Behavioral effects of the 5-hydroxytryptamine3 receptor agonists 1-phenylbiguanide and m-chlorophenylbiguanide in rats
Higgins, G.A.; Joharchi, N.; Sellers, E.M.
Journal of Pharmacology and Experimental Therapeutics 264(3): 1440-1449
1993
ISSN/ISBN: 0022-3565 PMID: 8450478 Document Number: 413731
We have investigated the behavioral effects of the 5-hydroxytryptamine-3 (5-HT-3) receptor agonists 1-phenylbiguanide (PBG) and m-chlorophenylbiguanide (mCPBG) in rats after i.p. and i.c.v. injection. It was hoped that this approach may provide an alternative means of studying the role of 5-HT-3 receptors on animal behavior, for the majority of related studies have used antagonists at this subtype. Both PBG (3-60 mg/kg, i.p.) and mCPBG (1-30 mg/kg i.p.) produced abdominal constrictions, writhing and salivation in some, but not all, rats. The most marked behaviors were seen after mCPBG (30 mg/kg, i.p.), where paw shakes and chin rubbing was also recorded. Almost certainly as a consequence of these behaviors, PBG (3-30 mg/kg, i.p.) and mCPBG (0.3-1 0 mg/kg, i.p.) produced a conditioned place aversion. Pretreatment with the 5-HT-3 antagonists ondansetron (0.01-0.1 mg/kg, s.c.), ICS205-930 and quaternized ICS205-930 (both 0.1 mg/kg, i.p.) blocked the PBG (30 mg/kg, i.p.)-induced place aversion. PBG (30 mg/kg, i.p.) and mCPBG (10 mg/kg, i.p.) also produced a conditioned taste aversion. The central administration of PBG (1-30 mu-g, i.c.v.) and mCPBG (0.1-10 mu-g, i.c.v.) enhanced locomotor- and gnawing-related behavior, although the effects with PBG seemed more consistent. These PBG (10 mu-g, i.c.v.)-induced behaviors were completely blocked by haloperidol (0.01-0.1 mg/kg, s.c.). In contrast, ondansetron (0.0001-1 mg/kg, s.c.) and ICS205-930 (0.1 mg/kg, i.p.) produced only a mild and inconsistent attenuation of these responses. PBG (1-30 mu-g, i.c.v.) failed to produce any place conditioning (i.e., neither a preference nor aversion was found). It is concluded that activation of peripheral 5-HT-3 receptors leads to aversive-type behaviors, which may be related to gastrointestinal discomfort or malaise. In contrast, central injection of PBG and mCPBG produced a range of dopamine-related behaviors; however, a 5-HT-3 receptor involvement is unclear. Because both PBG and mCPBG have dopamine releasing properties, the use of 5-HT-3 agonists lacking such effects and/or the use of more discrete microinjection studies are needed to more clearly elucidate the roles of 5-HT-3 receptors in the central nervous system.