Too many treatments for Parkinson's disease: how should they be used?

Surgical ablation for Parkinson's disease was abandoned in the 1970s after successful clinical trials of L-DOPA and L-DOPA/decarboxylase inhibitor combinations and early dopamine receptor agonists were added to prolong a viable therapeutic window beyond 5 years. The development of newer agonists with variations in receptor subtype specificity and new enzyme inhibitors with combinations of central and peripheral effects have continued to attract attention as therapeutic alternatives. Treatment options are now coming full circle with a rebirth of stereotactic neurosurgical alternatives to a wide variety of pharmacologic paradigms. The authors propose a rationale for selecting differing treatment options within historical perspective and modern treatment goals using both medical and surgical alternatives.

Effect of cocaine metabolites on behavior: possible neuroendocrine mechanisms.

The predominant cocaine metabolites were tested for central nervous system effects by intracerebroventricular (ICV) administration in rats. We found two types of responses: cocaine, norcocaine (NC), benzoylecgonine (BE), and benzoylnorecgonine (Nor BE) produced stimulatory effects, whereas ecgonine methyl ester (EME) and ecgonine (EC) resulted in no specific effect or sedation. A novel metabolite interaction was revealed when rats were pretreated with EME, which inhibited both analgesia and seizures by subsequently administered cocaine. Pretreatment with EC inhibited both cocaine and BE seizures and seizure-associated death. Direct injection of EME into the nucleus accumbens significantly suppressed systemic cocaine potentiation of intracranial electrical self-stimulation of the ventral tegmental area, whereas corticotropin releasing hormone injected ICV selectively potentiated BE-induced seizures and death. These results confirm multiple, metabolite-mediated activities in the central nervous system. Pharmacological interactions of the metabolites with each other and/or with neurohormones may help explain some of the pathophysiological effects seen in human chronic cocaine abuse.

Cocaine analgesia: an in vivo structure-activity study.

Hot plate testing of rats was performed to determine the optimal analgesic doses of intracerebroventricularly (ICV) administered cocaine, significant cocaine metabolites, and selected structurally similar molecules. Optimal, (subseizure) analgesic doses for cocaine and selected cocaine analogues were (in microM): cocaine, 0.37; cocaethylene, 0.09; benzoylecgonine, 0.35; norcocaine, 0.43; and ecgonine, 2.1. Ecgonine methyl ester was not analgesic at < or = 3.7 microM. These results, in conjunction with findings on other structurally similar molecules suggest that, of the molecules tested, (a) a hydrophobic group at the C-3 attached carbon is critical for analgesia; (b) a hydrophobic C-2 ester group can enhance analgesic activity (e.g., cocaethylene); (c) the N-methyl position is minimally important for analgesia; and (d) isomeric configurational changes can influence analgesia.

Selective impairment of neuroendocrine and hemodynamic responses to a mu-opioid peptide in aged rats.

The objective of this study was to determine if there are age-related alterations in hemodynamic and/or neuroendocrine responses to the mu-opioid receptor agonist, [D-Ala2,MePhe4,Gly(ol)5] enkephalin (DAMGO), or corticotropin releasing hormone (CRH) administered centrally. To this end, DAMGO (1-3 nmoles) or CRH (1 nmole) was injected intracerebroventricularly (icv) to freely moving young (6-8 month) and aged (24-26 month) Fischer 344 male rats. Blood pressure, heart rate (HR), and plasma concentrations of norepinephrine (NE), epinephrine (EPI), adrenocorticotropin (ACTH), and prolactin (PRL) were measured over time. Under basal conditions, NE levels were higher and blood pressures were lower in aged rats, whereas there were no significant differences in EPI, ACTH, or PRL levels. The stimulatory effect of DAMGO on blood pressure, HR, and plasma EPI and ACTH was attenuated, but the PRL response was enhanced in aged cohorts. In contrast, there were no age-related differences in the NE responses to DAMGO or CRH nor in CRH-induced increases in EPI or ACTH. The sympathoadrenal and hemodynamic effects of DAMGO were blocked by naloxone in both age groups. These results indicate that alterations in mu-opioid function with age are specific for the opioid system and do not reflect a generalized decline in central regulation of neuroendocrine and cardiovascular function.

Myoclonus in adult Huntington's disease.

Two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after the first signs of the disease. Their electroencephalograms were consistent with a primary generalized epilepsy, although neither man had seizures. The myoclonus was controlled with valproic acid therapy.

Role of the central nervous system in hemodynamic and sympathoadrenal responses to cocaine in rats.

These studies were undertaken to examine the contribution of central nervous system mechanisms to the cardiovascular and sympathoadrenal effects of cocaine. Changes in systolic and diastolic blood pressure, heart rate and plasma catecholamine concentrations were determined in response to cocaine injected i.a. or i.c.v. in conscious unrestrained rats. Systemically administered cocaine produced brisk, transient dose-related increases in systolic and diastolic pressure at doses of 0.05 to 5 mg/kg i.a. Plasma catecholamine concentrations increased in a dose-related manner, reaching peak levels at 5 to 10 min after i.a. cocaine injection. Only the higher doses of cocaine induced reflex vagal bradycardia that was blocked by atropine (0.4 mg/kg i.a.). Propranolol (1 mg/kg i.a.) prolonged the duration of cocaine-induced hypertension and bradycardia. Ganglionic blockade with chlorisondamine (7.5 mg/kg i.a.) antagonized completely the cardiovascular and sympathoadrenal effects of cocaine, indicating that intact ganglionic transmission is required for full expression of the autonomic responses. Antagonist drugs selective for the D-1 or D-2 dopamine receptors attenuated effects of cocaine on plasma catecholamine concentrations but not on cardiovascular parameters. Intracerebroventricular injection of cocaine (50-250 micrograms) increased systolic pressure and plasma catecholamine concentrations, providing direct evidence for an action of cocaine in the central nervous system. These results demonstrate that cocaine acts centrally to increase sympathetic outflow leading to hypertension and reflex bradycardia in conscious rats.

Effects of propylthiouracil on growth hormone and prolactin messenger ribonucleic acids in the rat pituitary.

The effects of hypothyroidism induced by propylthiouracil (PTU) treatment on growth hormone (GH) and prolactin (PRL) messenger ribonucleic acid (mRNA) levels were analyzed in adult female rat adenohypophyses by in situ hybridization histochemistry and Northern hybridization analyses. Twenty-eight days of PTU treatment produced a significant decrease in GH mRNA levels and a smaller decrease in PRL mRNA determined by both in situ hybridization histochemistry and Northern hybridization analyses. A combined procedure of in situ hybridization histochemistry followed by immunochemistry on the same sections revealed mammosomatotropic cells expressing GH mRNA and PRL protein in the same pituitary cells from all treatment groups. Cells expressing GH mRNA and thyroid-stimulating hormone protein were not detected by this method. Immunochemical staining revealed a decrease in GH cells and an increase in thyroid-stimulating hormone cells in hypothyroid rats. Cells expressing both GH and thyroid-stimulating hormone protein were not detected by immunostaining. These results indicate that hypothyroidism produces significant decreases in GH mRNA and also decreases PRL mRNA and that mammosomatotropic cells can be detected in pituitaries from normal and hypothyroid rats.

Maternal modulation of growth hormone secretion in the neonatal rat. I. Involvement of milk factors.

The present experiments investigated the time course of maternal modulation of GH secretion and examined the possible role of milk in the regulation of GH secretion in neonatal rats. Serum GH concentrations in neonatal rats were high at birth and declined over time postpartum. Separation of rat pups from their mothers decreased, while a subsequent period of suckling increased, serum GH levels in rat pups on postpartum days 1-14, but not on day 20. The water-soluble fraction (infranatant) of rat milk contained immunoreactive (ir) rat GH-releasing hormone (rGHRH)-like material (725.06 +/- 81.29 pg/ml), ir-somatostatin-like activity (1.64 +/- 0.2 ng/ml), and irGH (4.79 +/- 0.73 ng/ml). The concentrations of these hormones tended to decrease with time postpartum and were positively correlated with each other (r = 0.70; P less than or equal to 0.0001). IrPRL was also present in the infranatant (148.44 +/- 14.55 ng/ml), but levels were not correlated with the other hormones detected. Milk infranatant stimulated GH secretion from perifused neonatal rat pituitary glands in vitro. Milk infranatant also stimulated GH secretion in vivo when administered sc or intragastrically to 2- or 8-day-old rat pups. The GH-releasing effect was not due to gastric distension or nonspecific nutritive components, as neither 0.9% saline nor nutrients (5% glucose and 10% BSA) increased serum GH levels. The presence of high concentrations of irGHRH in rat milk infranatant and the strong correlation between the irGHRH concentrations of milk samples and the in vitro GH response (r = 0.71; P less than or equal to 0.005) suggested that this peptide is a major candidate for producing the in vitro and in vivo GH-stimulating activity in rat milk. However, the minimally effective concentration of synthetic rGHRH required to stimulate GH release in the superfusion system was between 1-10 nM, which exceeds milk irGHRH levels by 100- to 1000-fold. Moreover, in vivo administration of synthetic rGHRH (sc or intragastrically) was unable to increase serum GH concentrations in 2-day-old pups, although a large dose (100 ng/g) of human GHRH sc was effective. These findings indicate that rat milk may be an important maternal factor that modulates GH secretion and, consequently, growth during the neonatal period. Rat milk has GH-releasing activity both in vivo and in vitro in neonatal rats, but the GH-releasing activities of milk are probably only minimally due to its rGHRH content.

Dopamine D-1 and D-2 receptor antagonists potentiate analgesic and motor effects of morphine.

To examine the role of dopamine receptor subtypes mediating analgesic and motor responses to opioids, rats were pretreated with either saline or a selective D-1 or D-2 dopamine receptor antagonist 10 min prior to morphine (12 mg/kg IP). Analgesic response latency was determined using the hot plate test (52.5 degrees C and 55 degrees C), and catalepsy was assessed using the abnormal posture test. Morphine increased analgesic response latency to 44.5 +/- 7.9% of the maximum possible response, but had no cataleptic effect in the abnormal posture test. Pretreatment with either the D-1 antagonist, SCH 23390 (50-100 micrograms/kg), or the D-2 antagonist, eticlopride (20-150 micrograms/kg), potently enhanced morphine analgesia as measured on the 52.5 degrees C hot plate. Peak analgesic responses to morphine increased to 100 +/- 0% and 91.9 +/- 7.5% of maximum with the highest doses of SCH 23390 and eticlopride, respectively. These treatments also produced catalepsy. Increasing the hot plate temperature to 55 degrees C reduced response latency in groups treated with either dopamine receptor antagonist plus morphine. This indicates that the animals were capable of responding at a shorter latency and demonstrates that motor impairment cannot account for potentiation of morphine analgesia by D-1 and D-2 antagonists at 52.5 degrees C. These results show that the relationship between dopamine and opioids with respect to analgesic and motor systems involves both dopamine receptor subtypes.

Cocaine: evidence for supraspinal, dopamine-mediated, non-opiate analgesia.

Cocaine (25 mg/kg i.p.) produces analgesia in the rat within 5 min and for a duration of 90 min as determined by the formalin test or for 30 min as determined by the hot plate test. Cocaine analgesia is unaffected by doses of naloxone that are sufficient to attenuate morphine analgesia in both tests. Chlorpromazine (3 mg/kg i.p.), SCH 23390 (100 micrograms/kg i.p.; a D1 dopamine receptor antagonist), and eticlopride (75 micrograms/kg i.p.; a D2 dopamine receptor antagonist) each attenuate cocaine analgesia in both tests at doses that alone do not affect performance in either test. Measurements of blood pressure and heart rate indicate that cocaine analgesia is not due to the activation of baroreceptor reflex afferents. We conclude that cocaine is a supraspinally acting, dopamine-mediated, non-opiate analgesic in the rat.

Differential effects of chronic partial myelotomies on monoamine levels in cat spinal cord.

The concentrations of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) were measured in samples of lumbar and cervical spinal cords from 6 cats with chronic (over 2 months) lesions of the thoracic spinal cord and from 7 unoperated cats. Lesions confined to the dorsal thoracic spinal cord significantly lowered lumbar concentrations of NE, but not 5-HT, compared with control lumbar or matched paired cervical samples. Both NE and 5-HT were significantly reduced by dorsal or ventral lesions that involved tissue ventral to the central canal. Only the largest lesion could be shown to reduce lumbar DA concentration.

Regulation of thyrotropin secretion by the central epinephrine system. Studies in the chronically cannulated rat.

In the present investigation CNS epinephrine (EPI) biosynthesis was selectively interrupted with specific norepinephrine N-methyltransferase (NMT) inhibitors, SK&F 64139 (Smith, Kline & French Laboratories) and LY 78335 (Eli Lilly & Co. Research Laboratories), to determine the effects of central EPI depletion on basal and cold, thyrotropin-releasing hormone, and hypothalamic somatostatin antiserum induced thyrotropin (TSH) secretion in chronically cannulated rats. Because these NMT inhibitors also are alpha 2-adrenergic receptor blockers, the effects of alpha 2- and alpha 1-adrenergic blockade and alpha 2-activation on plasma TSH were assessed with rauwolscine and corynanthine and B-HT 933, respectively. Serum T4 and plasma corticosterone were also measured. Blockade of CNS EPI synthesis resulted in inhibition of basal and cold and thyrotropin-releasing hormone induced TSH release, suppression of serum T4, and increased corticosterone release. The stimulatory effect of SRIF antiserum on plasma TSH was not altered by SK&F 64139. alpha 2-adrenergic blockade suppressed plasma TSH levels, but not to the same degree as the NMT inhibitors; activation of alpha 2-receptors enhanced TSH secretion. Thus, it is possible that part of the effect of the NMT inhibitors on TSH was due to alpha 2-blockade. alpha 1-adrenergic blockade also lowered plasma TSH. These results indicate that central EPI systems have a stimulatory role in TSH regulation, possibly mediated by alpha 2-adrenergic receptors, cold-induced TSH release is mediated, in part, by EPI, and central EPI systems exert an inhibitory effect on the hypothalamic-pituitary-adrenal axis.

Regulation of growth hormone and thyrotropin secretion by somatostatin systems in rat brain.

Somatostatin inhibits growth hormone (GH) and thyrotropin (TSH) secretion in the rat. Previous studies have shown that small discrete lesions of the periventricular hypothalamic (PV) and medial-basal amygdaloid (AMG) nuclei, which contain high concentrations of somatostatin neurons, reduce somatostatin-like immunoreactivity (SLI) in the median eminence (ME) by approximately two thirds and one third, respectively. The present study assessed the function of the PV and AMG somatostatin systems in the regulation of basal episodic GH and TSH secretion. Three experiments were performed in freely behaving, chronically cannulated adult male rats. In experiment 1, bilateral electrolytic lesions (20 mC) were placed in the PV at the level of the paraventricular nucleus. In experiment 2, bilateral thermal lesions (55 degrees C X 1 min) were placed in the AMG. In experiment 3, thermal lesions were placed in both the PV and AMG (PV/AMG). Blood samples were removed from animals every 15 min for 5.5 h 14-21 days postoperatively. The ME was microdissected for determination of SLI content. PV, AMG and PV/AMG lesions reduced ME SLI by 59, 26, and 91%, respectively. PV or AMG lesions had no effect on the amplitude or frequency of GH secretory peaks, GH trough levels or the total amount of GH secreted, whereas combined PV/AMG lesions reduced GH peak levels. Lesions of the AMG caused a 34% increase in mean plasma TSH levels, while PV or PV/AMG lesions reduced TSH. The latter effect was probably caused by damage to thyrotropin-releasing hormone neurons and/or axons, which are also located in the PV region. These results suggest that PV and AMG somatostatin systems may not have a significant role in the regulation of basal episodic GH secretion and the putative AMG somatostatin system exerts a significant inhibitory influence on TSH secretion.

Cysteamine effects on monoamines, dopamine-beta-hydroxylase and the hypothalamic-pituitary axis.

Cysteamine (beta-mercaptoethylamine, MEA) is a naturally occurring sulfhydryl compound that depletes pituitary PRL, causes a reduction in brain and gut somatostatin (SRIF), and suppresses norepinephrine (NE) and epinephrine (EPI) synthesis by inhibition of dopamine-beta-hydroxylase (DBH). SRIF inhibits GH and TSH secretion, whereas, NE and EPI facilitate their release. The objectives of this investigation were to: (1) determine the dose-response and time course of DBH inhibition by MEA in vivo and in vitro, and correlate these findings with MEA tissue levels and (2) assess the function of SRIF and NE/EPI in regulation of episodic GH and TSH secretion using MEA. Animals were administered MEA (75-300 mg/kg, s.c.) and hypothalamic levels of dopamine (DA), NE, EPI, serotonin (5-HT) and MEA were measured by high-performance liquid chromatography (HPLC) and electrochemical detection. DBH activity was measured in vitro after exposure to MEA +/- N-ethylmaleimide (NEMI). Chronically cannulated rats were administered MEA (100 or 300 mg/Kg) and serial blood samples were removed in undisturbed animals, and after 30 min swimming stress. Cannulated rats with bilateral lesions of the ventromedial/arcuate nuclei (VMN/ARC) were administered MEA (150 mg/kg). MEA caused a dose-related decrease in NE/EPI nd in increase in DA at doses greater than or equal to 150 mg/kg. Tissue MEA was highest at 4 h (679 +/- 64 pM/mg tissue), but still measureable after 24 h. MEA inhibited DBH in vitro (95% inhibition at 10(-3) M); NEMI blocked inhibition. Stress-induced GH supression and corticosterone release were partially blocked by a low dose of MEA (100 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic monoaminergic activity and pituitary function in male rats with estrogen-induced pituitary hyperplasia.

The mechanism by which estrogen enhances prolactin (PRL) secretion and induces hyperplasia of lactotrophs is not defined clearly. The objective of this study was to examine hypothalamic monoaminergic PRL regulatory systems and pituitary hormone secretion in the early and later stages of estrogen-induced hyperprolactinemia and pituitary hyperplasia. Dopamine (DA) and serotonin (5-HT) turnover were determined in microdissected brain regions 3 and 30 days after a single subcutaneous dose of estradiol (2 mg) to male ACI rats. Plasma samples were collected in animals with indwelling intra-atrial cannulae. 3 days after estrogen there was a significant increase in plasma PRL, pituitary PRL and growth hormone (GH), and DA turnover in the median eminence and arcuate nucleus. Plasma concentrations and pituitary content of PRL increased at 30 days. The responsiveness of PRL to thyrotropin-releasing hormone (TRH) was enhanced at both times. Concentrations of DA decreased considerably in the median eminence and arcuate nucleus by 30 days, and turnover decreased in the median eminence. 5-HT turnover was not affected in the early stages of hyperprolactinemia. Plasma GH increased and TSH was unchanged, even though pituitary content of both hormones decreased at 30 days. Estrogen had no effect on plasma corticosterone. These findings support the hypothesis that estrogen induces pituitary hyperplasia by antagonizing DA inhibition of PRL-secreting cells and by enhancing their responsiveness to TRH.

Somatostatin metabolism: differences in clearance of N-terminal and central portions of molecule during perfusion of rat liver.

Clearance of cyclic somatostatin (SRIF) from a plasma-free recirculating medium containing human erythrocytes and a bovine albumin fraction was measured with site-specific N-terminal (sheep B) and central core-directed (R101) radioimmunoassays during perfusion of the isolated rat liver (3-4 g). With the N-terminal radioimmunoassay (RIA), the t 1/2, hepatic clearance, and extraction of somatostatinlike immunoreactivity (SLI) were 20.9 +/- 2.0 (SE) min, 2.82 +/- 0.27 ml/min, and 35.2 +/- 3.4%. Corresponding values for the centrally directed assay were 51.0 +/- 6.3 min, 1.16 +/- 0.14 ml/min, and 14.4 +/- 1.8%. Clearances of immunoprecipitable 125I-Tyr-SRIF and [125I-Tyr11]SRIF were 6.56 and 1.06 ml/min, respectively, and were not saturable by 1 microM Tyr-SRIF and SRIF, respectively. SRIF (1.26 +/- 0.09 nM) and SRIF-28 (1.34 +/- 0.14 nM) clearances determined by R101 RIA were similar. After SRIF-28 perfusion, high-performance liquid chromatographic analysis of SLI showed 86% to be retained with the SRIF-28 peak and 14% with the SRIF peak, suggesting no major conversion of SRIF-28 to SRIF. Des-(Ala1,Gly2)-N3-Ac-SRIF and dihydrosomatostatin were cleared more rapidly than SRIF. Clearance of SLI by the perfusate without the liver was 12-43% of liver clearance, depending on the peptide examined. These results support the hypothesis that aminopeptidase and endopeptidase activities are involved in SRIF clearance by the intact liver. The activities appear to function independently. The intrachain disulfide bond of SRIF may confer relative stability during its hepatic metabolism.

Role of central epinephrine in regulation of anterior pituitary hormone secretion.

Hypothalamic regulation of anterior pituitary hormones is thought to be mediated by the release of stimulatory and/or inhibitory peptides that are, in turn, regulated by catecholaminergic neurons. The recent development of selective epinephrine (EPI) synthesis inhibitors has made it possible to disrupt central EPI neurotransmission without affecting norepinephrine or dopamine. These compounds were used in the present investigation to assess the involvement of brain EPI systems in regulation of GH, LH, and prolactin (PRL) in male and ovariectomized female rats. Inhibition of central EPI synthesis (1) inhibited episodic and morphine-, but not clonidine-induced GH release, and (2) blocked the LH surge induced by estrogen and progesterone, but did not affect episodic LH release in hormonally untreated rats. Inhibition of peripheral (adrenal) EPI synthesis had no effect on these hormones. Results of these studies suggest an excitatory role for EPI in regulation of GH and LH secretion, mediated by stimulation of GH-releasing hormone and LHRH, respectively. EPI does not appear to have a major function in regulation of PRL secretion.

Regulation of episodic growth hormone secretion by the central epinephrine system. Studies in the chronically cannulated rat.

Catecholamines are postulated to regulate growth hormone (GH) secretion by their influence on the release of two hypothalamic substances, somatostatin, which inhibits GH release, and GH-releasing factor, as yet unidentified. Extensive pharmacologic studies in man and animals indicate a stimulatory effect of central norepinephrine and dopamine on GH, but the function of epiphephrine (EPI) is uncertain. Furthermore, many of the agents used to study the role of catecholamines in GH regulation are not selective in that they affect adrenergic as well as nor-adrenergic and/or dopaminergic neurotransmission. In the present investigation, central nervous system (CNS) EPI biosynthesis was selectively interrupted with the specific norepinephrine N-methyltransferase inhibitors, SK & F 64139 (Smith, Kline & French Laboratories) and LY 78335, (Eli Lilly & Co. Research Laboratories) and the effects of central EPI depletion on episodic GH secretion in the chronically cannulated rat model were determined. Inhibition of CNS EPI synthesis with SK & F 64139 caused complete suppression of episodic GH secretion and concomitantly reduced the EPI level in the hypothalamus without affecting dopamine or norepinephrine. Administration of LY 78335 produced similar effects on pulsatile GH. Morphine-induced, but not clonidine-induced, GH release also was blocked by SK & F 64139. These results indicate that (a) the central EPI system has a major stimulatory function in episodic GH release, (b) morphine-induced GH release is mediated by the central EPI system, and (c) clonidine stimulates GH release by activation of postsynaptic alpha-adrenergic receptors. Drugs that affect CNS adrenergic systems have a potential role in the diagnosis and treatment of disorders of GH secretion.

The effects of lateral hypothalamic-medial forebrain stimulation and somatostatin antiserum on pulsatile growth hormone secretion in freely behaving rats: evidence for a dual regulatory mechanism.

The purpose of this investigation was to examine the role of somatostatin (SRIF) and electrical stimulation of the lateral hypothalamic-medial forebrain bundle (LH-MFB) on dynamics of pulsatile GH secretion in freely behaving, chronically cannulated male rats with implanted brain electrodes. The effects of administration of anti-SRIF serum (AS-SRIF) on pulsatile GH and on TSH and PRL secretion was also studied. The results are: 1) circulating AS-SRIF increases trough levels of GH in freely behaving rats but has no significant effect on the amplitude of GH secretory bursts or mean GH levels; 2) LH-MFB excitation can stimulate GH release if delivered when circulating GH levels are low; 3) LH-MFB stimulation inhibits secretion of GH if given at the time of a spontaneous GH burst; 4) stimulation-induced GH inhibition is prevented by pretreatment with AS-SRIF, suggesting that this response is mediated by endogenous SRIF; and 5) AS-SRIF increases TSH secretion but has no effect on PRL. These results provide evidence to support the hypothesis that pituitary GH secretion is regulated by a combination of excitatory and inhibitory influences, the inhibitory component of which is mediated by SRIF.