ABSTRACT
The rank order of potency to activate central dopamine autoreceptors of seven compounds known to possess central nervous system dopamine agonist activity were assessed with the following techniques: (1) inhibition of dopaminergic neuronal firing in anesthetized rats, (2) inhibition of dopamine synthesis in rats pretreated with gamma-butyrolactone, and (3) inhibition of mouse locomotor activity. The compounds were also examined for their ability to induce stereotypic behaviors in rats as an index of postsynaptic dopamine receptor activation. The compounds under investigation were apomorphine, N-n-propyl-norapomorphine, lergotrile, bromocriptine, RU 24926 and 6-ethyl-9-oxaergoline (EOE). There was a high degree of correlation between the rank order of potency of the compounds in all three of the presumptive autoreceptor tests and with minor variations the following rank order of potency was found: N-n-propylnorapomorphine greater than or equal to EOE greater than apomorphine greater than lergotrile greater than or equal to RU 24926 greater than bromocriptine. However, in the induction of stereotypies, the rank order of potency was considerably different: N-n-propylnorapomorphine greater than apomorphine greater than EOE greater than RU 24926 greater than lergotrile greater than bromocriptine. There was a poor and statistically significant degree of correlation between the rank order of potency of the test compounds to induce stereotyped behaviors and any of the other three test procedures. Altogether, these data confirm and extend the suspected dopaminergic agonist properties of the compounds under investigation and additionally lend credence to the assumption that the three putative autoreceptor assays employed do in fact reflect dopaminergic autoreceptor activation.
Subject(s)
Dopamine Antagonists , Receptors, Dopamine/drug effects , 4-Butyrolactone/pharmacology , Animals , Brain/cytology , Electrophysiology , Ergolines/pharmacology , Female , Locomotion/drug effects , Morphine Derivatives/pharmacology , Neurons, Efferent/physiology , Phenethylamines/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
Administered intracisternally, adenosine (ADO), 2-chloroadenosine (CADO), adenosine-5'-cyclopropylcarboxamide (ACC) and adenosine-5'-ethylcarboxamide (AEC) caused dose-related increases in hot plate reaction times in mice. The rank order of potency was AEC=ACC greater than CADO greater than ADO and ACC exerted demonstrable effects with doses as low as 10 ng/mouse. ADO itself was more potent than AMP, ADP, ATP and several other related compounds of interest. Theophylline, caffeine and 8-phenyltheophylline antagonized the antinocisponsive effect of CADO or ACC. Papaverine (an adenosine uptake blocker) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA: an adenosine deaminase inhibitor) potentiated the effect of ADO. EHNA did not potentiate the action of CADO in this procedure. The antinocisponsive effect of CADO was not antagonized by a host of neurally active agents including naloxone, clonidine and RO 20-1724. Time course studies indicated that the antinocisponsive effect of ADO was transient with the peak effect occurring 5 min after injection and disappearing by 60 min, whereas the effect of CADO persisted for at least 90 min. Intracisternally administered CADO also caused a pronounced hypothermia, loss of muscle tone and was active in the mouse writhing test. Taken together, these data demonstrate that purine exert potent in vivo behavioral effects and are consonant with the existence of a central purinergic P1-receptor which is amenable to selective pharmacological manipulation.
Subject(s)
Analgesics/pharmacology , Behavior, Animal/drug effects , Central Nervous System/drug effects , Purines/pharmacology , Receptors, Drug/drug effects , Animals , Drug Synergism , Female , Hot Temperature , Mice , Mice, Inbred Strains , Purines/antagonists & inhibitors , Reaction Time/drug effects , Receptors, Purinergic , Xanthines/pharmacologyABSTRACT
Administered by either intravenous (i.v.) or intracisternal (i.cis.) injections, MK-771 and TRH induced a dose-related increase in EMG activity recorded from the flexor ulnaris muscle in pentobarbital-anesthetized rats. By the i.v. route, MK-771 was 6 times more potent than TRH and with i.cis. administration MK-771 was some 30 times more active than TRH. At equieffective doses of the two peptides, MK-771 exhibited a greater (approximately 3 fold) duration of action than TRH. In unanesthetized, spinally transected rats MK-771 was also more potent than TRH in eliciting EMG activity recorded from the biceps femoris muscle. Substance P, administered by the i.cis route failed to induce EMG activity. Intracisternally administered neurotensin, which did not affect EMG activity by itself, antagonized the actions of MK-771 while somatostatin was inactive in this regard. Neurotensin did not affect the EMG activity induced by physostigmine. While these studies do not delineate the mechanism whereby TRH and MK-771 induce EMG activity, it appears reasonable to suggest that TRH and related peptides, such as MK-771, may have some influence in functional disorders of human muscle.
