Ocular hypotensive action of a dopaminergic (DA2) agonist, 2,10,11-trihydroxy-N-n-propylnoraporphine.

The dopamine (DA2) receptor agonist 2,10,11-trihydroxy-N-n-propylnoraporphine (TNPA) was tested for effects on 1) intraocular pressure (IOP), 2) aqueous humor flow rate, 3) electrically induced contractions of the cat nictitating membrane, 4) 3H-NE release from isolated rabbit iris-ciliary bodies and 5) cAMP accumulation in the isolated rabbit iris-ciliary body. Unilateral, topical administration of TNPA lowered IOP bilaterally in a dose-related fashion and inhibited the bilateral rise in IOP caused by water gavage. Topical pretreatment with metoclopramide, a DA antagonist, inhibited the ocular hypotensive response to TNPA. Subsequently, TNPA was shown to decrease aqueous humor inflow and IOP in normal rabbit eyes but not in surgically sympathectomized rabbit eyes. TNPA caused dose-dependent suppression of contractions of the cat nictitans, which was inhibited competitively by domperidone, a relatively selective DA2 receptor antagonist. In a test of prejunctional activity, TNPA caused dose-related inhibition of 3H-NE release from isolated, field-stimulated rabbit iris-ciliary bodies, which was inhibited by pretreatment with sulpiride, a relatively selective DA2 receptor antagonist. In a test of postjunctional activity, isoproterenol-stimulated cAMP accumulation in the isolated rabbit ciliary body was not affected by TNPA pretreatment. These results indicate that TNPA's suppressive action on aqueous humor flow rate and IOP is exerted predominantly on prejunctional (DA2) receptors of peripheral sympathetic nerves.

Differences in the nature of the stereotyped behaviour induced by aporphine derivatives in the rat and in their actions in extrapyramidal and mesolimbic brain areas.

Apomorphine, (minus)-N-n-propylnorapomorphine [ (minus)-NPA ] and (plus or minus)-N-n-propylnorapomorphine [ (plus or minus)-NPA ] each caused stereotyped behaviour patterns in the rat which could be differentiated into two components, sniffing and repetitive head and limb movements (low intensity component) and gnawing, biting and licking (high intensity component). Low intensity components occurred at low doses of apomorphine and high intensity components at larger doses but the two components never occurred independently for (minus)-NPA or (plus or minus) NPA. Biting was the predominant effect of these agents which were shown to be at least twenty times more potent than apomorphine. The (minus)-isomer of NPA was the more potent. The two components of stereotypy were differentiated both pharmacologically (using amantadine, reserpine plus alpha-methyl-p-tyrosine and haloperidol) and by lesions placed in areas of the extrapyramidal (caudate--putamen, globus pallidus, substantia nigra) and mesolimbic (nucleus accumbens septi, tuberculum olfactorium, nucleus amygdaloideus centralis) systems. However, both sniffing and biting responses were reduced by lesions of the serotonergic raphe nuclei. The two stereotypic components were differentially induced by intracerebral injections of apomorphine and (minus)-NPA into the caudate--putamen, nucleus accumbens septi and tuberculum olfactorium. Injections into the central nucleus of the amygdala were ineffective. The degree of involvement of the different areas was shown to differ for apomorphine and (minus)-NPA, in particular the nucleus accumbens septi appeared more important for the action of (minus)-NPA and the tuberculum olfactorium for apomorphine. Intracaudate (minus)-NPA was less active than apomorphine but, generally, intracerebrally applied (minus)-NPA was twice as potent as apomorphine. Both (minus)-NPA and apomorphine caused circling behaviour in animals with asymmetric medial raphe nucleus lesions (contralateral) or unilateral lesions of the substantia nigra (ipsilateral). In these experiments (minus)-NPA was ten times more potent than apomorphine.