) residual 3H-( +)SKF 10,047 Animals. Male CD- 1 mice (20-24 gm) were purchased from Charles River (St.-Constant, Quebec, Canada). Animals were housed in a tem- hippocampal binding accounted for only 1.48 fmol/mg of pro- perature- and humidity-controlled room on a 12 hr: 12 hr light/dark tein, revealing that approximately 90% (13.52 fmol/mg protein) cycle, and were fed ad libitum with standard laboratory chow and tap of total labeling was sensitive to the prototypical g ligand (Fig. water. They were kept under these conditions for at least 24 hr prior to 1). The NMDA/phencyclidine (PCP) receptor ligand MK-801 the experiment. Animal care was according to protocols and guidelines approved by McGill University and the Canadian Council for Animal did not inhibit the specific )H-(+)SKF 10,047 labeling in the Care. mouse hippocampal formation at intraperitoneal doses of 0.05, Binding experiments. For in vivo binding experiments, mice were 0.1, 0.2, and 0.5 mg/kg (n = 26; data not shown). injected at time (t) = 0 with 2 mg/kg haloperidol (100 ~1, i.p.), MK- 801 (0.05,0.1, 0.2, or 0.5 mg/kg 100 ~1. i.p.), or saline (0.9% NaCl, 100 Competition by NPY-related peptides ~1, i.p.) in order to determine the proportion of in vivo 3H-(+)SKF 10,047 labeling that can be related to r sites. At t = 15 mitt, under light ether As shown in Figure 3, NPY, NPY,_,,, Leu31,Pro34-NPY (a pur- anesthesia, animals received either a peptide injection (3 ~1, i.c.v.) or ported Y, agonist; Fuhlendorff et al., 1990), and PYY were able saline (3 ~1, i.c.v.).
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