Postsynaptic dopamine/adenosine interaction: II. Postsynaptic dopamine agonism and adenosine antagonism of methylxanthines in short-term reserpinized mice.
Caffeine and its first-stage metabolites (paraxanthine, theophylline and theobromine) caused a significant potentiation of the locomotor activity induced by bromocriptine, 5 mg/kg, in mice pretreated with reserpine, 5 mg/kg (4h prior to the start of motor activity recordings). None of these substances significantly enhanced locomotor activity in reserpinized mice when administered alone. The rank order of potency was caffeine greater than paraxanthine greater than theophylline greater than theobromine. A high dose of a D-2 antagonist (sulpiride 100 mg/kg) caused a marked inhibition of the locomotor activity induced by bromocriptine, 5 mg/kg, plus 25 mg/kg of caffeine, paraxanthine or theophylline. However, a high dose of a D-1 antagonist (SCH-23390 1 mg/kg) caused a significant decrease of the locomotor activity induced by bromocriptine 5 mg/kg, plus 25 mg/kg of caffeine or paraxanthine, but did not change the locomotor activity caused by bromocriptine, 5 mg/kg, plus theophylline 25 mg/kg. The inhibitory effect of 5'-(N-ethyl)carboxamido-adenosine (NECA), 0.025 mg/kg, on bromocriptine-induced locomotor activation in reserpinized mice was reversed by the simultaneous administration of 10, 25 and 50 mg/kg of caffeine, paraxanthine or theophylline. The rank order of potency for reversal was theophylline greater than paraxanthine = caffeine. We suggest that methylxanthines act postsynaptically by potentiating the effects of D-2 stimulation and that this potentiation can be produced by D-1 agonism (paraxanthine or caffeine) and by adenosine antagonism (theophylline, paraxanthine or caffeine), most probably involving A-2 receptors.
Ferré
S
S
Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Herrera-Marschitz
M
M
Grabowska-Andén
M
M
Casas
M
M
Ungerstedt
U
U
Andén
N E
NE
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012110:Reserpine / Q000494:pharmacology*; D013469:Sulpiride / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014970:Xanthines; D019830:Adenosine-5'-(N-ethylcarboxamide); D001971:Bromocriptine; D002110:Caffeine; D013469:Sulpiride; D012110:Reserpine; D013806:Theophylline; D000241:Adenosine; C021183:1,7-dimethylxanthine; D004298:Dopamine