Ipsapirone and 8-OH-DPAT reduce ethanol preference in rats: involvement of presynaptic 5-HT1A receptors.
The selective serotonin(5-HT)1A receptor agonists 8-OH-DPAT and ipsapirone were tested in selectively inbred Wistar rats, with high preference [70-90%: defined as the ratio of ethanol (EtOH) to total fluid intake] for EtOH (10% v/v) over water in a two-bottle free choice situation. Rats were injected shortly before the overnight test session (8:00 P.M.-8:00 A.M.). EtOH and water consumption were determined in 20-min intervals; food consumption after the session. 8-OH-DPAT (ED50: 2.4 mg/kg, SC) and ipsapirone (ED50: 12.5 mg/kg, SC) reduced EtOH preference in a dose-dependent manner. In addition, 8-OH-DPAT increased total fluid intake, whereas ipsapirone enhanced total food intake. The EtOH preference reduction was time-dependent and reached a maximum within the second 4 h after application of 8-OH-DPAT (-73%) and ipsapirone (-72%). The preference reducing effect of ipsapirone (20 mg/kg, PO) was completely blocked by the nonselective 5-HT1A antagonist spiperone (0.05 mg/kg, SC). Local application of 8-OH-DPAT (10 micrograms, 0.5 microliters) into the dorsal raphe nucleus (DRN, a brain area rich in somatodendritic 5-HT1A autoreceptors), reduced the EtOH preference significantly as compared to the saline injection in the same animal (-12%, 8:00-12:00 P.M.). Only marginal effects on ingestion behavior were observed after microinjection into the nucleus accumbens. Reduction of brain 5-HT levels by pretreatment with the 5-HT synthesis inhibitor pCPA (2 x 150 mg/kg, IP) resulted in a short lasting, marked reduction (-54%) and a long lasting, small attenuation of the EtOH preference. Total food consumption was strongly decreased but returned soon to normal; total fluid intake was only slightly decreased. The EtOH preference reducing effect of ipsapirone (5 and 20 mg/kg, SC) was attenuated in pCPA-pretreated rats. The present data suggest that 5-HT1A receptor ligands reduce EtOH preference via stimulation of 5-HT1A receptors in the DRN. The possibility of additional mechanism(s) is discussed.
Schreiber
R
R
Institute for Neurobiology, Department of Psychopharmacology, Cologne, Germany.
Opitz
K
K
Glaser
T
T
De Vry
J
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology*; D000818:Animals; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D009714:Nucleus Accumbens / Q000502:physiology; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D017661:Receptors, Presynaptic / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D011743:Pyrimidines; D017661:Receptors, Presynaptic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin