Dopaminergic Compounds Research Articles

Effect of chronic bromocriptine treatment on psychological profile of patients with PRL-secreting pituitary adenomas

Hyperprolactinaemic patients are characterized by an altered psychological profile, positively modified by the administration of dopaminergic drugs. This would suggest that the same neurochemical disorder is responsible for both hyperprolactinaemia and abnormal psychological profile in these patients. To identify depression, anxiety, and aggressiveness, nine women affected by prolactin (PRL)-secreting pituitary adenomas were studied before and after 6 and 12 mo of bromocriptine therapy, by the use of different psychometric tests (Mean Minnesota Multiphasic Personality Inventory [MMPI], State-Trait Anxiety Inventory [STAI], and State and Trait Aggressiveness Scale [STAS]). As a group, the patients did not show any depressive, anxious, or aggressive tendencies. Furthermore, no significant modifications were observed during dopaminergic treatment. Patients bearing PRL adenomas seem to be characterized by a dopaminergic background different from that found in functional hyperprolactinaemia. This hypothesis could explain the different psychological configuration and behavior in response to the administration of dopaminergic compounds.

Biphasic dose-dependent effects of dopamine and involvement of dopamine autoreceptors on intra-ocular pressure in the rabbit.

1. This work was conducted to provide new data concerning the possible dose-dependent activity of dopamine (DA) after ocular instillation. Experiments were done in rabbits with normal intraocular pressure (IOP), or after transitory induced ocular hypertension in water-loaded animals. 2. In ocular normotensive animals, a biphasic dose-dependent activity is observed, with no significant effect for 0.001% and 0.003% DA, a decrease in IOP after 0.005% and 0.01% DA instillation, then an important increase in IOP at concentrations from 0.05% onwards. 3. During transitory ocular hypertension, this phenomenon was confirmed, with a marked ocular hypotensive activity for 0.01% DA, no effect after 0.005% DA, then an important ocular hypertension with 0.05% and 0.5% DA as compared to the control group (0.9% NaCl). 4. An immediate and similar ocular hypertensive effect with DA could be reproduced by a subsequent instillation at high concentration (1%), while the hypotensive activity induced at low concentration (0.01%) is followed by a long-lasting refractory period (about 18 h). 5. Such a dose-dependent biphasic effect was also observed with N-methyl-dopamine (NMDA) after ocular instillation. The effects of instilled dopaminergic compounds were tested and ocular hypotensive activities of the S(-)enantiomer of the DA analogues 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), and of thiothixene (TIX) were also demonstrated. 6. The possible relationships to DA1 and DA2 receptors of the dual effect is discussed.

Serine mutations in transmembrane V of the dopamine D1 receptor affect ligand interactions and receptor activation.

Several serines present in transmembrane domain V are conserved among members of the G-protein-coupled receptor family that bind catecholamines. Two of these serines that are present in the beta-adrenergic receptor were previously shown by site-directed mutagenesis to affect agonist binding and receptor activation (Strader, C. D., Candelore, M. R., Hill, W. S., Sigal, I. S., and Dixon, R. A. F. (1989) J. Biol. Chem. 264, 13572-13578). We investigated the role of the serines present in transmembrane V of another catecholamine receptor, the dopamine D1 receptor, by site-directed mutagenesis, and the results show that mutations at serines 198, 199, and 202 affect dopamine binding. The substitution of serine 198 or serine 199 by an alanine also affects the binding of several other agonist and antagonist dopaminergic compounds while an alanine substitution at serine 202 has no effect on the binding of these compounds. Moreover, each single serine mutation decreased the maximal cAMP accumulation elicited by a dopamine D1 partial agonist. These results suggest that serines present in transmembrane V of the D1 receptor affect ligand interactions and receptor signal transduction, but not entirely in the manner that would be predicted from the model proposed for the beta-adrenergic receptor.

Putative neurotoxicity of SKF 38393 and other D1 dopaminergic drugs investigated in rat striatum.

The recently alleged neurotoxicity of the D1 receptor agonist, SKF 38393, was investigated in rat striatum by measuring the enzymes acetylcholinesterase (AChE) and glutamate decarboxylase (GAD). First, unilateral intrastriatal microinjection of the excitotoxin kainic acid (2 micrograms in 1 microliter) was shown to evoke vigorous contraversive circling, followed 1 or 2 weeks later by profound decreases in striatal AChE (24 and 54%), GAD (51 and 75%), and protein (36 and 47%), as well as loss of GAD (45% at 2 weeks) in the ipsilateral substantia nigra. Similar striatal treatments with SKF 38393 (30 micrograms in 0.5-1 microliter), the related benzazepines SKF 82526 (D1 agonist, 30 micrograms in 1 microliter) and SCH 23390 (D1 antagonist, 5 micrograms in 1 microliter), or the phenanthridine D1 agonist CY 208-243 (5 micrograms in 1 microliter) failed to affect the rats' behaviour or their striatal levels of AChE, GAD, and protein. Intrastriatal SKF 38393 (30 micrograms in 0.5 microliter) also had no influence on these enzymes in the substantia nigra. It is concluded that none of the D1 dopaminergic compounds examined here was neurotoxic toward the many different cell groups that contain AChE and/or GAD in the striatum.

Synthesis and dopamine receptor affinities of 1-aminoethylhetero-tetralines

A series of 1-aminoethylhetero-tetralines 3–6, which can be considered as opened-structure analogues of previously studied dopaminergic compounds 2, were synthesized. In the binding studies, to evaluate D-1 and D-2 activity, no significant affinity was observed towards both dopaminergic receptors.

Behavioural profile of partial D2 dopamine receptor agonists

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kg d-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blocked d-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208-911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced by d-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208-911. The profiles of SDZ 208-912 and terguride were intermediary to those of SDZ 208-911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kg d-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dose d-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208-911, preclamol and terguride was accompanied only by the low dose d-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208-912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased by d-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced by d-amphetamine.

Yawning produced by dopamine agonists in rhesus monkeys

Yawning was recorded from five rhesus monkeys restrained in a chair after i.m. injection of dopaminergic compounds: apomorphine (0.03 mg/kg), quinpirole (0.01 mg/kg), and (−)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (1 mg/kg). SKF 38393 or physostigmine produced no yawning. Yawning from apomorphine was blocked by chlorpromazine or SCH 23390 (0.03 mg/kg). Sulpiride (10 mg/kg) was ineffective. The difference between rats and monkeys in their yawning response to dopaminergic compounds is discussed.

Carbamate Ester Prodrugs of Dopaminergic Compounds: Synthesis, Stability, and Bioconversion

Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1 W-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be highly unstable at pH 7.4 and 37 °C, the half-lives of hydrolysis being between 4 and 40min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the W-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas W-monosubstituted carbamates appear to be too chemically and enzymatically labile.

Behavioral Complications of Drug Treatment of Parkinson's Disease

A variety of neuropharmacologic agents, including anticholinergic drugs, amantadine hydrochloride, levodopa, selegiline, bromocriptine, and pergolide, are now available for the treatment of Parkinson's disease. Of patients treated with dopaminergic agents, 30% develop visual hallucinations, 10% exhibit delusions, 10% have euphoria, 1% have mania, 10% to 15% experience increased anxiety, 15% have confusional periods, and a few exhibit altered sexual behavior. Anticholinergic drugs have a greater tendency to produce confusional states than dopaminergic compounds. Elderly patients and those with underlying dementia are most likely to have untoward side effects with anti-parkinsonism treatment. Dosage reduction is the optimum management strategy, although anti-psychotic agents may be necessary in patients with delusions, and lithium may help control drug-induced mania. Dopaminergic agents share the property of stimulation of D2 dopamine receptors, and this action may play an essential role in mediating their neuropsychiatric effects.

Ibopamine-induced reduction of serum prolactin level and milk secretion in puerperal women

Ibopamine, a peripheral dopamine agonist, was administered to 80 postpartum women to assess its effect on prolactin (PRL) and milk production. The acute administration of 400 mg significantly decreased serum PRL for more than 240 min. Women given ibopamine 400 mg t.d.s. for 5 to 10 days showed suppression of PRL and milk letdown was prevented in the latter group. No side effects were observed on repeated administration. Ibopamine may be a useful alternative to other dopaminergic compounds for the inhibition of puerperal lactation.

Computer design of potentially bioactive molecules by geometric searching with ALADDIN

Structurally novel potential dopamine agonists were designed by searching databases of 3D structures to find templates that match geometric criteria and can be modified into molecules suggested for synthesis. A search of 54,296 3D structures from three different databases generated 499 structurally unique molecules that meet our geometric criteria for D-2 dopaminergic activity. The search identified 8 of 9 classes of known fused ring phenolic dopaminergic compounds and 62 other classes of fused ring compounds with potential activity. The low observed frequency of finding the same ring class more than once suggests that additional searches will design many additional molecules. Compound design based on 3D substructure searching methods appears to be equally applicable to suggesting new classes of compounds for beginning or for mature medicinal chemistry investigations and does not require the construction of special libraries of templates.

Quinelorane (LY163502), a D2 dopamine receptor agonist, facilitatesseminal emission, but inhibits penile erection in the rat

Dopaminergic compounds have been shown to facilitate male sexual responses in various contexts. We investigated the effects of a specific D2 dopamine receptor agonist, quinelorane (LY163502), on sexual responses elicited in the restrained supine male rat (i.e., ex copula reflex tests). Penile erections, evoked by retraction of the penile sheath, were inhibited by systemic administration of 10 micrograms/kg quinelorane; however, the occurrence of seminal emission was dramatically increased. A smaller dose of 0.25 ng/kg was without effect. In a second experiment, intracranial microinjection of quinelorane was followed by ex copula reflex tests. The medial preoptic area (MPOA) has been previously implicated in the dopaminergic regulation of male copulatory behavior. The effects of an intra-MPOA injection of quinelorane on seminal emission and erectile responses were similar to those observed following systemic administration. These results are consistent with the hypothesis that DA receptors in the MPOA are important in the regulation of male sexual behavior and suggest that D2 receptors in the MPOA may decrease ejaculatory threshold while inhibiting erectile mechanisms.

Effectiveness and Tolerability of Long Term Treatment with Cabergoline, a New Long-Lasting Ergoline Derivative, in Hyperprolactinemic Patients*

Cabergoline (CAB) is a new oral dopaminergic compound showing a very long-lasting PRL-lowering activity and reported to be well tolerated. The efficacy and tolerability of chronic treatment with CAB in 30 female hyperprolactinemic patients, aged 18-52 yr (6 microadenomas, 3 macroadenomas, and 21 functional hyperprolactinemias), were studied. In a group of 10 patients who received CAB (0.8 mg once weekly or 0.4 mg twice weekly) for 8 weeks PRL levels normalized while on treatment and remained normal (8 patients) or greatly reduced (1 patient) for 1-2 months after discontinuation of the drug. Twenty-six patients underwent chronic treatment (6-12 months) with an initial dose of 0.5 mg once weekly, subsequently increased to 1-2 mg in 10 patients and decreased in the other 2. Due to severe side-effects CAB was discontinued in 3 patients, in 1, 8, and 12 weeks. A significant reduction of PRL levels was already observed after the first week of treatment (mean +/- SEM basal values, 90.1 +/- 13.3 vs. 29.5 +/- 6.3 micrograms/L; P less than 0.001). Twenty-two patients had normal PRL levels in 1-36 weeks (mean, 6 weeks) with 0.5-2 mg CAB. Twenty-two patients resumed regular menses; 2 patients became pregnant after 3-11 months of treatment. Thirteen patients complained of side-effects (nausea, hypotension, headache, gastric pain, dizziness, and weakness) that disappeared with time in 10 of them. The comparison with a previous bromocriptine treatment regimen in 20 patients had shown that the number of patients requiring discontinuation of the latter drug was significantly higher (7 vs. 3 patients; P less than 0.001). However, 2 patients who needed to discontinue CAB were able to tolerate bromocriptine therapy. A computed tomographic scan performed after 12 months of therapy in 7 patients showed a significant reduction (50%) of the adenoma in 5. In conclusion, our results show that CAB is a well tolerated new dopamine agonist with long-lasting activity that represents an advance in chronic medical treatment of hyperprolactinemic conditions.

Reduction in the size of prolactin-producing pituitary tumor after Cabergoline administration

Different weekly doses (400 to 3,000 micrograms) of the new, long-acting dopamine agonist Cabergoline (Farmitalia Carlo Erba, Milan, Italy) were given to 11 hyperprolactinemic women with pituitary tumor. Pituitary computerized tomography (CT) scans were performed before the start of treatment and after 3 (n = 5), 6 (n = 3), and 9 (n = 3) months of Cabergoline administration. Plasma prolactin (PRL) was determined in blood samples collected before and at weekly intervals during Cabergoline administration. Cabergoline induced marked inhibition of PRL secretion in conjunction with a CT demonstration of reduction in the pituitary tumor size in all patients. The potent, long-lasting PRL inhibitory effect of Cabergoline and the absence of side effects typical of dopaminergic compounds suggest that the use of this drug is advantageous over others in the medical treatment of hyperprolactinemia.

Pathogenesis of Arterial Lesions Induced by Dopaminergic Compounds in the Rat

Fenoldopam mesylate (FM), a selective post-junctional dopaminergic (DA1) vasodilator, causes lesions of large caliber splanchnic arteries (100-800 microns) in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat, or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (less than 100 microns) of the splanchnic, cerebral, coronary and renal vascular beds. Dopamine is an alpha- and beta-adrenoceptor and a dopaminergic receptor agonist. Because these arterial lesions are thought to result from the pharmacologic activity of these 2 compounds, we sought to ascertain the presence of DA1 receptors in mesenteric arteries of the rat and to determine the role of these or other vascular receptor subtypes in lesion induction. We also studied the process of repair after arterial injury caused by FM or dopamine. The presence of DA1 receptors was confirmed in isolated perfused mesenteric arteries by standard pharmacologic techniques; stimulation by FM resulted in vasodilation which was inhibited by the DA1 receptor antagonist SK&F 83566-C. Likewise, SK&F 83566-C prevented the induction of hemorrhagic lesions of large caliber arteries in rats upon infusion of FM or dopamine. In rats co-exposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions of large caliber arteries were increased, but PBZ prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and FM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA1 receptors. Fibrinoid lesions of small arteries (alpha-adrenoceptor-mediated) were repaired, as observed morphologically by 14 d after exposure to dopamine. Hemorrhagic lesions of large caliber arteries (DA1 receptor-mediated) had undergone significant repair by 28 d after exposure to FM but these arteries possessed a thicker media surrounded by adventitial fibrosis. Thus, morphologically distinct receptor-mediated splanchnic arterial lesions induced by dopaminergic and alpha-adrenoceptor agonists follow a markedly different course of repair. Arterial lesions induced by FM or dopamine by activation of post-junctional dopaminergic DA1 receptors may represent a model of polyarteritis nodosa.

Alterations in hypothalamic serotonergic-catecholaminergic relationships in aging C57BL/6J female mice

The effects of aging and estradiol on the three major hypothalamic monoaminergic systems were measured in female C57BL/6J mice. Both aging and estradiol treatment induced small (10–15%) changes in the levels and ratios of the monoamines and their catabolites. In addition, the levels of 5-hydroxyindoleacetic acid, the major serotonergic catabolite, were strongly correlated with the levels of the two major dopaminergic catabolites, 3,4-dihydrophenylacetic acid and homovanillic acid. Aging affected the relattionship between 5-hydroxyindoleacetic acid and the dopaminergic catabolites such that the slope of the regression lines of 5-hydroxyindoleacetic acid on the dopaminergic compounds was increased in order mice. The age-related alteration in the correlations between the serotonergic and dopaminergic compounds may be due to an effect of aging on the acid export system.

Acute effects of lithium on dopaminergic responses: iontophoretic studies in the rat visual cortex.

The interactions between lithium and cortical dopaminergic receptors were investigated using the iontophoretic technique to record and apply dopaminergic compounds, GABA, acetylcholine and LiCl on neurons in the primary visual cortex of the rat. The main responses to dopamine (DA) or to the D1 agonist (+/- )SKF38393 on spontaneously-active (SA) or visually-driven (VD) units was a prolonged decrease in firing and a reduction in the responsiveness to pulses of acetylcholine. The D1 antagonist SCH23390, applied iontophoretically or intravenously, blocked or attenuated the inhibitory responses to both DA and (+/- )SKF38393. The D2 agonist quinpirole (LY171555) either produced only slight excitations or had no effects on both VD and SA units. The concomitant application of lithium blocked the inhibitory responses to DA and to (+/- )SKF38393 but did not modify the responsiveness to LY171555. In addition, the DA- and (+/- )SKF38393-induced decreases in responsiveness to acetylcholine were also suppressed by lithium. These effects were on dopaminergic mechanisms, since the excitatory responses to acetylcholine alone as well as the inhibitions caused by GABA were unchanged by the application of lithium. These results imply that the modifications in sensitivity to dopaminergic agents induced by lithium are mediated by dopamine D1 receptors and are discussed in relation to adenylate-cyclase.

The feasibility of effective psychopharmacological treatments for alcoholism.

SummaryThe effects of lithium, anxiolytics, dopaminergic compounds, serotonin uptake inhibitors, opiates, opiate antagonists, and alcohol‐sensitizing drugs on the alcohol consumption of human alcoholics and laboratory animals are reviewed. There is increasing evidence that each of these classes of drugs might be beneficial in reducing alcohol abuse, including recent controlled studies on alcoholics with lithium, serotonin uptake Mockers, and disefulram. The usefulness of all of the current drugs, however, appears limited, and the ideal drug for use in treating alcoholism awaits discovery. Nevertheless, the fact that some drugs acting on the central nervous system are able to promote abstinence supports the feasibility of psychopharmacological treatment for alcoholism. Furthermore, since the known drugs that appear beneficial against human alcohol abuse also suppress voluntary alcohol selection by experimental animals, it seems likely that studies with animals could be used for screening other potentially effective drugs.

Dose-related prolactin inhibitory effect of the new long-acting dopamine receptor agonist cabergoline in normal cycling, puerperal, and hyperprolactinemic women.

Two different single doses (400 and 600 micrograms) of the new long-acting dopamine agonist cabergoline (CBG) were given to 12 normal cycling women, 17 puerperal women, and 24 hyperprolactinemic women (12 with idiopathic hyperprolactinemia and 12 with pituitary adenoma). Plasma PRL was determined in blood samples collected before and at frequent intervals for 5 days after CBG administration. Both CBG doses induced marked inhibition of PRL secretion in all women. A decrease in plasma PRL levels was evident 1-2 h after CBG administration and persisted for up to 5 days. The 600-micrograms CBG dose had a more potent (P less than 0.05) PRL inhibitory effect than the 400-micrograms dose in normal, puerperal, and hyperprolactinemic women. Moreover, while 400 micrograms CBG prevented lactation in 3 of 7 puerperal women, 600 micrograms CBG prevented lactation in 5 of 5 puerperal women. A moderate blood pressure decrease occurred 3-6 h after CBG treatment, but no other side-effects occurred. These results demonstrate that CBG induces a dose-related inhibition of PRL secretion in normal women as well as in puerperal and hyperprolactinemic women. The potent long-lasting PRL inhibitory effect of CBG in conjunction with the absence of side-effects typical of dopaminergic compounds suggest that this drug is an advance in the medical treatment of hyperprolactinemia.

Dopamine regulates expression of the glandular-type kallikrein gene at the transcriptional level in the pituitary.

A glandular-like kallikrein enzyme, a member of a well-characterized family of specific arginyl endopeptidases that may be involved in prohormone processing, has previously been shown to be present in the anterior and neurointermediate lobes of the rat pituitary. We isolated glandular-like kallikrein cDNAs from cDNA libraries prepared from these two tissues. By nucleotide sequence, restriction endonuclease, solution hybridization/nuclease protection, and blot analyses, we showed that, of the 8-10 rat kallikrein-encoding genes, it is the true glandular kallikrein mRNA that is expressed in both pituitary lobes. RNA blot-hybridization analysis of anterior and neurointermediate lobe pituitary RNA revealed a kallikrein mRNA of approximately equal to 900 base pairs. As analyzed by blot-hybridization and solution hybridization/nuclease protection analyses, the true glandular kallikrein mRNA was present at low levels: approximately equal to 0.05% of total mRNA in both male and female neurointermediate lobes. Similar low levels of the glandular kallikrein mRNA were found in the male anterior lobe, whereas the levels were 10- to 15-fold higher in the female anterior lobe. In vivo administration of a dopamine agonist (bromocryptine) or antagonist (haloperidol) caused a decrease or increase, respectively, in the amount of true glandular kallikrein mRNA in the neurointermediate lobe of both sexes that closely paralleled changes in proopiomelanocortin mRNA levels. Bromocryptine decreased and haloperidol increased true glandular kallikrein mRNA levels in the female anterior lobe but had no effect in the male anterior lobe. Nuclear transcription run-on studies showed that the changes in mRNA were due, at least in part, to parallel effects of haloperidol on kallikrein gene transcription. Thus, these studies have demonstrated that the pituitary expresses the glandular-type member of the kallikrein gene family and that dopaminergic compounds elicit changes in kallikrein mRNA, at least in part, by modulating transcription. In the intermediate lobe, regulation of true glandular kallikrein gene expression is parallel to that of proopiomelanocortin gene expression, suggesting that the enzyme may play a physiological role in the production and/or secretion of the proopiomelanocortin peptides in this tissue.