Computer-aided drug screening by molecular docking, molecular dynamics (MD) and structural-activity relationship (SAR) can offer an efficient approach to identify promising drug repurposing candidates for COVID-19 treatment. In this study, computational screening is performed by molecular docking of 1615 Food and Drug Administration (FDA) approved drugs against the main protease (Mpro) of SARS-CoV-2. Several promising approved drugs, including Simeprevir, Ergotamine, Bromocriptine and Tadalafil, stand out as the best candidates based on their binding energy, fitting score and noncovalent interactions at the binding sites of the receptor. All selected drugs interact with the key active site residues, including His41 and Cys145. Various noncovalent interactions including hydrogen bonding, hydrophobic interactions, pi-sulfur and pi-pi interactions appear to be dominant in drug-Mpro complexes. MD simulations are applied for the most promising drugs. Structural stability and compactness are observed for the drug-Mpro complexes. The protein shows low flexibility in both apo and holo form during MD simulations. The MM/PBSA binding free energies are also measured for the selected drugs. For pattern recognition, structural similarity and binding energy prediction, multiple linear regression (MLR) models are used for the quantitative structural-activity relationship. The binding energy predicted by MLR model shows an 82% accuracy with the binding energy determined by molecular docking. Our details results can facilitate rational drug design targeting the SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.

Both low solubility and high hepatic metabolism cause low oral bioavailability of bromocriptine mesylate (BM) leading to very low drug amount in brain. Self-microemulsion (SME) tablets were developed to improve solubility, stimulate lipoprotein synthesis to promote lymphatic transport, avoid hepatic metabolism and target drug to brain. SME liquid containing castor oil, Tween(®) 80 and Cremophor(®) EL was prepared and then adsorbed onto solid carries, Aerosil(®)200, Aeroperl(®)300 or NeusilinUS2(®), yielding SME powders. The optimal ratios of SME liquid to carriers determined from flowability and scanning electron photomicrographs before tableting were 1.5:1, 2:1 and 2.5:1 for Aerosil(®)200, Aeroperl(®)300 and NeusilinUS2(®), respectively. Only Aeroperl(®)300 SME tablet had comparable dissolution to BM commercial tablet. From in vitro study in Caco-2 cells, fluorescein loaded SME tablet showed higher uptake than fluorescein loaded in either oil or surfactant. Although significantly lower amount of drug was permeated from SME tablet than from commercial tablet, higher drug uptake was obviously observed (P<0.05). In addition, higher lipoprotein synthesis expressing as content of apolipoprotein B (apo-B) found in secreted chylomicron resulted in higher drug uptake in co-culture of brain endothelial cells (bEnd.3) and astrocytes (CTX TNA2) from drug loaded SME tablet when compared to commercial tablet (P<0.05) due to binding of apo-B to LDL receptors expressed on the surface of endothelial cells. Therefore, tablet of SME adsorbed onto porous carrier potentially delivered BM to brain via lymphatic transport by increasing the lipoprotein synthesis.

The contribution of conformational heterogeneity to cooperativity in cytochrome P450 3A4 was investigated using the mutant L211F/D214E/F304W. Initial spectral studies revealed a loss of cooperativity of the 1-pyrenebutanol (1-PB) induced spin shift (S(50)=5.4 microM, n=1.0) but retained cooperativity of alpha-naphthoflavone binding. Continuous variation (Job's titration) experiments showed the existence of two pools of enzyme with different 1-PB binding characteristics. Monitoring of 1-PB binding by fluorescence resonance energy transfer from the substrate to the heme confirmed that the high-affinity site (K(D)=0.3 microM) is retained in at least some fraction of the enzyme, although cooperativity is masked. Removal of apoprotein on a second column increased the high-spin content and restored cooperativity of 1-PB binding and of progesterone and testosterone 6beta-hydroxylation. The loss of cooperativity in the mutant is, therefore, mediated by the interaction of holo- and apo-P450 in mixed oligomers.

R-Apomorphine (APO) the catechol-derived dopamine D1-D2 receptor agonist has been shown to be highly potent iron chelator and radical scavenger and inhibitor of membrane lipid peroxidation in vitro, in vivo and in cell culture employing PC12 cells. Its potency has been compared to the prototype iron chelator desferrioxamine (desferal), dopamine, nifedipine and dopamine D2 receptor agonists, bromocriptine, lisuride, pergolide and pramipexole. APO also inhibits brain and mitochondrial protein oxidation. In vivo APO protects against MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)- induced striatal dopaminergic neurodegeneration in C57 black mice with as low as 5 mg/kg. APO is a reversible competitive inhibitor of monoamine oxidase (MAO) A and B with IC50 values of 93 and 214 uM, respectively. The iron chelating and radical scavenging actions of desferal and APO explains their ability to inhibit iron and 6-hydroxydopamine (6-OHDA)-induced neurodegeneration and activation of redox-sensitive transcription factor NF-kappa B and the subsequent transactivation of promoters of genes involved in inflammatory cytokines. Iron is thought to play a pivotal role in neurodegeneration, and APO may be an ideal drug to investigate neuroprotection in Parkinson's disease where iron and oxidative stress have been implicated in the pathogenesis of nigrostriatal dopamine neuron degeneration.

The present study is an attempt to find sites of dopaminergic inhibition along the transduction cascades culminating in gonadotropin (GtH) release in a teleost fish, tilapia. Experiments were carried out on perifused pituitary fragments and in primary culture of trypsinized pituitary cells. Salmon GnRH, chicken GnRH I and II stimulated GtH release in culture with estimated ED50 values of 15.56 pM, 2.55 nM and 8.65 pM, respectively. Apomorphine (APO; 1 microM) totally abolished this stimulation. Dopamine (DA; 1 microM) reduced both basal and GnRHa-stimulated GtH release from perifused pituitary fragments but did not alter the formation of cAMP. In a similar perifusion experiment DA abolished GtH release in response to forskolin (10 microM) with no reduction in cAMP formation. This indicates that one site of the dopaminergic inhibition is distal to cAMP formation, an indication not compatible with the classic characteristic of DA D2 type mode of action. The inhibition of GtH release in culture, caused by 1 microM APO, the specific DA D2 agonists LY 171555 (LY) or bromocryptine (BRCR) could not be reversed by activating protein kinase C (PKC) by DiC8 or the phorbol ester TPA. This would indicate a site for DA action distal to PKC. However, the stimulatory effect of arachidonic acid (AA; 50 microM) in perifusion was not reduced by DA (1 microM) or by APO, LY or BRCR in culture, which suggests a site for DA action proximal to AA formation. APO, LY and BRCR reduced GtH release in response to the Ca2+ ionophore A23187, however, their inhibitory effect was reversed by 10 microM ionomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Three behavioral models were used to characterize the pharmacological action of BCH 325 on central dopaminergic transmission. The effect of acute SC treatment with BCH 325 upon dopaminergic mechanisms affecting motor activity was studied on the climbing behavior of mice. It was shown that the beta-casomorphin analogue evoked a dose-dependent increase in apomorphine (APO)-induced hypoactivity that was reversed by sulpiride (SULP). In in vitro studies on slices of nucleus accumbens of mice it could be demonstrated that 10(-6) M APO caused a reduction of K(+)-stimulated [14C]dopamine (DA) release that was potentiated following simultaneous incubation with 10(-6) M BCH 325. To prove a postsynaptic influence in D1 receptor-mediated behavior pattern, the action of BCH 325 was studied on bromocriptine (BROMO)-evoked yawning behavior of rats after pretreatment with reserpine (RES) or saline. The peptide could not influence the BROMO yawning after saline administration, but it was able to normalize the number of yawns, which were reduced after RES. To investigate the effect of BCH 325 on postsynaptic D2 receptors, jerking behavior on RES-pretreated rats after a high dose of BROMO was used. Following RES pretreatment only, the number of BROMO-induced jerks was decreased by treatment of rats with 0.5 mumol/kg BCH 325. In contrast, the jerking behavior was enhanced by 0.5 mumol/kg BCH 325 in rats that were additionally treated with alpha-methyl-p-tyrosine (MPT). In biochemical studies on slices of the nucleus accumbens of mice, the in vivo pretreatment with RES caused a reduction of K(+)-stimulated [14C]DA release that was blocked by the SC administration of 0.5 mumol/kg BCH 325.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol (ETOH) administered acutely to castrate male rats caused a decline in pituitary luteinizing hormone (LH) and prolactin (PRL) secretion. This was associated with an elevation in hypothalamic and median eminence stores of dopamine (DA) that was related to the dose of alcohol given. Pituitary stalk transection (PST) resulted in a significant rise in plasma PRL levels compared to sham control animals, which suggests that DA in the hypophysial portal blood exerted an inhibitory influence on pituitary PRL secretion. The DA agonist bromocriptine failed to alter mean plasma LH levels in stalk-transected rats. The ETOH-treated castrated rats showed a significant rise in circulating PRL after injection of the DA receptor antagonist haloperidol metabolite II (HAL), but the administration of the DA receptor agonist R(-)-apomorphine HCL (APO) caused plasma PRL to decline to near undetectable levels. Plasma LH levels remained unchanged in the HAL- and APO-treated rats and were similar to those of sham controls. These results suggest that lactotroph DA receptors were still functional. Thus our previous finding of ETOH-induced reduction on LH secretion may be attributable to an inhibitory effect by DA on the luteinizing hormone-releasing hormone (LHRH) peptidergic neurons rather than a direct inhibition by DA on the pituitary gonadotroph.

1. The effects of dopamine agonists on the immobility time in mice were examined. 2. Apomorphine (APO), bupropion (BUP), bromocriptine (BRC) and quinpirole but not SKF 38393 elicited anti-immobility effect. The effect of the agonists was decreased by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. 3. In animals pretreated with reserpine, the anti-immobility effects of APO and quinpirole were potentiated, while the response of BPU was decreased and that of BRC was not changed. 4. It is concluded that D-2 dopamine receptors are involved in the anti-immobility effects of dopaminergic agents, D-2 dopamine receptors may become hypersensitive by reserpine and BUP exerts its response through indirect dopaminergic if mechanism.

Apomorphine (Apo), a D1/D2 Dopamine (DA) agonist, at high doses (500 micrograms/kg) induces a short-lasting insomnia, antagonized by a secondary injection of corticotropin-like intermediate lobe peptide (CLIP, 10 ng); these effects are also observed with hypophysectomized (hypoX) rats. The administration of the serotonin (5-HT) agonist 8-hydroxy-2-di-n-propylamino-tetralin (8-OHDPAT, 0.3 mg/kg) induces also an insomnia which, unlike Apo, is followed by a significant PS rebound. CLIP, again, antagonizes the 8-OHDPAT-induced insomnia. Finally, Bromocriptine (5 mg/kg), an agonist for both DA and 5-HT, induces first an insomnia (antagonized by CLIP), followed by a PS rebound; these effects persist in hypoX rats.

The ability of bromocriptine (BRC), a dopamine D-2 receptor agonist, to induce climbing behaviour was studied in mice. BRC (2-32 mg/kg IP) evoked climbing behaviour. The maximum effect was obtained with 8 mg/kg, while higher doses of BRC (16 and 32 mg/kg) were less effective. Climbing began about 2 h after injection and was most marked 5 h after bromocriptine administration. Pretreatment of animals with the dopamine antagonist pimozide (0.5 mg/kg IP) decreased BRC-induced climbing. Sulpiride (0.25-1.25 mg/kg IP), a potent D-2 antagonist and/or SCH 23390 (0.025 and 0.05 mg/kg SC), a D-1 receptor antagonist, also decreased the response. Furthermore, the climbing behaviour induced by BRC was abolished by pretreatment with reserpine plus alpha-methyl-p-tyrosine (AMPT). Concomitant administration of apomorphine (APO) and BRC potentiated the effect of APO on climbing. Concomitant injection of BRC and SKF 38393 (SKF, D-1 agonist) reduced the effect of SKF on climbing, while administration of BRC 4 h before SKF potentiated the effect of both drugs. It is suggested that BRC induces climbing through D-1 and/or D-2 dopamine receptors.

1. The erectile response to the short-acting dopamine (DA) receptor agonist, apomorphine (Apo) HCl (0.25, 0.5, 0.75 and 1.0 mg sc), and placebo was evaluated in 28 impotent patients and penile circumference monitored using a mercury strain gauge and strip chart recording. 2. A full erection (increment in penile circumference greater than 2 cm and lasting at least one minute) occurred in 17 patients with Apo; no erection developed after placebo. An erection occurred in 6/8 patients with impaired glucose tolerance, 2/6 patients with diabetes mellitus and in both patients on lithium. 3. Nine patients who responded to Apo were treated in an open trial with bromocriptine; 6 reported improvement in potency. 4. Impairment in DA function may play a role in idiopathic impotence and in impotence associated with impaired glucose tolerance and diabetes mellitus. 5. An erectile response to Apo may predict therapeutic response to bromocriptine or other long acting dopaminergic agents. 6. Lithium, which inhibits DA-sensitive adenylate cyclase, does not prevent Apo-induced erections. This provides further support indicating that Apo induces erections by an effect on D2 receptors. 7. The yawning response to placebo and four doses of Apo HC1 (3.5, 5.0, 7.0, and 10.5 ug/kg sc) was evaluated in five normal men using a polygraphic technique. The yawning response was also assessed in normal young (less than 30 yrs; N = 16) and elderly (greater than 60 yrs; N = 12) volunteers. 8. Under experimental conditions of study, placebo induced spontaneous yawning. This was antagonized by 3.5 and 5.0 ug/kg Apo HC1 but increased by 7.0 ug/kg Apo HC1. These observations are compatible with the view that Apo HC1 in doses of 3.5-5.0 ug/kg stimulates presynaptic DA receptors whereas 7.0 ug/kg stimulates postsynaptic DA receptors. 9. Spontaneous and Apo-induced yawning were significantly decreased in the elderly which suggests that D2 receptor function declines with normal aging.

All the dopamine agonists (apomorphine, dipropylamino-5,6-dihydroxytetrahydronaphtalene, piribedil, bromocriptine, CBM 36-733) tested in the 'behavioral despair' test performed in mice had a dose-dependent anti-immobility effect, with the exception of the D-1 dopamine agonist, SKF 38393. This effect occurred at doses that reduced locomotor activity and decreased colonic temperature. A profound hypothermia of the same amplitude resulted from the immersion in water of the control and apomorphine (Apo)-treated mice. The anti-immobility effect of dopamine agonists depends on the stimulation of central dopamine receptors; this effect was antagonized more easily by haloperidol than by domperidone, and dipropylamino-5,6-dihydroxytetrahydronaphtalene was more effective than amino-5,6-dihydroxytetrahydronaphtalene. Their high sensitivity to sulpiride make it likely that the receptors involved correspond to the D-4 subtype. Blockade of dopamine receptors by haloperidol for about 5 days induced a slight hypersensitivity to the Apo effects. In contrast, tolerance to Apo occurred after administration of Apo, 5 mg/kg s.c., 24 and 16 h before testing. These data might reflect the potential antidepressant activity of direct dopamine agonists.

Different effects of chronic treatment with bromocriptine (BRO) on D-1 and D-2 receptors in the rat were studied through behavioral observation and DA receptor binding assays. Chronic BRO led to enhancement of stereotypy to apomorphine (APO), at the same time it increased the density of D-1 receptor binding by 43% and decreased that of D-2 receptor binding by 21%. Our data suggest that BRO has different effects on D-1 and D-2 receptors and the behavioral hypersensitivity caused by BRO may be relevant to the proliferation of D-1 receptor.

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.

Chronic treatment of rotating rats with equipotent doses of the dopamine (DA) agonists apomorphine (APO), 3-(3,4-dihydroxyphenyl)-1-n-propylpyrrolidine hydrobromide (DPPP) and bromocriptine (BRO) for four weeks resulted in marked differences in rotational activity following acute administration of these agonists. Whereas chronic treatment with APO and DPPP failed to produce any significant changes in agonist-induced rotational behavior, chronic BRO treatment induced a progressive increase in rotational activity up to a mean 200% increase over controls at four weeks. These findings may, in part, explain the long-term clinical efficacy of bromocriptine in patients with Parkinson's disease.

The authors investigated the mechanisms by which inhibitors of the neuronal uptake (NUI) of dopamine (DA) and prolonged stimulations at high rates antagonize the inhibition of acetylcholine (ACh) release from rabbit striatal slices produced by DA receptor agonists. Nomifensine (1 microM) reduced the potency and efficacy of apomorphine (APO) in inhibiting the evoked release of ACh (0.3 Hz, 39 pulses) (noncompetitive kinetics). Highest inhibitory potency and efficacy of APO were obtained at 0.3 Hz and 39 pulses. Increases in stimulation rates and number of pulses (3 Hz and 120 pulses) reduced APO potency and efficacy for inhibition of ACh release (noncompetitive kinetics). At 10 Hz and 500 pulses APO efficacy was further reduced, and the APO concentration-effect curve was biphasic. Inhibition of DA and ACh release produced by other DA receptors agonists such as bromocriptine, piribedil and LY-171555 was also reduced by prolonged stimulations at high frequencies. Depletion of endogenous DA stores by reserpine pretreatment abolished the antagonism of APO produced by NUI and reduced considerably the antagonism produced by high pulses and high rates of stimulation of APO- and LY-171555-induced inhibition of ACh release. However, even after combined pretreatment with reserpine and alpha-methylparatyrosine, the potency and efficacy of APO in inhibiting ACh release at 10 Hz and 500 pulses were less than the values obtained in 0.3 Hz and 39 pulses and at 3 Hz and 120 pulses. The biphasic nature of the APO concentration-effect curve at 10 Hz and 500 pulses was no longer present after reserpine. Interestingly, reserpine pretreatment failed to modify APO-induced inhibition of ACh release at 0.3 Hz and 39 pulses, suggesting that the sensitivity of the DA release modulatory receptors was not affected by the pretreatment. These results indicate that the high synaptic concentration of DA achieved at low stimulation rates in the presence of NUI and at high stimulation rates reduces the potency and efficacy of DA agonists in inhibiting ACh release. However, for prolonged stimulations at high rates not all of the changes seen with DA agonists are mediated by endogenous DA. At high concentrations (10 microM), cocaine and nomifensine inhibited the evoked release of ACh even after depletion of tissue DA stores by reserpine in the absence or presence of a alpha-methylparatyrosine.(ABSTRACT TRUNCATED AT 400 WORDS)

Agonist-induced rotation and striatal binding of [3H]spiperone ([3H]SPIP) were assessed in rats with unilateral lesions of the substantia nigra during and after a period of chronic bromocriptine administration. Agonist-induced rotation significantly increased over a three week period of daily administration of bromocriptine (10 mg/kg i.p.); control animals were tested for agonist-induced rotation at one week intervals, which remained constant. Rotation was increased by chronic bromocriptine administration in response to either of two DA agonists, apomorphine (APO) and bromocriptine, suggesting that increased agonist sensitivity did not reflect a reduction in the metabolism of bromocriptine. Striatal binding of the dopamine D2 radioligand, [3H]SPIP, was significantly increased in the denervated striata of nigra-lesioned rats. Chronic bromocriptine administration decreased binding in denervated striata to levels not significantly different from control values. [3H]SPIP binding in intact striata was significantly reduced by bromocriptine to below control values. Differences in receptor levels reflected changes in the maximum density of binding sites with no change in affinities. Paradoxical behavioural hypersensitivity developing during chronic bromocriptine levels is not apparently mediated by changes in striatal D2 binding sites.

Effects of dopamine agonists upon phrenic output were studied in decerebrate, vagotomized, paralyzed, carotid-body denervated dogs. Intravenous administration of dopamine was without effect in these dogs. Apomorphine (APO) increased phrenic minute activity while bromocriptine (BRO) decreased phrenic minute activity following intravenous injection at doses of 100 micrograms/kg for each drug. BRO-induced decreases in phrenic minute activity were associated with decreases in phrenic amplitude; burst frequency remained unchanged. Conversely, APO-induced increases in phrenic minute activity resulted from significant increases in both frequency and amplitude. Both APO and BRO significantly prolonged inspiratory duration and shortened expiratory duration. Responses to APO and BRO were abolished with haloperidol. These results confirm previous evidence for the existence of dopaminergic receptors within the central nervous system, which are inaccessible to exogenous dopamine, and which can alter timing as well as amplitude characteristics of the integrated phrenic neurogram. Both excitation and inhibition of phrenic activity following administration of APO and BRO are mediated by mechanisms within or below the caudal brainstem.

The following synthetic, structural analogs of dopamine (DA) were examined for their ability to produce hyperglycemia in conscious unrestrained rats: APO (apomorphine), RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane), di-n-propyldopamine, 2-di-n-propylamino-5,6-dihydroxytetralin, 2-dimethylamino-6,7-dihydroxytetralin, lergotrile, pergolide, bromocriptine and d-amphetamine. All the compounds demonstrated dose- and time-dependent hyperglycemic actions. The most potent DA analog to induce hyperglycemia was 2-di-n-propylamino-5,6-dihydroxytetralin (0.18 mumol/kg) and, at the doses used, 2-dimethylamino-6,7-dihydroxytetralin produced the greatest elevation in blood glucose (227% control). APO and RDS-127 were used in experiments designed to provide additional mechanistic information concerning their hyperglycemic action. The hyperglycemia produced by APO or RDS-127 was blocked by adrenalectomy, adrenodemedullation or prior administration of pimozide, a DA receptor antagonist. Phentolamine, an alpha adrenergic receptor antagonist had no effect on the hyperglycemia induced by APO or RDS-127. Oral glucose tolerance tests indicated that APO and RDS-127 caused abnormal glucose tolerance and inhibited the compensatory increase in serum immunoreactive insulin. These effects were prevented by pimozide or phentolamine pretreatment. The potencies of the compounds to produce increases in serum glucose concentrations (SG), inhibit the accumulation of DOPA using the in vivo gamma-butyrolactone procedure (DOPA) and inhibit food intake (FI) were subjected to correlation analysis. Positive correlations were found for FI vs. DOPA, r = 0.96; SG vs. decreases DOPA, r = 0.98 and SG vs. FI, r = 0.98.(ABSTRACT TRUNCATED AT 250 WORDS)

Apomorphine HCl (Apo) (0.25, 0.5 or 0.75 mg sc), a dopamine (DA) receptor agonist, induced penile erections (PEs) (monitored by mercury strain gauges and continuous recording on paper strip charts) in 7 out of 9 normal subjects and placebo in 1 of these 9 (p less than 0.05). Apo-induced PEs recurred in each of the 6 subjects retested. Benztropine (2 mg iv) had no effect on Apo-induced penile tumescence (PT). These data suggest (a) DA mechanisms play a role in normal erectile function (b) DA-mediated PT is not modulated by cholinergic systems (c) evaluation of the erectile response to Apo may provide a simple ancillary test to the investigation of impotence and a way of identifying a subpopulation of impotent subjects with impaired DA function who may respond to long-acting DA agents (d) Apo-induced PT may provide a novel way of studying DA function in man.

Increasing doses of apomorphine (APO) induced the dose-dependent appearance of yawns in rats at doses up to 0.1 mg X kg-1 and their disappearance from 0.1 to 0.6 mg X kg-1. A similar biphasic effect on yawning was observed with increasing doses of n-propyl norapomorphine, piribedil, S 584, bromocriptine, lergotrile, lisuride, CQ 32084 and L-DOPA. APO, n-propyl norapomorphine, piribedil and CQ 32084 had similar ED50 on the induction of sniffing and on the disappearance of yawns. All the neuroleptics tested antagonized the yawns induced by 0.1 mg X kg-1 APO. Increasing doses of haloperidol, chlorpromazine, mezilamine, metoclopramide and thioridazine made the yawns reappear in rats injected with 0.6 mg X kg-1 APO. The ID50 were similar to those for the antagonism of sniffing. On the other hand, increasing doses of clozapine, (+/-)- or (-)-sulpiride, veralipride and DAN 2163 did not make the yawns reappear in rats injected with 0.6 mg X kg-1 APO although sniffing was antagonized. These results are discussed in terms of the ability of sulpiride, veralipride and DAN 2163 to distinguish between the dopamine (DA) receptors involved in the appearance of yawns at low doses of DA agonists and in their disappearance at higher doses. The decreased APO-induced yawning observed concomitantly with increased sniffing in rats with 6-hydroxydopamine-lesioned olfactory tubercles suggests that yawning and sniffing could be mutually exclusive.

A mechanographic method was used to assess the locomotor performance induced by apomorphine or other dopaminergic drugs in reserpine-treated rats. Reserpine was found to induce locomotor hypokinesia. The hypokinesia was dose-dependently reversed by apomorphine (APO), bromocriptine and pergolide. Locomotion was induced by microinjection of APO into the nucleus accumbens. No locomotor effect was found after injection into corpus striatum. Injection into both nuclei was not superior to accumbens only. Intra-striatal or intraaccumbens injections of trifluoperazine blocked the effect on locomotion by systematic apomorphine. The results confirmed that reserpine-induced locomotor hypokinesia is reversed by dopaminergic stimulation in the nucleus accumbens. There were indications that blockade of striatal or accumbens' dopamine receptors counteracts apomorphine-induced locomotion presumably by interaction with postural motor control. Evidence was found for separate dopaminergic control of locomotion and muscletone. This may be of importance for the development of new antiparkinson drugs.

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.

The recovery of prolactin (PRL) secretion following dopaminergic inhibition was studied in vitro using pituitary monolayer cultures. PRL secretion over 4 h was inhibited comparably by 10(-6) M dopamine (DA), 10(-7) M apomorphine (APO), and 10(-10) M bromocriptine (45%, 42%, 51%, respectively) with reciprocal increases in intracellular hormone content. After drug removal, the PRL secretion rate in the cultures that had been treated with DA was 208% of the control cultures by the 2nd h but returned to control values by 4 h, whereas the secretion rate after APO was 131-142% of control throughout the 4-h recovery period. In contrast, PRL secretion remained significantly less than control 20 h after the removal of bromocriptine. Although haloperidol (10(-7) M) prevented the inhibitory action of bromocriptine when added simultaneously, the addition of haloperidol did not restore PRL secretion when added in the posttreatment period. Thus, DA and APO inhibition of PRL release is readily reversible and is followed by early PRL hypersecretion. However, bromocriptine's effects are sustained and once started are not reversed by DA antagonists.

The effect of 3 dopamine (DA) mimetic drugs, i.e. bromocriptine (Bro), apomorphine (Apo) and L-3,4-Dihydroxpenylalanine (L-dopa), was evaluated on plasma growth hormone (GH) levels in 18 patients with Huntington's chorea (HC). 27 Nonobese hospitalized patients were used as controls. Mean baseline GH levels were not altered in patients with HC. Oral administration of Bro (2.5 mg po) or L-dopa (500 mg), or subcutaneous administration of Apo (1.0 mg) resulted in a significantly greater and more prompt (Bro, L-dopa) increase in plasma GH in patients than in controls. These results suggest that presence of an altered dopaminergic regulation of GH secretion in HC.