Abstinence from U-50,488H, a kappa-opiate receptor agonist, decreases the binding of [3H]DPAT to 5-HT1A receptors in the hypothalamus of the rat.
The effect of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzene-acetamide methane sulfonate (U-50,488H), a kappa-opiate agonist-induced tolerance and abstinence on 5-HT1A receptors was determined in regions of the brain and spinal cord of the rat. The administration of U-50,488H (25 mg/kg, i.p., twice daily) to male Sprague-Dawley rats for 4 days resulted in the development of almost complete tolerance to its analgesic and hypothermic effects. On day 5, the animals were divided into tolerant and abstinent groups and sacrificed. The brain and spinal cord were excised from all groups of rats and the brain was dissected into 6 regions, namely, amygdala, hypothalamus, striatum, midbrain, pons+medulla and cortex. The 5-HT1A receptors were characterized by using [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]DPAT) as the ligand. The binding constants (Bmax and Kd values) of [3H]DPAT in regions of the brain and spinal cord of rats tolerant to U-50,488H and vehicle did not differ. However, the Bmax value of [3H]DPAT in the hypothalamus of U-50,488H-abstinent rats was decreased but the Kd value did not change. In the other regions of the brain and spinal cord of U-50,488H-abstinent rats, the Bmax and Kd values of [3H]DPAT were unaffected. Subcutaneous administration of DPAT produced hypothermic response in vehicle- and U-50,488H-treated rats. The intensity of this effect was more marked in U-50,488H-abstinent group. It is concluded that 5-HT1A receptors are down-regulated in the hypothalamus of U-50,488H-abstinent rats but the hypothermic response to 5-HT1A agonist is intensified.
Reddy
V P
VP
Department of Pharmacodynamics, University of Illinois, Chicago 60612.
Bhargava
H N
HN
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D004361:Drug Tolerance; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects*
D011759:Pyrrolidines; D011985:Receptors, Serotonin; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin