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PNAS 102 (48): 17489-17494

Copyright © 2005 by the National Academy of Sciences.

Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299

Chad J. Swanson *, {dagger}, Thomas P. Blackburn * {ddagger}, Xuexiang Zhang *, Kang Zheng §, Zhi-Qing David Xu §, Tomas Hökfelt §, , Toni D. Wolinsky *, Michael J. Konkel *, Heidi Chen *, Huailing Zhong *, Mary W. Walker *, Douglas A. Craig *, Christophe P. G. Gerald *, and Theresa A. Branchek *

*Lundbeck Research USA, Inc., Paramus, NJ 07652-1431; and §Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden



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Fig. 1.. SNAP 37889 is a competitive antagonist at the Gal3 receptor, producing dose-related shifts in the concentration-effect curve to galanin in the adenylyl cyclase assay. (Inset) Schild regression of the mean EC50 values affords a slope of 0.92 ± 0.04 and, when constrained to a unit slope, a pKb value of 7.54 (Kb = 29 nM; n = 4).

 


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Fig. 2.. The Gal3-selective antagonist SNAP 37889 displays acute anxiolytic- and antidepressant-like activity in animal models. (A) Acute (1 h) treatment with SNAP 37889 (3, 10, and 30 mg/kg, p.o.) produced a dose-dependent increase in social interaction time. The maximum effect was comparable to that of the positive control, CDP (5 mg/kg, p.o.). After 14 days of chronic administration, SNAP 37889 (30 mg/kg, i.p.) significantly increased social interaction time, whereas social interaction time in rats receiving CDP (5 mg/kg per day, i.p.) was not different from the control (n = 9 per group). (B) Pretreatment with SNAP 37889 increased punished responding during Vogel conflict test in rats. The Gal3 antagonist produced an increase in drinking in water-deprived animals at each dose tested (3 and 10 mg/kg, i.p.). The increase in drinking was accompanied by an increase in the number of shocks tolerated. In each case, the effect at the highest dose tested was equivalent to that of the positive control, CDP (5 mg/kg, i.p.) (n = 10 per group). (C) Acute (1 h) pretreatment with SNAP 37889 produced a dose-dependent decrease in immobility and parallel increase in swimming time during the 5-min test. The maximum effect was similar to the control antidepressant agent, fluoxetine (10 mg/kg, p.o.). Animals treated chronically (21 days) with SNAP 37889 (30 mg/kg, i.p.) also exhibited a significant decrease in immobility (I) and increase in swimming (S) time relative to vehicle-treated controls (n = 10 per group). Data are represented as mean ± SEM for each dose. *, P < 0.05; **, P < 0.01; #, P < 0.001 relative to the vehicle control group.

 


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Fig. 3.. Gal3- and 5-HT1A-receptor interactions modulate the reduction of extracellular 5-HT output in vHip produced by central injection of galanin. Galanin (1.5 nmol/1 µl, i.c.v.) caused a significant reduction in basal vHip 5-HT in vehicle-pretreated animals. Pretreatment with either SNAP 37889 or WAY100635 resulted in an attenuation of the galanin-mediated effect. Combined administration of SNAP 37889 and WAY100635 produced an additive and significant reversal of the galanin-induced decrease in vHip 5-HT. The number of animals used in each pretreatment group is indicated within each bar. Data are represented as the mean ± SEM for each treatment over the 3.5-h sampling period, beginning 1 h after galanin administration. *, P < 0.05; ***, P < 0.001 when compared with the vehicle - galanin control group. #, P < 0.05 when compared with the SNAP 37889 + WAY100635 pretreatment group.

 


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Fig. 4.. The soluble Gal3-selective antagonist, SNAP 398299, reverses the in vivo electrophysiological effects of galanin in the DRN. (A) (Upper) Representative histogram from a single DRN neuron demonstrating that vehicle (i.v.) administration has no effect on the galanin-induced (i.c.v.) reduction of spike activity. (Lower) Representative histogram from a single DRN neuron indicating that infusion of SNAP 398299 (i.v.) attenuates the galanin-induced reduction in spike output. (B) Mean effect of vehicle and SNAP 398299 in four to five DRN neurons. Data are depicted as spikes per 10 s (A) or the mean ± SEM (B). ***, P < 0.001 when compared with the vehicle control group.

 


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Fig. 5.. Representative traces demonstrating that SNAP 398299 attenuates the galanin-mediated increase in outward currents in the DRN in vitro. (A) Galanin evoked an outward current in the DRN slice preparation (top trace), and this effect was partially attenuated after application of SNAP 398299 (1 µM) (middle trace). The effects of SNAP 398299 are reversible, as indicated by the return of the galanin-induced outward current after washout of the antagonist (bottom trace). (B) SNAP 398299 attenuates the galanin-evoked outward current. Data are represented as mean ± SEM for data from five cells. *, P < 0.05 when compared with the vehicle control group.

 


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