Discriminative stimulus properties of clenbuterol: evidence for beta adrenergic involvement.
Thirty rats were trained to discriminate the centrally acting beta adrenergic agonist clenbuterol (0.1 mg/kg) from saline using a water-reinforced (fixed-ratio 10 schedule) two-lever operant task. Discrimination acquisition required a mean +/- S.E.M. of 42 +/- 7 training sessions (median of 26 training sessions). The clenbuterol stimulus was dose-dependent (ED50 = 0.03 mg/kg) and stereoselective, and had a rapid onset (5 min) and a duration of approximately 1 hr. The beta adrenergic antagonist propranolol fully antagonized the clenbuterol discriminative stimulus (IC50 = 0.18 mg/kg). Other beta adrenergic agonists such as SOM 1122 (ED50 = 0.01 mg/kg), zinterol (ED50 = 0.03 mg/kg), salbutamol (ED50 = 0.23 mg/kg) and prenalterol (ED50 = 1.91 mg/kg) substituted for clenbuterol. The monoamine uptake inhibitor despiramine (ED50 = 2.25 mg/kg), the psychomotor stimulants amphetamine (ED50 = 0.33 mg/kg) and pentylenetetrazol (ED50 = 0.31 mg/kg), and the dopamine receptor antagonists haloperidol (ED50 = 0.08 mg/kg) and chlorpromazine (ED50 = 2.32 mg/kg) similarly substituted for clenbuterol. However, chlordiazepoxide, pentobarbital, fentanyl, cocaine and fenfluramine produced little or no clenbuterol lever selection up to doses that decreased response rate markedly. The ability of SOM 1122, zinterol, salbutamol, despiramine, amphetamine, pentylenetetrazol and haloperiol to substitute for the clenbuterol stimulus was antagonized by prior treatment with propranolol. Taken together, these results suggest that the discriminative stimulus properties of clenbuterol are mediated, at least in part, through an interaction with beta adrenergic receptors. The same drugs also were assayed for in vitro inhibition of [125I]iodopindolol binding to beta adrenergic receptor preparations of rat cerebral cortex and cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)
McElroy
J F
JF
Life Sciences Division, Los Alamos National Laboratory, New Mexico.
O'Donnell
J M
JM
D000420:Albuterol / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology; D002976:Clenbuterol / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007536:Isomerism; D008297:Male; D010433:Pentylenetetrazole / Q000494:pharmacology; D011294:Prenalterol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; C002904:zinterol; D000661:Amphetamine; D006220:Haloperidol; D011294:Prenalterol; D000420:Albuterol; D003891:Desipramine; D002746:Chlorpromazine; D010433:Pentylenetetrazole; D002976:Clenbuterol