ergoline and naxagolide

The involvement of D1 and D2 subtypes of dopamine receptors in behavioral effects of methamphetamine was studied in squirrel monkeys using a two-lever drug discrimination procedure. In monkeys that discriminated i.m. injections of 0.3 mg/kg methamphetamine from saline, methamphetamine (0.03-0.3 mg/kg), cocaine (0.1-1.0 mg/kg) and the selective dopamine uptake inhibitor, GBR 12909 (3.0-17.8 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and, at the highest doses, full substitution. In contrast, the norepinephrine and serotonin uptake inhibitors, tomoxetine (1.0-17.8 mg/kg) and fluoxetine (0.3-10.0 mg/kg), respectively, did not substitute appreciably for methamphetamine. Substitution for methamphetamine also was observed with the D1 receptor agonists, SKF 81297, SKF 82958 and dihydrexidine, and the D2 receptor agonist, (+)-PHNO in the majority of monkeys. Lower-efficacy D1 or D2 agonists substituted for methamphetamine either partially (SDZ 208-911) or not at all (SKF 77434, SDZ 208-912). Pretreatment with dopamine receptor blockers [D1 (SCH 39166, 0.1 mg/kg) or D2 (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D1 (SKF 77434; 3.0 mg/kg) or D2 (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine. In separate studies, comparable doses of each of these drugs, except SKF 77434, induced significant levels of catalepsy-associated behavior. These results support the view that both dopaminergic D1 and D2 mechanisms mediate the discriminative-stimulus effects of methamphetamine; further, they indicate that selected dopamine D1 partial agonists may have antagonist actions at doses that do not produce undesirable effects associated with dopamine receptor blockade.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adrenergic Agents; Animals; Benzazepines; Catalepsy; Discrimination Learning; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Ergolines; Male; Methamphetamine; Oxazines; Receptors, Dopamine D1; Receptors, Dopamine D2; Saimiri

Topics: Animals; Apomorphine; Corpus Striatum; Dopamine; Dopamine Agonists; Ergolines; Male; Mice; Mice, Inbred Strains; Microdialysis; Neurons; Nucleus Accumbens; Oxazines; Quinolines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydronaphthalenes

A previous study demonstrated a dopamine D1 receptor-dependent inhibition of zero Mg(2+)-induced epileptiform discharges in the rat cingulate cortex slice suspended in a grease-gap bath. This investigation considers the role of dopamine D2 receptors in the modulation of paroxysmal activity in this in vitro model. Some 123 of 143 slices exhibited spontaneous paroxysmal depolarizations, which in 105 cases were accompanied by secondary depolarizing after-potentials (SDAPs). In 43.5% of slices tested, dopamine preferentially and irreversibly facilitated SDAP production at low bath concentrations (1-100 microM), but at concentrations > 100 microM suppressed all components of the epileptiform responses. Similar dose-related bimodal responses were obtained with the D2 agonists LY 171555, PHNO and 7-OH-DPAT, but not with lisuride or RU 24213, which were exclusively inhibitory. The excitatory response to LY 171555 was attenuated by the D2 antagonist raclopride (2 microM), but not by the D1 antagonist SCH 39166 (0.5 microM). On the other occasions, the sole effect of dopamine (56.5% of slices) and the other D2 agonists, was to preferentially suppress SDAP number at low concentrations (1-100 microM) and to suppress all parameters of the epileptiform response at higher concentrations. The inhibitory effect of the D2 agonist LY 171555 on SDAP formation was paradoxically attenuated by the D1 antagonist SCH 39166, but not by the D2 antagonist raclopride. These results support the notion that dopamine can modulate epileptiform activity differentially, through its actions at D1 and D2 receptors. The possibility that these effects of dopamine may be mediated indirectly is discussed.

Topics: Animals; Benzazepines; Dopamine D2 Receptor Antagonists; Epilepsy; Ergolines; Evoked Potentials; Female; Gyrus Cinguli; In Vitro Techniques; Lisuride; Magnesium; Male; Oxazines; Phenethylamines; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Tetrahydronaphthalenes

The regulation of the basal forebrain cholinergic system by D1 and D2 dopamine receptors was assessed in the rat using in vivo microdialysis of cortical acetylcholine. The D1 agonist CY 208-243 significantly increased cortical acetylcholine release; in contrast, the D2 agonists quinpirole and (+)-4-propyl-9-hydroxynaphthoxazine were without significant effects. Moreover, when administered in combination with CY 208-243, quinpirole failed to potentiate the D1 agonist-induced increases in cortical acetylcholine release. The non-selective dopamine receptor agonist apomorphine also increased cortical acetylcholine release, and this was completely blocked by the selective D1 receptor antagonist SCH 23390 and slightly, but not significantly attenuated by the D2 antagonist raclopride. The present results indicate that stimulation of D1 receptors activates cortically-projecting cholinergic neurons; however, a minor contribution of D2 receptors cannot be excluded.

Topics: Acetylcholine; Animals; Apomorphine; Benzazepines; Cerebral Cortex; Dialysis; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Ergolines; Indoles; Male; Nerve Endings; Oxazines; Phenanthridines; Quinpirole; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides

(+)-4-Propyl-9-hydroxynaphthoxazine (PHNO) is a highly potent, D2-selective dopamine (DA) receptor agonist. In the present study, we have examined the electrophysiological effects of PHNO on identified nigrostriatal DA (NSDA), mesoaccumbens DA (MADA) and Type I caudate neurons. Intravenous PHNO dose-dependently inhibited the firing rate of NSDA and MADA neurons in both chloral hydrate (CH)-anesthetized rats (ED50 values = 21.2 +/- 1.2 and 26.5 +/- 1.4 ng/kg, respectively) and locally anesthetized, paralyzed rats (ED50 values = 105.0 +/- 1.4 and 109.1 +/- 1.4 ng/kg, respectively). PHNO was significantly more potent in the CH-anesthetized rats. There was a significant, positive correlation between basal firing rate and log ED50 for NSDA neurons in both preparations and for MADA cells only in CH-anesthetized animals. Neither pretreatment with the D1 receptor agonist SKF 38393 nor hemitransection of the forebrain altered the rate-dependent nature of PHNO-induced inhibition of NSDA neurons. Likewise, depletions of serotonin with either p-chlorophenylalanine or 5,7-dihydroxytryptamine failed to alter the rate-dependent PHNO-induced inhibition of NSDA neurons. Iontophoretically applied PHNO inhibited both NSDA and MADA neurons to a similar degree as either DA or the D2 agonist quinpirole. In contrast, the similar effects of PHNO and quinpirole on Type I caudate neurons were significantly different than those of DA. These results suggest that PHNO inhibits midbrain DA neurons via stimulation of somatodendritic autoreceptors and that PHNO exhibits an electrophysiological profile characteristic of D2 agonists. In contrast to quinpirole, however, the rate-dependent nature of PHNO-induced inhibition of these cells was resistant to modulation.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 5,7-Dihydroxytryptamine; Animals; Antiparkinson Agents; Corpus Striatum; Dopamine Agents; Ergolines; Iontophoresis; Male; Nucleus Accumbens; Oxazines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2

Four daily injections of pergolide, an ergoline dopamine agonist, made male rats tolerant to the corticosterone-elevating effects of an acute injection of pergolide on the fifth day. This tolerance occurred not only to acute treatment with pergolide, but also to other dopamine agonists differing in structure, potency and receptor subtype selectivity. Plasma corticosterone was elevated following administration of opioid or serotonin agonists in both vehicle- and pergolide-pretreated rats. The current findings strengthen the conclusion that tolerance to the acute elevation of corticosterone by pergolide is not due to impairment of pituitary-adrenocortical function but instead to changes in dopamine receptors that initiate the response.

Topics: Animals; Corticosterone; Dopamine; Dopamine Agents; Ergolines; Male; Oxazines; Pergolide; Pharmaceutical Vehicles; Quinolines; Quinpirole; Rats; Rats, Inbred Strains

The intrinsic activity of the potent dopamine (DA) agonist 4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] was examined in receptor binding assays for the following receptors: DA, alpha-1 and alpha-2 adrenergic, serotonin-1 and -2, neuroleptic, beta adrenergic, anxiolytic, adenosine A-1, gamma-aminobutyric acid, muscarinic and opiate. (+)-PHNO exhibited strong to moderate potencies [IC50 (nanomolars) in parentheses] in binding to DA (24), "neuroleptic" (67), alpha-2 adrenergic (77) and serotonin-1 (277) sites. The pharmacological activity of the naphthoxazine both in vivo and in vitro was contrasted with the known DA agonists apomorphine, pergolide, lisuride and 6-ethyl-9-oxaergoline in tests of DA, alpha-2 adrenergic and serotonergic function. Each compound was examined in vitro in receptor binding assays for interactions with DA, alpha-2 adrenergic, serotonin-1 and serotonin-2 receptors and for alpha-2 adrenergic activity in inhibiting field-stimulated contractions of the vas deferens of the rat. In vivo, alpha-2 adrenergic activity was assayed via measurement of mydriasis after i.v. injections in the rat, whereas serotonin activity was assayed by measuring drug-induced inhibition of 5-hydroxytryptophan accumulation, and DA activity was assessed by quantifying stereotyped behavior after both i.p. and i.v. injections. Selectivity ratios for the DA receptor were derived from effective dose values determined in these tests and demonstrated that only apomorphine was more selective as a DA agonist than (+)-PHNO in vivo. (+)-PHNO was the least active agent at the alpha-2 receptors in the vas deferens and with serotonergic mechanisms in vivo to reduce 5-hydroxytryptophan accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Apomorphine; Cats; Clonidine; Ergolines; In Vitro Techniques; Lisuride; Male; Muscle Contraction; Mydriatics; Oxazines; Pergolide; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Serotonin; Serotonin; Vas Deferens

Replacement of the pyrrole ring system in the dopaminergic oxaergolines (e.g. RU 29717) by a phenolic OH group leads to the hydroxy-hexahydronaphthoxazines, a new group of potent dopamine agonists which exhibit increased selectivity due to their lower affinity for adrenergic and 5-HT receptors.

Topics: 4-Butyrolactone; Animals; Binding, Competitive; Brain Chemistry; Chemical Phenomena; Chemistry; Clonidine; Dopamine; Ergolines; Homovanillic Acid; Humans; In Vitro Techniques; Mianserin; Oxazines; Prazosin; Rats; Receptors, Adrenergic; Receptors, Serotonin; Stereotyped Behavior