Biomedical subjects

W Vale

Publications and source records attributed to W Vale.

At least 127 records · Page 7Linked to original sources

PubMed1991

Effect of recombinant human inhibin on gonadotropin secretion by the male rat.

We have examined the effect of recombinant human inhibin-A on basal and GnRH-induced gonadotropin secretion by male rats or cultured anterior pituitary cells. Inhibin, administered sc 6 h before the experiment, induced dose- and time-related decreases in plasma FSH, but not LH, levels in both intact and castrated male rats. Inhibin also significantly interfered with the in vivo stimulatory effect of 20-500 ng GnRH on FSH release, but had inconsistent and usually modest effects on the LH response. While exposure of cultured pituitary cells to inhibin for 72 h has been reported to interfere with GnRH-induced gonadotropin release, we examined here the effects of shorter exposure periods relevant to in vivo experiments. Exposure of the cells to inhibin (31.3-312.5 pM) for 2-6 h measurably (P less than or equal to 0.01) decreased the ability of 10 nM GnRH to stimulate both FSH and LH released by cultured cells. In contrast, lower (3.1 and 9.4 pM) doses of inhibin had little or no effect. Longer exposures to inhibin (10, 24, and 72 h) increased the inhibitory effect of 31.3-312.5 pM inhibin, while 3.1 and 9.4 pM remained ineffective at all times. These results indicate that exposure of the male rat to inhibin for 6 h decreases FSH secretion, and that this effect is at least partially mediated through blunting of the pituitary response to GnRH. In contrast, the ability of inhibin to interfere with LH release, which is readily apparent in cultured pituitary cells, appears to be of lesser importance in the intact male rat.

Animals↗

PubMed1991

Effect of recombinant inhibin on follicle-stimulating hormone secretion by the female rat: interaction with a gonadotropin-releasing hormone antagonist and estrogen.

There is considerable support for the hypothesis that one component of FSH secretion is independent of GnRH. The ability of follicular fluid preparations containing inhibin to suppress FSH release in the absence of GnRH drive has suggested that this component might be responsive to gonadal proteins. However, follicular fluid contains several proteins that either stimulate or inhibit FSH secretion, thus complicating interpretation of the results. The recent availability of recombinant human (rh) inhibin-A has allowed us to specifically investigate the effect of this protein on FSH secretion by rats whose GnRH release and/or effect was blocked by a specific antagonist, [Ac-D2Nal1,DCpa2, D3Pa13,Arg5, D5-(p-methoxyphenyl) 5-oxo-2-aminopentanoic acid16, DAla10]GnRH, or by estradiol (E2). In a first experiment, the GnRH antagonist (100 micrograms/kg, injected sc 21 h earlier) lowered plasma immunoactive FSH levels by 36%, and rh-inhibin-A (25 micrograms/kg, injected iv 6 h earlier) lowered them by 44%. The combination of both treatments decreased FSH values by 82% (P less than or equal to 0.01 vs. either compound alone). Inhibin and the antagonist also significantly (P less than or equal to 0.01) decreased FSH bioactivity. A second experiment investigated the independent or combined effects of inhibin and E2. E2 (40 micrograms/kg, injected sc at -36 and -12 h) lowered FSH levels by 53%, and inhibin (25 micrograms/kg, injected iv at -6 h) decreased FSH concentrations by 37%. Administration of both compounds produced a 63% inhibition (P less than or equal to 0.05 vs. inhibin alone; P less than or 0.01 vs. E2 alone). Finally, we studied the interaction among the GnRH antagonist, inhibin, and E2. In this protocol plasma FSH levels in rats injected with inhibin and the antagonist did not show an additional decrease after treatment with E2. These results indicate that plasma FSH levels in rats whose GnRH receptors or secretion are blocked can be further lowered by inhibin. Thus, the ability of rh-inhibin-A to interfere with FSH secretion in the ovariectomized rat appears to involve a mechanism independent of the GnRH drive.

Animals↗

PubMed1991

Transforming growth factor-beta: role in mediating serum-induced endothelin production by vascular endothelial cells.

Studies were performed to characterize the identity of the factors present in calf serum that stimulate endothelin (ET) production by vascular endothelial cells in culture. Two putative candidates responsible for the ET-releasing activity present in serum are members of the transforming growth factor-beta (TGF beta) superfamily, TGF beta 1 and activin A. TGF beta 1 antiserum was used to block the actions of TGF beta 1, and follistatin was used to block the actions of activin. Treatment of serum with TGF beta 1 antiserum attenuates ET production by vascular endothelial cells. TGF beta 1 antiserum (1 microliters) completely prevents the release of ET produced by 0.1% and 0.3% serum. Follistatin is a potent inhibitor of activin-induced ET release but does not alter serum-induced ET production. Because serum-induced ET release is dependent on TGF beta, it may be a physiological regulator of ET production by vascular endothelial cells.

Activins↗

PubMed1991

Effect of recombinant activin-A on gonadotropin secretion in the female rat.

Repeated injections of recombinant human (rh) activin-A over a 2- to 3-day period are reportedly needed to stimulate the in vivo secretion of FSH. In this paper we present results showing that acute treatment with rh-activin-A caused marked and dose-dependent increases in plasma FSH, but not LH, levels in adult female rats. After one injection, maximum FSH release was observed 4 h after the administration of activin, while two injections of 100 micrograms activin/kg, 5 h apart, maintained elevated FSH levels for more than 10 h in intact diestrous day 1 females. Removal of the GnRH drive by pretreatment of ovariectomized animals with the GnRH antagonist ([Ac-D2Nal1,DCpa2,D3Pal3,Arg5,D-p-methoxyphenyl) 5- oxo-2-amino-pentanoic acid6, DAla10]GnRH; 100 micrograms/kg;) or repeated injections of the GnRH agonist ([DTrp6,Pro9,NEt,NH2]GnRH; 1 microgram/h for 5 days) did not prevent the stimulatory action of activin. Concomitant treatment with rh-inhibin-A (30 micrograms/kg], on the other hand, completely blocked FSH secretion induced by 100 micrograms activin/kg. These results indicate that activin-A is a powerful stimulus for FSH secretion in the female rat and exerts this effect independently of GnRH.

Activins↗

PubMed1991

Follicular arrest during the midfollicular phase of the menstrual cycle: a gonadotropin-releasing hormone antagonist imposed follicular-follicular transition.

The functional dependency of the dominant follicle on pulsatile gonadotropin inputs was evaluated by using a GnRH antagonist as a probe. Hormonal dynamics, particularly the relationship of FSH, estradiol, and inhibin, during and after the withdrawal of GnRH receptor blockade achieved by treatment with Nal-Glu GnRH antagonist (50 micrograms/kg, im) for 3 days in the midfollicular phase of the cycle (days 7-9) were ascertained. Daily blood samples were obtained for LH, FSH, estradiol (E2), progesterone, and immunoreactive inhibin (i-INH) measurements by RIA during 2 consecutive (control and treatment) cycles in 12 women. In 5 women, LH pulsatility was assessed by 10-min blood sampling for 12 h before, during, and after Nal-Glu treatment. The administration of Nal-Glu prolonged both follicular phase (14.0 +/- 0.5 vs. 19.7 +/- 0.8 days; P less than 0.0001) and total cycle length (28.1 +/- 0.5 vs. 34.1 +/- 1.2 days; P less than 0.0001). Gonadotropin suppression (50-60%) was achieved, as reflected by a marked decrease in mean LH levels (14.3 +/- 1.9 to 5.4 +/- 0.5; P less than 0.01) and LH pulse amplitude (5.5 +/- 0.7 to 2.4 +/- 0.3 IU/L; P less than 0.01) in response to Nal-Glu antagonist. The number of LH pulses was reduced (36%), but pulses remained discernible. Concentrations of FSH (10.8 +/- 1.4 to 5.9 +/- 0.4 IU/L; P less than 0.05), E2 (322.7 +/- 71.9 to 84.8 +/- 7.7 pmol/L; P less than 0.01) and i-INH (284.0 +/- 25.9 to 164.4 +/- 7.5 U/L; P less than 0.01) decreased concomitantly. Within 24-48 h of the last injection of Nal-Glu, all hormones had returned to pretreatment levels. This was followed by normal functional expression of follicular growth and maturation, as reflected by an increase in E2 and i-INH levels, timely ovulation, and normal luteal function. These findings indicate that an approximately 50% decline in gonadotropin support to the dominant follicle leads to functional arrest, but not demise, of the developing follicle(s) without triggering new folliculogenesis. The follicular apparatus retained its ability to reinitiate its original functionality once appropriate gonadotropin inputs were reinstated.

Adult↗

PubMed1991

Localization and secretion of inhibin/activin subunits in the human and subhuman primate fetal gonads.

Little is known about the ability of the fetal primate gonads to produce inhibin/activin. We investigated the presence of the alpha-, beta A-, and beta B-subunits of inhibin/activin in fetal human (16-23 weeks gestational age) and rhesus monkey (days 150-157 of gestation; term = 165 days) testes and ovaries by immunocytochemistry. The regulation of alpha-inhibin secretion by gonadotropins was studied in fetal testicular cultures. In the human fetal testis, alpha-subunit immunostaining was found in interstitial and intratubular cells, while beta A- and beta B-subunit immunostaining occurred in clusters of Leydig cells that were clearly demarcated from groups of Leydig cells that were immunonegative. In the late gestational monkey testis, the alpha-subunit was localized in tubular cells, and the beta B-subunit was present in the tubules and interstitium. Testicular cells from midgestation human testes secreted detectable immunoreactive alpha-inhibin in response to FSH and hCG stimulation; alpha-inhibin levels were significantly higher after hCG than FSH. In contrast, levels of alpha-inhibin secreted by rhesus monkey testicular cells were significantly increased by FSH, but not hCG. In the ovary, only weak beta B-subunit immunoreactivity was detected in granulosa cells of a few primary follicles from midgestational human fetal ovaries. In contrast, all three subunits were found in granulosa cells of numerous primary and secondary follicles in the late gestation rhesus monkey ovary. In light of recent evidence that inhibins/activins have actions on gonadal differentiation and growth modulation in vitro, as well as endocrine effects on the fetal pituitary, we propose that these proteins may have intragonadal and endocrine roles in human and subhuman intrauterine gonadal development.

Activins↗

PubMed1991

Activin-A inhibits proopiomelanocortin messenger RNA accumulation and adrenocorticotropin secretion of AtT20 cells.

The complexity of corticotropic cell regulation by multiple central and peripheral factors is well recognized. The present study provides evidence for the participation of an additional factor in the regulation of this cell type of the anterior pituitary. Using the clonal AtT20 cell line as a model for corticotropes, homodimeric activin-A was observed to suppress basal ACTH secretion and POMC mRNA accumulation by approximately 50%. These effects required prolonged treatment with activin-A and were concentration dependent; the half-maximum concentration was in the range of 30-50 pM. Consistently, AtT20 cells were found to express specific high affinity binding sites for [125I]activin-A. The simultaneous addition of inhibin-A along with increasing concentrations of activin-A did not alter the characteristics of the inhibition of ACTH secretion by activin-A alone. This is in contrast to observations with gonadotropes of the anterior pituitary as well as a number of other cell types in which inhibin-A can partially antagonize the biological actions of activin-A. The results may suggest the participation of a subclass of activin receptors that mediate effects on ACTH secretion and POMC mRNA accumulation. As previously shown, the incubation of AtT20 cells with a synthetic glucocorticoid, dexamethasone, attenuated basal ACTH secretion and POMC expression in a concentration-dependent manner. The inhibition of both of these parameters by activin-A, however, was independent of glucocorticoids, because the two agents were additive in their actions. In addition to effects on secretion and mRNA levels, treatment with activin-A also inhibited the rate of proliferation of AtT20 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Activin Receptors↗

PubMed1991

Intracellular responses to gonadotropin-releasing hormone in a clonal cell line of the gonadotrope lineage.

We recently derived a GnRH-responsive pituitary cell line of the gonadotrope lineage (alpha T3-1) by targeted oncogenesis in transgenic mice. Here, we report studies characterizing the GnRH receptors present in these cells and the intracellular responses to GnRH treatment. The receptors in alpha T3-1 cells show specificity for different GnRH analogs, with dissociation constants very similar to those found in normal rat and mouse pituitary. The concentration of receptors is within the range found in normal pituitary. The addition of GnRH or GnRH agonists increases phosphoinositide turnover and protein kinase-C translocation to membranes, and enhances activation of voltage-sensitive calcium channels. However, GnRH does not affect cAMP levels. Analysis of alpha-subunit mRNA levels demonstrated induction by GnRH and phorbol esters. Our results indicate that GnRH initiates a cascade of intracellular events that generate a set of second messengers, one or more of which is involved in the regulation of gene expression. The responses of alpha T3-1 cells to GnRH appear to have characteristics equivalent to those of primary pituitary gonadotropes, indicating the utility of this cell line as a model system for the study of GnRH responses.

Animals↗

PubMed1991

Antagonism of central growth hormone-releasing factor activity selectively attenuates dark-onset feeding in rats.

Exogenous growth hormone-releasing factor (GRF) has been shown to activate feeding by central mechanisms involving the suprachiasmatic nucleus/medial preoptic area (SCN/MPOA). Until now, however, the role played by endogenous GRF in the SCN/MPOA in naturally occurring eating has remained unknown. To investigate this, the effects of SCN/MPOA injections of GRF antiserum (AS-GRF) on feeding in rats were studied. In light of SCN involvement in the control of circadian rhythms, AS-GRF was tested during the light and dark phases of the photoperiod. Results indicated that AS-GRF significantly attenuated dark-onset feeding but had no effect on feeding during the mid-dark, mid-light, or light-onset periods. These results suggest that endogenous GRF does play a role in naturally occurring feeding and that it may be involved in the circadian organization of feeding.

Animals↗

PubMed1991

Differential regulation of corticotropin-releasing factor mRNA in rat brain regions by glucocorticoids and stress.

The regulation of corticotropin-releasing factor (CRF) mRNA expression in the rat brain by glucocorticoids and stress was examined by Northern blot analysis and in situ hybridization histochemistry. Rats either were exposed to a single electrical footshock session and killed 2, 4, 12, or 24 hr later (acute stress), or were subjected to the same regimen twice daily for 3 or 7 d and killed on the day following the last session (chronic stress). Rats placed in the experimental chamber but not administered shock comprised a "sham-handling" group. Chronic (7 d) intermittent footshock stress resulted in an 84 +/- 26% (P less than 0.05) increase in CRF mRNA levels in the whole hypothalamus as detected by Northern blot analysis and a 97 +/- 29% (P less than 0.05) increase in the paraventricular nucleus (PVN) as detected using in situ hybridization. No significant change in CRF mRNA levels was observed in the hypothalamus at any time up to 24 hr after a single exposure to footshock stress. A different pattern of results was obtained in other CRF-expressing cell groups. In Barrington's nucleus (a pontine micturition center), both acute and chronic stress produced significant increases in CRF mRNA, while in the olfactory bulb, both paradigms resulted in decreased levels. By Northern blot analysis, CRF mRNA in the olfactory bulb declined steadily, beginning at 4 hr after acute stress, and reached significance at 24 hr (69.2 +/- 1.9% of control, P less than 0.05). Levels from chronically (7 d) stressed animals declined to 54.1 +/- 5.1% of control value (P less than 0.05). Analysis of hybridization histochemical material revealed that both the number of positively hybridized cells and the number of silver grains per cell in the mitral and external plexiform layers of the bulb decreased following acute and chronic stress. However, CRF mRNA levels in the olfactory bulb were decreased to a comparable extent in the sham-handling group, suggesting that exposure to a novel environment can effect a decrease in CRF mRNA levels in the olfactory bulb. To provide comparisons with the effects of manipulation of glucocorticoid status, comparable analyses were carried out in separate groups of animals following adrenalectomy (ADX) with and without corticosteroid replacement. After ADX, CRF mRNA levels in the whole hypothalamus increased 60 +/- 5% (P less than 0.05) and were normalized following dexamethasone replacement. In contrast to the hypothalamus, no effects of steroid manipulation on CRF mRNA levels in the olfactory bulb, midbrain, cerebral cortex, or brain stem were detected.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenalectomy↗

PubMed1990

Endothelin releasing activity in calf serum and porcine follicular fluid.

Bovine calf serum (CS) and porcine follicular fluid (PFF) added to bovine aortic endothelial cells (BAEC) in culture stimulate endothelin (ET) release. Sorbent extraction of acidified calf serum and PFF using Bond Elut C18 yields a product with an activity 30% that of the starting material. Fractionation of Bond Elut C18 extracted CS or PFF using HPLC yields peaks of activity with retention times similar to those of TGF beta and activin A, respectively. TGF beta is 10-fold more potent than activin A to stimulate ET release from BAECs. The observation that TGF beta and activin A are dose-additive but not effect-additive to stimulate ET release is compatible with the conclusion that these two substances act through a similar mechanism. Thus, TGF beta and/or activin A-related peptides may contribute to the ET releasing activity observed in acidified Bond Elut C18 extracted CS and PFF. The identity of ET-releasing activity in native CS and PFF remains to be established.

Activins↗

PubMed1990

Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures.

We show that mammalian and Xenopus activins induce dorsal axial mesoderm and anterior structures in explants of Xenopus blastula cells that would otherwise form epidermis. The induced explants of animal cap cells can form notochord, muscle, neural tissue, and eyes all arranged in a rudimentary axial pattern. Activin A shares inductive properties and antigenic determinants with PIF, an inducing factor recently isolated from mouse macrophage culture supernatants. Genes encoding Xenopus activin beta A and beta B chains were cloned. Activin beta B transcripts are first detected in Xenopus blastula, whereas activin beta A transcripts do not appear until the late gastrula stage. Recombinant Xenopus activin beta B protein induces mesodermal and neural tissues similar to those induced by mammalian activin A and PIF. Furthermore, ectopic expression of Xenopus activin beta B produces a second body axis in embryos injected with synthetic mRNA. Our results suggest that early induction and axial patterning are accomplished by endogenous activin B, not activin A, in Xenopus.

Activins↗

PubMed1990

Prolonged exposure to alcohol: effect on CRF mRNA levels, and CRF- and stress-induced ACTH secretion in the rat.

We have conducted studies in intact adult male rats, designed to examine the effect of a 3- or 7-day exposure to alcohol (EtOH) on the pituitary's response to corticotropin-releasing hormone (CRF) or stress, and on CRF expression in the hypothalamus. In a first series of experiments, rats exposed to EtOH vapors for 7 days had mean blood alcohol levels (BAL) of 127 +/- 12 mg%. At the end of the 7-day period, basal plasma ACTH levels were 69 +/- 10 pg/ml in control rats and 121 +/- 23 pg/ml in EtOH animals (P less than or equal to 0.01). Resting corticosterone levels were 39 +/- 11 ng/ml in control animals, and 101 +/- 24 ng/ml in EtOH rats (P less than or equal to 0.01). In all experiments described here, there was no statistical difference (P greater than 0.05) between the body weights of controls (animals kept in chambers with normal atmosphere) and EtOH-exposed animals. In control animals, the injection of 0.3-10 micrograms ovine CRF per rat caused dose-related increases in plasma ACTH levels measured 10 min later. All doses of CRF also significantly (P less than or equal to 0.01) stimulated ACTH secretion by EtOH rats, but there was no clear dose-response curve. Though EtOH-treated animals responded to the lower dose of CRF (0.3 microgram) with larger increases in plasma ACTH levels than control rats, the only statistical difference (P less than or equal to 0.01) between control and EtOH rats was observed following administration of 10 micrograms CRF, which caused a blunted response in EtOH animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1990

Central administration of a CRF antagonist blocks the development of stress-induced behavioral sensitization.

This experiment examined the effects of intracerebroventricular (i.c.v.) administration of a corticotropin-releasing factor (CRF) antagonist on the development of stress-induced sensitization of the behavioral response to amphetamine. Restraint stress was found to enhance both the locomotor response to a s.c. injection of saline and the intensity of stereotypy induced by a s.c. injection of 3.0 mg/kg D-amphetamine. Both of these effects of restraint stress were severely attenuated in rats that had been injected with the CRF antagonist prior to restraint stress. This result is compatible with the hypothesis that CRF is critically involved in initiating behavioral and physiological responses to aversive stimuli.

Amphetamines↗

PubMed1990

Beta-lipotropin-beta-endorphin response to low-dose ovine corticotropin releasing factor in endogenous depression. Preliminary studies.

Studies in depression using a maximal stimulatory dose of corticotropin releasing factor have concluded that elevated resting cortisol levels in depressed patients exert a negative feedback effect on the corticotroph, resulting in a decreased corticotropin response. In this preliminary report, we examine the effects of a submaximal dose of corticotropin releasing factor on the release of another corticotroph secretory product, beta-lipotropin-beta-endorphin. We observed a decreased beta-lipotropin-beta-endorphin response in depressed subjects, but a normal adrenal cortisol response. Although the total beta-lipotropin-beta-endorphin response was decreased, the initial secretory response did not differ between patients and normal controls. Rather, the patients appeared to turn off secretion faster. This rapid shutoff was seen in all patients regardless of resting cortisol levels, suggesting that resting cortisol levels alone do not explain the decreased response seen in depressed patients.

Adult↗

PubMed1990

Design of biologically active, conformationally constrained GnRH antagonists.

The introduction of conformational constraints into a flexible peptide hormone can be exploited to develop models for the conformation required for receptor binding and activity. In this review, we illustrate this approach to analog design using our work on antagonists of gonadotropin-releasing hormone (GnRH). Design of a conformationally constrained, competitive antagonist of GnRH, cyclo[delta 3,4 Pro-D4ClPhe-DTrp-Ser-Tyr-DTrp-NMeLeu-Arg-Pro-bet a Ala] led to the prediction of its bioactive conformation. Template forcing experiments show that this conformation is accessible to other active GnRH analogs. Two-dimensional NMR studies verified the predicted conformation in solution. The predicted binding conformation has recently been used to design two new analogs incorporating side chain-side chain linkages suggested by the conformational model: Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-DTrp-Leu-Arg-Asp-Gly- NH2 and Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-D2Nal-Leu-Arg-Pro-Asp -NH2. These analogs were synthesized and the one predicted to be most similar to the parent conformation had equivalent potency while the second, designed to refine the conformational hypothesis, was found to exhibit enhanced potency, thus confirming the original binding conformation hypothesis. These compounds and their derivatives now provide a new class of GnRH antagonists possessing both high biological potency and limited conformational flexibility, thus making them ideal for both biophysical and structure-activity studies.

Amino Acid Sequence↗

PubMed1990

In vitro responses of rainbow trout (Oncorhynchus mykiss) somatotrophs to carp growth hormone-releasing factor (GRF) and somatostatin.

To study the hypothalamic control of growth hormone (GH) release in lower vertebrates, we employed an in vitro technique using a monolayer cell culture system of rainbow trout pituitary glands. Two newly purified carp brain growth hormone-releasing factors, carp GRF(1-45) and carp GRF(1-29), and synthetic somatostatin-14 (SST-14) were applied to the cultured pituitary cells. The results indicate that: (1) The carp GRFs had a dose-related potency in stimulating growth hormone release. The dose of half maximum effect (ED50) for carp GRF(1-45) was 0.107 nM, and an equal potency for carp GRF(1-29) was 0.388 nM. (2) SST-14 inhibited GH release having a dose-dependent potency with an ED50 of 0.186 nM. (3) Osmotic pressure did not influence SST-14 inhibited GH secretion but did affect spontaneous GH release. (4) The response of cultured cells was not affected by length of incubation period with SST-14 or carp GRF but was affected by cell density.

Animals↗

PubMed1990

Critical role of the hypothalamic pituitary adrenal axis in amphetamine-induced sensitization of behavior.

Behavioral sensitization can be observed with repeated administration of amphetamine where the intensity of motor stimulation increases over time. The process of sensitization has been well characterized, however, the neurochemical mechanisms that are critical for the development of sensitization are not known. In the present study, the role of the hypothalamic pituitary adrenal axis (HPA) in the development of behavioral sensitization to amphetamine was explored by pretreating rats with an intravenous administration of an antiserum to corticotropin-releasing factor in a volume that has been shown to block significantly stress- and cocaine-induced activation of the HPA. Four groups of eight rats were pretreated intravenously with either heparinized saline or CRF antiserum and subcutaneously with saline or d-amphetamine in a balanced design. The rats were then returned to their home cages and left undisturbed for seven days after which they were given three consecutive behavioral tests with saline SC, 0.75 mg/kg d-amphetamine SC, and 3.0 mg/kg d-amphetamine SC. The rats pretreated with intravenous CRF antiserum showed a significant attenuation of the development of d-amphetamine-induced sensitization but the antiserum did not alter the magnitude of the behavioral response to the initial, sensitizing dose of d-amphetamine. These results suggest that activation of the hypothalamic pituitary adrenal axis may be of critical importance to the development of behavioral sensitization to amphetamine.

Animals↗