Stereospecificity of the dopamine receptor mediating the growth hormone response to apomorphine in man

Summary The stereospecificity of the D-2 receptor mediating the growth hormone (GH) response to apomorphine (Apo) and the D-2 receptor regulating prolactin (PRL) secretion were investigated in 10 normal men by examining the effects of cis-flupenthixol (cis-Fx) and trans-flupenthixol (trans-Fx). cis-Fx (1 mg six hourly times four doses) antagonized the GH response to Apo HCl (0.5 mg sc) and increased basal serum PRL concentrations whereas the transisomer showed no effect. These findings (a) provide further evidence that the GH response to Apo is mediated by stimulating dopamine (DA) receptors, and, (b) demonstrate stereospecificity of the DA receptor mediating the GH response to Apo and the DA receptor regulating PRL secretion.     

Reduced growth hormone response to apomorphine in schizophrenic patients with poor premorbid social functioning

Summary The apomorphine-induced growth hormone (GH) response of 16 drug-free schizophrenic patients and nine control subjects were studied. The sub-group of nine patients with poor premorbid psychosocial functioning had a significantly lower GH response than the controls. Additional evidence for state dependent effects is provided.     

Gonadotropin responses to naloxone may depend upon spontaneous activity in noradrenergic neurons at the time of treatment

The opiate system is thought to modulate gonadotropin secretion by its effect on catecholamine secretion. This action may be produced by opiates regulating the amount of catecholamine released from presynaptic terminals at a given frequency of depolarization and/or by increasing the rate of impulse traffic within catecholamine neurons. We examined the effects of naloxone, an opiate receptor antagonist, on luteinizing hormone (LH) and prolactin (Prl) secretion in 3 sex steroid-treated, gonadectomized rat models in which we have considerable information on the rates of turnover of norepinephrine (NE) and dopamine (DA) in the hypothalamus. In 7 day ovariectomized rats treated for 2 days with estradiol (E2), the injection of naloxone (10 mg/kg) at 09.15 h produced a small 3-fold rise in LH and a short-lived decline in Prl. In contrast, naloxone, given at 12.15 h, markedly amplified (10-fold) and advanced the time of the LH surge but did not affect afternoon Prl surges. Hypothalamic NE turnovers are low in the morning and high in the afternoon for such animals. Other ovariectomized (OVX) rats received E2 for 2 days and progesterone (P4) on day 2. Such treatment extinguishes the LH surges which normally occur the next day (day 3) but does not affect phasic Prl secretion. Naloxone, given at 09.15 h to E2P4-treated rats on day 3, did not affect basal LH levels but serum Prl declined for about 1 h. When given at 12.15 h, naloxone produced a small 3-fold rise in LH but did not affect phasic Prl release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential responses in prolactin levels induced by naloxone in humans

The plasma prolactin (PRL) response to the opiate antagonist naloxone was tested in drug-free healthy volunteers (10 men, 18 regularly menstruating women who were in the late follicular phase of their ovarian cycles, and seven post-menopausal women). Naloxone hydrochloride (2 mg intravenous bolus) and placebo (normal saline) were administered on two different days in a double-blind fashion. Blood samples were collected at -15, 0, 30, 60, 120, 180 and 240 min after the injection. In the women of reproductive age, naloxone reduced plasma PRL concentrations, whereas in the post-menopausal women and the men, naloxone resulted in no significant change. However, in the post-menopausal women treated with estrogen (intramuscular 17-beta-estradiol), the opiate antagonist was able to lower plasma PRL concentrations. Thus, it appears that opiate effects on PRL secretion are influenced by the gonadal steroid environment and that estrogens may play a modulating role.     

Failure of naloxone to reverse vascular neurologic deficits

Naloxone failed to improve motor strength in any of 19 patients with acute stroke, even though 4 patients eventually demonstrated complete recovery. Two patients worsened, and sensory abnormalities increased in two others. Motor tone increased in eight patients. Naloxone amelioration of stroke deficits is therefore not common, and this treatment may not be entirely benign.     

Morphine but not Naloxone Enhances Luteinizing Hormone-Releasing Hormone Neuronal Responsiveness to Norepinephrine

Some axon terminals of hypothalamic opiate neurons directly synapse on luteinizing hormone-releasing hormone (LHRH) neurons. To determine whether such synaptic connections affect LHRH neuronal activity, we have examined the profiles and concentrations of LH released in response to intracerebroventricular (icv) norepinephrine (NE, 45 μg) infusions alone or following medial preoptic area (MPOA) electrochemical stimulation (ECS) in estrogen-treated ovariectomized rats. Similar studies were performed in rats treated with naloxone (5 mg/kg ip) or morphine (20 mg/kg sc) given 15 min prior to MPOA-ECS or 30 min prior to icv NE. Naloxone neither augmented nor suppressed the LH response obtained with NE alone. MPOA-ECS evoked a significant increase in plasma LH. When the preoptic area was stimulated (0 min) and NE was infused at 30 min, a significant amplification of LH release occurred. Prior treatment of rats (-15 min) with naloxone had no effect on LH responses elicited by either preoptic stimulation alone or combined with icv NE. In the second study, morphine was given sc and had no effect on basal plasma LH levels. However, when morphine was given (-15 min) and icv NE infusions were made (30 min), the rise in plasma LH induced by NE was significantly enhanced. Preoptic ECS (0 min) evoked a rise in plasma LH and this response was also enhanced by morphine pretreatment. The major effect on LH release occurred when sc morphine injections (-15 min) were combined with MPOA-ECS (0 min) followed by icv NE (30 min). In these rats, a remarkable and highly significant release of LH occurred which reached peak levels even greater than those observed during spontaneous LH surges (2,392 versus 16 to 1,800 ng/ml). Since morphine has profound effects on the serotonergic system, in the third series of studies, morphine was infused into the dorsal raphe nucleus (DRN) and LH responses to MPOA-ECS or icv NE alone or following combined ECS + NE were examined. DRN morphine did not affect basal LH release but it produced a rapid and highly significant rise in plasma prolactin. When DRN morphine was given (-15 min) and NE was infused icv (30 min), there was marked amplification in LH release compared to those values observed after only NE. However, there were no appreciable differences in LH values obtained after sc versus DRN morphine injections in response to NE. Similarly, the amplification of LH release which occurred following DRN morphine (-15 min) + MPOA-ECS (0 min) was not different from that obtained after sc morphine. In the final group of rats, DRN morphine was given (-15 min), the preoptic area was stimulated (0 min) and NE was infused (30 min). Following this treatment, plasma LH release was also markedly enhanced and did not differ appreciably (except at 60 and 120 min) from the levels of LH released after sc morphine. Prolactin concentrations rose slowly after icv NE to reach peak levels 75 min after treatment. Combinations of morphine + MPOA-ECS without or with NE neither augmented nor suppressed the high prolactin concentrations achieved after only DRN morphine infusions. We conclude from these data that: 1) those opiate neuronal terminals which synapse directly on LHRH neurons do not affect LHRH neuronal responsiveness to either NE, to MPOA-ECS or to combined preoptic stimulation+ NE, and 2) morphine has profound effects on LHRH neuronal responsiveness to both NE, to MPOA-ECS and, in particular, to combined ECS + NE. Since amplification of LH release occurs after treatment of rats with morphine either by sc injections or DRN infusions, the augmented LH and prolactin responses observed are most likely due to the morphine-induced release of serotonin and not to direct morphine effects on LHRH neurons.     

Dissociated effects of apomorphine on various nociceptive responses in mice

Summary The effects of increasing doses of apomorphine were studied in mice in six nociceptive tests: (1) withdrawal of the tail immersed in hot water, (2) vocalization induced by the electrical stimulation of the tail, (3) tail flick using a radiant beam, (4) withdrawal of a tail-clip, (5) writhing induced by the i.p. injection of phenylbenzoquinone, (6) forepaw licking and jump latencies on a hot plate. Only in the tests (5) and (6), an apparent analgesia was obtained. Differences were observed between tests (5) and (6), as to: (i) the apparent relative effectiveness of (–)sulpiride (more effective in test [5] than in test [6]), (ii) the naloxone-induced modifications of apomorphine effects (whereas naloxone antagonized apomorphine effects in test [6], it did not in test [5]), (iii) the decrease of apomorphine-induced responses by prevention of hypothermia (in test [6] but not in test [5]). These data suggest that APO-induced increased jump latencies are at least partly related with hypothermia and endogenous opioid systems, whereas APO effect on the writhing test depends on the stimulation of dopamine receptors particularly sensitive to sulpiride and is independant from body temperature and opioidergic transmissions.     

Differential effects on naloxone on the release of neurohypophysial hormones in normotensive and spontaneously hypertensive rats

The hypothalamo-neurohypophysial system is altered in the spontaneously hypertensive rat (SHR). We hypothesized that an aberrant regulation of vasopressin (VP) and oxytocin (OT) release by endogenous opiod peptides alters this neuroendocrine system in the SHR. Concentrations of the neurohypophysial hormones in plasma and the pituitary were measured in 17-week-old SHRs and two strains of normotensive controls, Wistar Kyoto (WKY) and Sprague-Dawley rats. Animals were decapitated 20 min after s.c. injection of saline (1 ml/kg) or naloxone hydrochloride (1 or 10 mg/kg). In addition, neurohypophysial hormones excreted during the day (08.00–17.30 h) and night (17.30–08.00 h) were determined in urine from 16-week-old animals kept in metabolic cages for 5 days. VP at extrahypothalamic sites was also measured as [VP] in acid extracts of the subfornical organ area, hippocampal commissure-fornix and choriod plexus. Hormones were quantified by radioimmunoassay. The pituitary content, plasma concentration, and urinary excretion of OT were reduced (P < 0.05) in SHRs, whereas VP content was increased (P < 0.05) in the pituitary and plasma, but unchanged in urine, of hypertensive animals. In extrahypothalamic tissues, [VP] in the hippocampal commissure-fornix was increased in the SHR. Naloxone elevated (P < 0.05) the plasma concentration of OT in WKY animals and VP in SHRs. Neither [VP] nor [OT] in plasma was changed by naloxone in Sprague-Dawley rats. Pituitary stores of the neurohypophysial hormones were not altered by naloxone in either hypertensive or normotensive rats. In conclusion, endogenous opioid peptides tonically inhibit OT release in WKY rats, whereas VP releas is decreased by opioid peptides in SHRs, 16–17 weeks of age. The neuromodulatory role of opioid peptides in the release of neurohypophysial hormones appears to be altered in the SHR such that VP release is suppressed and OT release is augmented.     

Timing of yawns induced by a small dose of apomorphine and its alteration by naloxone

1. The report examines the temporal sequence of yawns induced by apanorphine and whether the opiate antagonist, naloxone, affects it.

2. Before administering apomorphine (0.075 mg/Kg) or saline, rats (n=8) were pretreated with naloxone (1 mg/kg) or saline. Each subject received all 4 possible treatments (saline-saline, saline-apamorphine, naloxone-saline, and naloxone-apomorphine) in random order.

3. Results indicate that yawning induced by apomorphine seems to come in fits; that is, there is a series of yawns spaced closely together and followed by a period of quiescence before the start of another cluster of yawns.

4. Naloxone reduced the number of apomorphine-induced yawns, and the occurrence of very short inter-yawn intervals.

5. It is suggested that the timing of yawns may provide useful information regarding some pathologies and that opiates may potentiate the action of dopaminergic systems.     

The clinical use of apomorphine in Parkinson's disease

Summary Our 2-year experience in the therapeutic use of subcutaneous apomorphine has involved 25 patients with Parkinson's disease, 10 of whom continue to use it chronically. On the basis of this experience, we have formulated certain indications for its use, together with suggested approaches to modify patients' oral drug regimes so that apomorphine can best be deployed to improve their quality of life.     

Dose-dependent protective effects of apomorphine against methamphetamine-induced nigrostriatal damage

(R)-apomorphine is a non-selective dopamine (DA) agonist which is used in the treatment of Parkinson's disease. In addition to symptomatic effects, apomorphine exerts a neuroprotective activity in specific experimental models. For instance, apomorphine prevents experimental parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroprotection obtained with apomorphine does not seem to be related to its dopamine (DA) agonist properties, instead it appears to be grounded on the antioxidant and the free radical scavenging effects of the compound. In this study, we sought to determine whether apomorphine protects against methamphetamine toxicity. We found that apomorphine (1; 5 and 10 mg/kg) dose-dependently protects against methamphetamine- (5 mg/kg X3, 2 h apart) induced striatal DA loss and reduction of tyrosine hydroxylase (TH) activity in the rat striatum. These protective effects are neither due to a decrease in the amount of striatal methamphetamine nor to hypothermia as indicated by measurement of striatal methamphetamine and body temperature at different time intervals after drug administration. The effects of apomorphine were neither opposite to, nor reversed by the DA antagonist haloperidol despite no decrease in body temperature was observed when apomorphine was given in combination with haloperidol. The present data are in line with recent studies suggesting a DA receptor-independent neuroprotective effect of apomorphine on DA neurons and call for further studies aimed at evaluating potential neuroprotective effects of apomorphine in Parkinson's disease.     

Effects of Novelty Stress on Vasopressin and Oxytocin Secretion by the Pituitary in the Rat

Effects of novel environmental stimuli on vasopressin and oxytocin secretion by the pituitary were studied in dehydrated male rats. As the novel environmental stimuli, rats were transferred to an experimental room, placed in a box painted black and given a pure tone auditory stimulus of 2 kHz. Exposure of rats to the novel environmental stimuli for a period of 2 min decreased plasma concentrations of vasopressin and increased plasma levels of adrenocorticotrophic hormone (ACTH) and prolactin, but did not significantly change the plasma level of oxytocin. The stimuli, however, became ineffective for producing the suppressive vasopressin response as the period of exposure was prolonged to more than 5 and up to 30 min, although the prolonged stimuli were still effective for inducing facilitatory ACTH and prolactin responses. After repeated exposures of rats to the environmental stimuli once a day for 5 or 10 days, the stimuli became disabled from producing the suppressive vasopressin response. However, the rats were still capable of responding to the novel stimuli of another kind. All these data suggest that novelty stress suppresses vasopressin secretion but does not change oxytocin secretion. In order to test the possibility that glucocorticoids expectedly secreted by the adrenals in response to the stress might have suppressed vasopressin secretion, a large amount of dexamethasone was administered to the rat before testing. Dexamethasone pretreatment depressed plasma levels of ACTH and vasopressin as reported previously and blocked the facilitatory ACTH response to the novelty stress. However, dexamethasone treatment did not affect the suppressive vasopressin response to the novelty stress. Thus, it is likely that the suppressive vasopressin response to novelty stress does not primarily depend upon endogenous glucocorticoids.     

Effects of Morphine and Naloxone on Prolactin and Growth Hormone Gene Expression in the Male Rat Pituitary Gland

It is generally admitted that opioids can stimulate the release of both prolactin (PRL) and growth hormone (GH). In order to investigate the role of opioids in the regulation of PRL and GH gene expression in the rat pituitary, we studied the effects of chronic administration of the opioid drug morphine and an opiate receptor antagonist naloxone on both PRL and GH gene expression as measured by in situ hybridization. Four-day treatment with morphine (40 mg/kg/day) produced a 12% increase in PRL mRNA levels. Conversely, naloxone (4 mg/kg/day) decreased the autoradiographic reaction by 10%. The concomitant administration of morphine and naloxone induced no significant changes in PRL gene expression. On the other hand, treatment with morphine produced a 22% decrease in GH mRNA levels, an effect which was prevented by the concomitant administration of naloxone. When injected alone, naloxone did not modify the hybridization signal. These results clearly indicate that opioids are involved not only in the regulation of GH and PRL release but also in the gene expression of the two hormones. The discordance observed between the acute effects of morphine on GH release and the effect of the opioid drug on mRNA levels remains to be clarified.     

Cyclosporine Effects on in vitro Responsiveness of Anterior Pituitary Hormone Release to Dopamine and Thyrotropin-Releasing Hormone in Young Female Rats

Endocrine side effects of the immunosuppressive drug cyclosporine (CyA) include changes in anterior pituitary hormone secretion. The aim of the present study was to examine the effects of CyA on the responsiveness of in situ and ectopic anterior pituitary prolactin (PRL), growth hormone (GH) and luteinizing hormone (LH) release response to dopamine (DA) and thyrotropin-releasing hormone (TRH) treatment in young female rats, and to evaluate the possible PRL participation in these effects. Thirty day old rats were rendered hyperprolactinemic by transplanting an anterior pituitary gland of a littermate donor, under the kidney capsule, and were then injected with CyA or vehicle for 2 or 8 days. Sham-operated rats were used as controls and treated in the same way. CyA treatment prevented the increase in plasma PRL levels which occurred in controls after pituitary grafting. In vitro basal PRL release of in situ pituitaries from either sham-operated and/or pituitary-grafted animals was decreased by CyA treatment at any point studied. Basal in vitro secretion of GH was only decreased in the in situ pituitaries from grafted animals after 2 days of CyA therapy. The presence of an ectopic pituitary lead to an increase in the in vitro basal LH secretion from in situ pituitaries as compared to those from sham-operated rats. Basal LH release rates were not changed by CyA treatment, although the LH release in vitro did increase in the in situ pituitaries from sham-operated animals treated with the drug for 2 days. DA addition to the incubation media decreased the in vitro release of PRL, GH and LH from the in situ pituitaries of sham-operated and pituitary-grafted animals treated with vehicle. In CyA treated animals, DA decreased in vitro PRL release from the in situ pituitaries of animals, independently of the presence or absence of an ectopic pituitary. Reductions of the in vitro GH and LH release after DA treatment were higher in the in situ pituitaries from grafted animals on day 8 of CyA or vehicle treatment. TRH increased the in vitro release of the three hormones with differential effects related to the length of the treatment with CyA and/or the presence of an ectopic pituitary. In vitro release of PRL and GH by ectopic pituitaries was inhibited by previous treatment with CyA and this effect was decreased proportional to the duration of the treatment with the drug, while LH secretion was not modified. Addition of DA to the incubation media resulted in a marked reduction of in vitro PRL and GH release, but only at day 8 of vehicle treatment on GH release did DA addition to media further decrease the release of both hormones from ectopic pituitaries from animals treated for 2 or 8 days with the drug, whereas LH secretion was not modified. TRH addition to the incubation media of ectopic pituitaries surprisingly reduced PRL and GH secretion on day 8 of CyA treatment or after surgery. The results of these studies suggest that CyA can act directly at the hypophyseal level modifying pituitary responsiveness to external stimuli. CyA seems to exert its main effects on lactotroph activity while its effects on somatotrophs and gonadotrophs are less.     

Effects of cholinergic stimulation on pituitary hormone release

Physostigmine was infused into human volunteers to assess the effect of central cholinergic stimulation on memory and on neuroendocrine function. Methscopolamine bromide, a peripheral anticholinergic agent, was given simultaneously. The lower dose of physostigmine (1.0 mg) produced no change in AVP, cortisol, melatonin, GH or LH in those subjects without unpleasant cholinergic side effects. Larger doses of physostigmine usually produced nausea, and were associated with marked elevations of AVP, cortisol and prolactin, but no change in GH, LH or melatonin. Thus, cholinergic agents easily induce a stress response, but the GH component of this response can be suppressed by peripheral cholinergic blockade.     

Effect of lysine vasopressin in depressed patients on mood and 24-hour rhythm of growth hormone, cortisol, melatonin and prolactin

Lysine-8-vasopressin (LVP) for 10 days and in doses up to 13.5 LVP units did not significantly alter the Hamilton Depression Rating Scale scores of 12 severely depressed, treatment-resistant patients who were evaluated in a double-blind crossover study. The 24-h rhythms of melatonin, cortisol, growth hormone and prolactin appeared remarkably stable over the course of repeated measurement. LVP administration did not affect these 24-h rhythms.     

Estrogen receptor-beta, but not estrogen receptor-alpha, is expressed in prolactin neurons of the female rat paraventricular and supraoptic nuclei: comparison with other neuropeptides

Estrogen receptor-alpha (ER-alpha) and ER-beta exhibit fine differences in their distributions in the rodent forebrain, and one such difference is observed in the paraventricular (PVN) and supraoptic (SON) nuclei. To investigate the functional significance of ER in these brain areas, we examined the neuropeptide characteristics of ER-expressing neurons in the PVN and SON of female rats by using dual-label immunocytochemistry. The distributions of ER-alpha immunoreactivity (ir) and ER-beta ir were nonoverlapping in the PVN and SON. Nuclear ER-alpha ir was found in a population of thyrotropin-releasing hormone (TRH)-expressing neurons in the PVN (5.93% +/- 1.20% SEM), but not in any other identified cell phenotype of the PVN and SON. The phenotype of neurons with the highest percentage expressing ER-beta was found to be prolactin (PRL) immunoreactive in both the parvocellular (84.95% +/- 4.11%) and the magnocellular (84.76% +/- 3.40%) parts of the PVN as well as the SON (87.57% +/- 4.64%). Similarly, most vasopressin-immunoreactive neurons were also ER-beta positive in the PVN (66.14% +/- 2.47%) and SON (72.42% +/- 4.51%). In contrast, although a high percentage of oxytocin (OXY) neurons coexpressed ER-beta in the PVN (84.39% +/- 2.99%), there was very little ER-beta/OXY colocalization in the SON. Low levels of corticotropin-releasing hormone neurons also expressed ER-beta ir in the PVN (12.57% +/- 1.99%), but there was no ER-beta colocalization with TRH. In summary, these findings further support the possibility of direct effects of estrogen on neuropeptide expression and implicate estrogen involvement in the regulation of various aspects of neuroendocrine function.     

Fluid consumption in water-deprived rats after administration of naloxone or quaternary naloxone

1. 1. Water-deprived male rats were given access to water, or to a 0.005M sodium saccharin solution, or to a 0.9% sodium chloride solution, during a 30 min test period.

2. 2. Naloxone (0.01–10.0 mg/kg) produced dose-dependent reductions in the consumption of each fluid. Saccharin-drinking was significantly reduced by 0.01 mg/kg naloxone, and water- and saline-drinking by 0.1 mg/kg naloxone. Quaternary naloxone (0.01–10.0 mg/kg) had no effect on drinking under any condition.

3. 3. Access to the saline solution resulted in hyperdipsia, due to a prolongation of the initial bout of avid drinking in the thirsty rats. Naloxone, in small doses, completely abolished this hyperdipsia. Since the quaternary compound had no effect, it was concluded that opiate antagonist suppression of saline-induced hyperdipsia was probably mediated at central opiate receptors.

Role of central nervous system neurotransmitters in mediating the effects of morphine on growth hormone-and prolactin-secretion in the rat

Unanesthetized adult male rats with indwelling right atrial cannulae were used in the majority of experiments. Morphine (MOR, 3.0 mg/kg) caused a large but transient increase in both GH and PRL levels, which could be prevented with naloxone. Disruption of central noradrenergic function with diethyldithiocarbamate (400 mg/kg) or phenoxybenzamine (15 mg/kg) abolished the GH-releasing effect of MOR, without interfering with the PRL secretory response. Depletion of brain serotonin stores with p-chlorophenylalanine (300 mg/kg) or 5,7-dihydroxytryptamine or administration of serotonin receptor blocker, cyproheptadine (2.5 mg/kg), did not diminish the GH respnse to MOR but it inhibited, or in the case of 5,7-DHT treatment abolished the activation of PRL secretion. Additionally, metergoline (0.1 and 1.0 mg/kg), another serotonin receptor blocker, caused an inhibition of the GH-releasing action of MOR; however, this inhibition was reversed by pretreatment with spiroperidol (0.1 mg/kg). Metergoline also markedly diminished the MOR-induced elevation of PRL. Inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine (alpha-MT, 250 mg/kg) blunted the effect of MOR on GH; however, dopamine receptor blockers, spiroperidol (0.01 and 0.1 mg/kg) or (+)butaclamol (0.3 and 1.3 mg/kg), were without any influence. alpha-MT or spiroperidol did not alter the effect of MOR on PRL secretion, but the higher dose of (+)butaclamol suppressed it. It is concluded that the GH-releasing action of MOR requires unimpaired functioning of the central noradrenergic system, while the serotonergic and dopaminergic systems appear to play no significant role in it. In contrast, serotonergic systems seem to be essential for the activation of PRL secretion, whereas the noradrenergic system is not involved. It remains uncertain whether morphine activtes PRL secretion also through inhibition of dopaminergic activity. We favor the view that the dopaminergic component participates in the PRL activation by MOR, but that its contribution to the overall effect is rather small.     

The pharmacokinetic and clinical effects of tolcapone on a single dose of sublingual apomorphine in Parkinson's disease

Apomorphine (APO) is a potent dopamine agonist that is partially metabolized by catachol-O-methyl transferase (COMT). Tolcapone was the first COMT inhibitor available for use as adjunctive therapy to levodopa in Parkinson's disease (PD). In order to determine whether this compound might increase the serum area under the curve (AUC) of APO and whether this results in any clinical benefit, we administered 200 mg doses of tolcapone to five fluctuating PD patients taking an investigational sublingual APO preparation. Serial tapping speed and gait speed were assessed at 15 min intervals over four hours, in conjunction with APO serum levels, following a single dose of APO, both before and five days after starting tolcapone (600 mg/day). Serum APO levels tended to be higher (12.6%), and clinical measures suggested improvement during the APO “on” period after the addition of tolcapone (22.5% improvement in gait speed, and 7.6% improvement in tapping speed), but neither reached statistical significance. Further trials, involving larger samples are needed to clearly establish the pharmacokinetic and clinical effect of tolcapone in PD patients taking APO.