Biomedical subjects

M A Villanua

Publications and source records attributed to M A Villanua.

15 recordsLinked to original sources

PubMed2001

Functional interaction between opioid and cannabinoid receptors in drug self-administration.

The present study was designed to explore the relationship between the cannabinoid and opioid receptors in animal models of opioid-induced reinforcement. The acute administration of SR141716A, a selective central cannabinoid CB1 receptor antagonist, blocked heroin self-administration in rats, as well as morphine-induced place preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with morphine-induced changes in the expression of CB1 receptor mRNA in specific nuclei of the reward circuit, including dorsal caudate putamen, nucleus accumbens, and septum. Additionally, the opioid antagonist naloxone precipitated a mild cannabinoid-like withdrawal syndrome in cannabinoid-dependent rats and blocked cannabinoid self-administration in mice. Neither SR141716A nor naloxone produced any intrinsic effect on these behavioral models. The present results show the existence of a cross-interaction between opioid and cannabinoid systems in behavioral responses related to addiction and open new strategies for the treatment of opiate dependence.

Animals↗

PubMed2001

The decrease in hepatic IGF-I gene expression in arthritic rats is not associated with modifications in hepatic GH receptor mRNA.

OBJECTIVE: Adjuvant-induced arthritis induces a catabolic response, and a decrease in circulating IGF-I. Hypermetabolism and GH insensitivity have been described in acute inflammation. The aim of this study was to analyze whether impaired IGF-I secretion in arthritic rats can be attributed to hepatic GH resistance. DESIGN AND METHODS: Male Wistar rats were injected with complete Freund's adjuvant, and 14 days afterwards arthritic and control rats were injected daily with recombinant human GH (rhGH) (3 IU/kg) or saline for 8 days. GH receptor (GHR) gene expression in the liver and the effect of rhGH on hepatic IGF-I synthesis in arthritic rats were examined. RESULTS: There was a significant decrease in hepatic concentrations of IGF-I (P < 0.01) as well as in the IGF-I gene expression in arthritic but not in pair-fed rats. In contrast, arthritis did not modify GHR mRNA levels in the liver. The 8 day administration of rhGH resulted in an increase in body weight gain in arthritic but not in control rats. There was an increase in hepatic IGF-I synthesis and in GHR mRNA levels after rhGH treatment, both in control and in arthritic rats. Two endotoxin lipopolysaccharide (LPS) (1 mg/kg) injections decreased hepatic concentrations of IGF-I and IGF-I mRNA (P < 0.01). Contrary to the results obtained in arthritic rats, mRNA expression of GHR in the liver was lower in LPS- than in saline-treated rats (P < 0.01). CONCLUSION: These data suggest that the decrease in IGF-I synthesis induced by chronic arthritis is not secondary to GH resistance.

Animals↗

PubMed1999

Extrapyramidal and neuroendocrine effects of AM404, an inhibitor of the carrier-mediated transport of anandamide.

A selective inhibitor of the carrier-mediated transport of endogenous cannabinoids, N-(4-hydroxyphenyl)-arachidonylethanolamide (AM404), has been recently synthesized and proposed as a useful tool for studying the physiological effects of endogenous cannabinoids and as a potential therapeutic agent in a variety of diseases. In the present study, we have examined the effects of this compound in two important brain processes in which a role for anandamide and other endogenous cannabinoids has been claimed: neuroendocrine regulation and extrapyramidal motor activity. A single and well-characterized dose of AM404, which presumably resulted in a significant elevation of the levels of endogenous cannabinoids, produced a marked decrease in plasma prolactin (PRL) levels, with no changes in luteinizing hormone (LH) levels. This decrease in PRL levels was accompanied by an increase in the activity of tyrosine hydroxylase (TH) in the medial basal hypothalamus. Both decreased PRL secretion and increased hypothalamic TH activity have been reported to occur after the administration of anandamide. Administration of AM404 also produced a marked motor inhibition in the open-field test, as also reported for anandamide, with a decrease in ambulatory and exploratory activities and an increase in the time spent in inactivity. This was accompanied by a decrease in the activity of TH in the substantia nigra, an effect also previously observed for anandamide.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Diurnal oscillation in glial fibrillary acidic protein in a perisuprachiasmatic area and its relationship to the luteinizing hormone surge in the female rat.

It is well known that the reproductive cycle in the female rat is closely associated with the circadian rhythms of motor activity and that this phenomenon requires the presence of estrogens. Estrogens induce plastic changes in neural connectivity and these changes could be the result of glial modifications. We have measured glial fibrillary acidic protein (GFAP) immunoreactivity in order to localize the area in which the coupling of the circadian rhythms to the generation of the luteinizing hormone (LH) surge may occur. As circadian rhythms are driven by the suprachiasmatic nucleus (SCN), GFAP immunoreactivity was measured in 5 areas of the SCN and surrounding regions. It was measured at two times during daylight (10.00 and 17.00 h) in ovariectomized (OVX) females implanted with Silastic capsules containing either estradiol benzoate (EB) or oil (control). Differences between morning and afternoon GFAP immunoreactivity were observed in a peri-SCN area, dorsal to the SCN and close to the 3rd ventricle, in estrogen-treated as well as in control OVX females. However, this difference increased in the subgroup of EB-treated females which displayed the strongest LH rhythmicity. These results suggest that the peri-SCN area could be an important locus for synaptic changes linking circadian rhythms with the estrogen-induced LH surge.

Animals↗

PubMed1998

Effects of cannabinoids on prolactin and gonadotrophin secretion: involvement of changes in hypothalamic gamma-aminobutyric acid (GABA) inputs.

CB1 cannabinoid receptors are located in hypothalamic nuclei and their activation alters several hypothalamic neurotransmitters resulting in, among other things, decreased prolactin (PRL) and luteinizing hormone (LH) secretion from the anterior pituitary gland. In the present study, we addressed two related objectives to further explore this complex regulation. First, we examined whether changes in gamma-aminobutyric acid (GABA) and/or dopamine (DA) inputs in the medial basal hypothalamus might occur in parallel to the effects resulting from the activation of CB1 receptors on PRL and gonadotrophin secretion in male rats. Thus, the acute administration of (-)-delta9-tetrahydrocannnabinol (delta9-THC) produced, as expected, a marked decrease in plasma PRL and LH levels, with no changes in follicle-stimulating hormone (FSH) levels. This was paralleled by an increase in the contents of GABA, but not of DA, in the medial basal hypothalamus and, to a lesser extent, in the anterior pituitary gland. The co-administration of delta9-THC and SR141716, a specific antagonist for CB1 receptors, attenuated both PRL and LH decrease and GABA increase, thus asserting the involvement of the activation of CB1 receptors in these effects. As a second objective, we tested whether the prolonged activation of these receptors might induce tolerance with regard to the decrease in PRL and LH release, and whether this potential tolerance might be related to changes in CB1-receptor binding and/or mRNA expression. The chronic administration of R-methanandamide (AM356), a more stable analog of anandamide, the putative endogenous cannabinoid ligand, produced a marked decrease in plasma PRL and LH levels, with no changes in FSH. The decreases were of similar magnitude to those caused by a single injection of this cannabimimetic ligand, thus suggesting the absence of tolerance. In parallel, the analysis of CB1-receptor binding and mRNA expression in several hypothalamic structures proved that the acute or chronic administration of AM356 did not affect either the binding or the synthesis of these receptors. In summary, the activation of CB1 receptors in hypothalamic nuclei produced the expected decrease in PRL and LH secretion, an effect which might be related to an increase in GABAergic activity in the hypothalamus-anterior pituitary axis. The prolonged activation of these receptors for five days did not elicit tolerance in terms of an attenuation in the magnitude of the decrease in PRL and LH, and, accordingly, did not alter CB1-receptor binding and mRNA levels in the hypothalamic nuclei examined.

Animals↗

PubMed1997

Time course of the effects of different cannabimimetics on prolactin and gonadotrophin secretion: evidence for the presence of CB1 receptors in hypothalamic structures and their involvement in the effects of cannabimimetics.

Several reports have demonstrated that (-)-delta9-tetrahydrocannabinol (delta9-THC) and arachidonylethanolamide [anandamide (AEA)] were able to inhibit prolactin (PRL) secretion from the anterior pituitary gland in male rodents, whereas ovarian phase-dependent effects were seen in females. However, in most of these studies, the analysis of PRL levels was performed at times longer than 30 min after cannabinoid administration. In the present study, we examined the time course of the effects of three different cannabimimetics, delta9-THC, AEA, and AM356 (R-methanandamide), a more stable analog of AEA, on PRL and gonadotrophin secretion in male Wistar rats. In addition, we characterized the presence of cannabinoid receptors in hypothalamic structures related to neuroendocrine control and studied their potential involvement in the effects of cannabimimetics. We found that the three compounds decreased plasma luteinizing hormone (LH) levels, although only the effects of delta9-THC were statistically significant. The inhibitory effect was already apparent at 40 min after administration, but only in the case of delta9-THC did it persist up to 180 min after administration. No significant changes were seen in plasma follicle-stimulating hormone (FSH) levels after the administration of any of the three different cannabimimetics at any of the four times analyzed. Both AEA and AM356 produced a significant decrease in plasma PRL levels, which appeared at 20 min after administration and persisted up to 60 min, waning after this time. Interestingly, the time course of the effect of delta9-THC resembled that of AEA and AM356 only during the later part of the response, because delta9-THC produced a marked increase in plasma PRL levels at 20 min, no changes at 40 min and a decrease from 60 min up to 180 min. In additional experiments, we tried to elucidate which of these two phases observed after delta9-THC administration was mediated by the activation of cannabinoid receptors. These receptors are present in hypothalamic structures related to neuroendocrine control, with the highest densities in the arcuate nucleus (dorsal area) and the medial preoptic area, and the lowest in the lateral hypothalamic area, although none of these regions exhibited high densities for this receptor as compared with classical regions containing cannabinoid receptors, such as the basal ganglia. The activation of these receptors by delta9-THC seems to be involved in the inhibitory phase of the effect of this cannabinoid on PRL release, but not in the early stimulation; when these receptors were blocked with a specific antagonist, SR141716, the stimulation by delta9-THC was still observed, but the late inhibition was abolished. In summary, AEA and AM356 markedly decreased PRL release and slightly decreased LH secretion, with no changes on FSH release. delta9-THC also produced a marked inhibition of LH secretion, but its effects on PRL were biphasic with an early stimulation not mediated by the activation of cannabinoid receptors, followed by a late and cannabinoid receptor-mediated inhibition. Their site of action may well be the hypothalamic structures related to neuroendocrine control, which contain a small, but probably very active, population of cannabinoid receptors.

Animals↗

PubMed1993

Thymostimulin effects on lymphoid organs in Ames dwarf mice.

This work was undertaken to study the effects of thymostimulin (TP-1) on the immune function in Ames dwarf mice, and to relate these effects to PRL and/or GH deficiency in these animals. Male Ames dwarf mice implanted with pituitaries from normal mice under the kidney capsule, sham-operated dwarf mice and normal immature or adult mice were injected daily for five days with TP-1. In comparison to normal animals, sham-operated dwarf mice had markedly lower body, thymus and spleen weights, as well as a lower number of lymphocytes in the spleen and in the thymus and the natural killer (NK) activity of spleen lymphocytes. Ectopic pituitary transplants produced the expected enhancement of body weight gain and increased spleen and thymus weights, which reached the values found in normal (non-dwarf) animals. The numbers of lymphocytes in the spleen and thymus were significantly increased in pituitary-grafted dwarf mice, but the grafts did not modify the cytotoxic activity of NK spleen cells, or the number of peripheral white blood cells (PWBC). In sham-operated dwarf mice, TP-1 treatment did not modify the number of cells in the spleen and thymus, or the NK activity. In pituitary-grafted dwarf mice, treatment with TP-1 induced an increase in the number of spleen lymphocytes and in the NK activity of spleen cells without affecting the weight of lymphoid organs or the number of thymic cells. Plasma prolactin (PRL) and growth hormone (GH) levels of pituitary-grafted dwarf mice were not changed after TP-1 administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1992

Changes in lymphoid organs of Ames dwarf mice after treatment with growth hormone, prolactin or ectopic pituitary transplants.

This study was performed to obtain more insight into the roles of PRL and GH in the control of immune functions in hereditary dwarf mice characterized by severe immunodeficiency. Adult female Ames dwarf mice (df/df) were injected daily for 10 days with ovine PRL (oPRL), bovine GH (bGH), oPRL+bGH or were implanted with a normal pituitary under the kidney capsule for 5 days. Only the treatment with bGH resulted in significant increases in the gain of body weight, and in absolute and relative thymus and spleen weights. Treatment with oPRL alone did not affect body weight gain or thymus and spleen weights. Treatment with oPRL+bGH produced a significant increase in the gain of body weight and in absolute and relative spleen weight but these effects were smaller than those measured in dwarf mice treated with bGH alone. Only bGH therapy resulted in extensive recovery of the absolute number of lymphocytes in the thymus and spleen of dwarf mice, with the values in treated dwarf mice not significantly different from those found in normal non-dwarf females. However, when these values were corrected for body weight, both the splenic and the thymic indices exceeded the values found in normal mice. The absolute numbers of lymphocytes in the spleen were also increased by oPRL+bGH treatment, but did not reach the values found in normal mice; however, the splenic index exceeded the values found in normal animals. Surprisingly, the absolute and relative numbers of lymphocytes found in the thymus of dwarf mice under oPRL+bGH therapy were indistinguishable from those found in oPRL or vehicle treated dwarf mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Effects of treatment of normal and hyperprolactinemic rats with cyclosporine in vivo on the release of gonadotropins and prolactin from their pituitaries in vitro.

Cyclosporine (CyA) is extremely useful as an immunosuppressant and it is believed that at least some of its actions are due to antagonizing PRL effects. To determine whether the reported ability of CyA to inhibit gonadotropin release can be modified by PRL, we have examined the effects of treatment of normal and hyperprolactinemic rats with CyA in vivo on the release of LH, FSH and PRL from their pituitaries in vitro. Hyperprolactinemia was induced by implantation of capsules containing diethylstilbestrol (DES) and the animals were examined while the capsules were still in place (DES-IN) or after they had been removed (DES-OUT). Treatment with CyA significantly reduced plasma LH levels in control DES-IN rats without reducing basal LH release from the pituitaries of these animals in vitro. In the DES-IN rats, CyA exposure in vivo did not modify plasma PRL levels, but reduced PRL release in vitro, and interfered with the inhibitory action of dopamine (DA) on PRL release. The effect of DA on gonadotropin release in vitro was modified by CyA treatment. Administration of CyA failed to antagonize the suppressive effects of hyperprolactinemia on plasma LH and FSH levels or on the basal rates of gonadotropin release by incubated pituitaries. We conclude that CyA can reduce PRL release but does not interfere with the actions of PRL on anterior pituitary function.

Animals↗

PubMed1992

Acute noise stress, ACTH administration, and blood pressure alteration.

Two groups of male Wistar rats were submitted to a single noise exposure (2640 Hz, 30 W, 102 dB, 15 min) (St group) or to a single dose of ACTH (1.5 IU/100 g b.wt.) (Ac group), respectively. A control group of nontreated rats (Co group) was used. Blood pressure (BP) was measured using an indirect tail cuff method and corticosterone (B) levels were measured by specific RIA. Haematocrit (Hc) and blood pH values were also evaluated. Acute treatments of both noise exposure and ACTH administration produced corticosterone hypersecretion and blood pressure elevation, with lower haematocrit and higher blood pH values than those found in the Co group. No differences were found between St and Ac treatments.

Adrenocorticotropic Hormone↗

PubMed1989

Melatonin effects on prolactin secretion in pituitary-grafted female rats.

Melatonin influences prolactin (PRL) secretion through unknown mechanisms. This work was undertaken to study the effects of melatonin administration of PRL secretion in pituitary-grafted female rats. Melatonin administration resulted in a marked and rapid decrease of previously high plasma PRL levels in pituitary-grafted rats. Luteinizing hormone releasing hormone (LHRH) administration resulted in a marked decrease of plasma PRL levels in both sham-operated and grafted animals given saline whereas a statistically significant increase was observed in grafted, melatonin-treated rats. Estradiol benzoate administration caused an increase in plasma PRL levels of greater magnitude in the afternoon than in the morning in sham-operated animals given saline whereas in grafted animals no response to estradiol benzoate was detected. Melatonin increased the plasma PRL response to estradiol benzoate in sham-operated rats as compared to vehicle-treated animals. A normalization of PRL response to estradiol benzoate was shown in melatonin-treated, pituitary grafted rats. While the suppressive effects of melatonin in plasma PRL levels of pituitary-grafted animals is substantial the mechanism of this inhibition remains unknown.

Animals↗

PubMed1989

Melatonin effects on prolactin secretion in pituitary-grafted male rats.

Melatonin influences prolactin (PRL) secretion through unknown mechanisms. This work was undertaken to study the effects of melatonin administration on PRL secretion in pituitary-grafted male rats. Melatonin administration 5 hours before dark resulted in a marked decrease of previously high basal plasma PRL levels in pituitary-grafted rats, whereas a marked increase was detected in sham-operated animals. Vehicle treatment did not modify basal PRL values in grafted or sham-operated animals. Luteinizing hormone-releasing hormone (LHRH) administration resulted in a marked decrease of plasma PRL levels in vehicle-treated, sham-operated or grafted rats, as well as in melatonin-treated sham-operated rats. An increase in PRL levels was shown in grafted rats treated with melatonin. Estradiol benzoate (EB) administration resulted in an increase in plasma PRL levels both in sham-operated and grafted vehicle-treated rats. No PRL response could be detected in sham-operated, melatonin-treated animals after EB administration. In pituitary-grafted animals given melatonin, PRL response to EB administration was slight and delayed. From these data, melatonin appears to modify PRL secretion through multiple complex mechanisms that may depend on the physiological status (hormonal and neurotransmitter) of the animals. A direct effect at the pituitary level altering lactotroph sensitivity seems to be one plausible explanation for the current findings, although an hypothalamic site of action cannot be excluded.

Animals↗

PubMed1988

Elevated environmental temperature alters the responses of the reproductive and thyroid axes of female Syrian hamsters to afternoon melatonin injections.

Female Syrian hamsters were kept in a light (14:10 h light:dark cycle, lights on 0600 h)- and temperature (22 or 30 degrees C)-controlled room; some groups were treated with an afternoon s.c. injection of melatonin (6.25, 12.5, or 25 micrograms/day) for 11 or 14 weeks. The melatonin-induced suppression of the reproductive system in hamsters maintained at 22 degrees C (as measured by vaginal cycles, uterine weights, ovarian histology, and plasma and pituitary prolactin levels) was delayed if hamsters were kept at 30 degrees C. The dose-related depression of thyroxine (T4) after melatonin injections for 14 weeks in 22 degrees C was not seen at 30 degrees C. Rather, the depression of plasma T4 and triiodothyronine (T3) seen at the end of 11 or 14 weeks of exposure to 30 degrees C without melatonin injections (vs. control levels at 22 degrees C) was offset by melatonin injections, raising T4 and T3 particularly at the lower doses. In contrast, there was no consistent effect of higher temperature alone on reproductive variables. The interactive effects of temperature and melatonin on the reproductive and thyroidal systems in female hamsters are apparently complex and probably provide a fine-tuning mechanism for the environmental control of endocrine physiology.

Animals↗

PubMed1987

Chronic noise stress and dexamethasone administration on blood pressure elevation in the rat.

In order to evaluate the role of ACTH and corticosterone in the elevated blood pressure produced by chronic noise, we have studied the effect of dexamethasone administration on blood pressure. Adrenal response was measured by alterations in plasma corticosterone levels in two experimental groups (Dexamethasone treated rats, Dexamethasone-noise stressed rats) and compared with a Control and a Noise-stressed group. Chronic noise stress with a frequency of 2640 Hz, power of 30 w and duration of 15 min daily was used for 30 consecutive days. Dexamethasone was administered by subcutaneous injection of 100 micrograms/100 g b.wt daily. Blood pressure was measured by an indirect tail cuff method and corticosterone levels by specific RIA. Dexamethasone administration decreases corticosterone levels but increases blood pressure. Dexamethasone-treated noise stressed rats show higher residual corticosterone levels and a more marked increase on blood pressure than rats treated with dexamethasone alone. Thus noise-stress and dexamethasone administration have opposing effects on corticosterone release and a synergistic effect on blood pressure elevation.

Animals↗

PubMedDate not supplied

Perinatal delta(9)-tetrahydrocannabinol exposure alters the responsiveness of hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats.

We have recently reported that perinatal cannabinoid exposure altered the normal development of dopaminergic neurons in the medial basal hypothalamus at early postnatal and peripubertal ages. Most of these effects tended to disappear in adulthood, although we suspect the existence of a persistent, but possibly silent, alteration in the adult activity of these neurons. To further explore this possibility, we evaluated the responsiveness of these neurons to pharmacological challenges with a variety of dopaminergic drugs administered to adult male and female rats that had been exposed to delta(9)-tetrahydrocannabinol (delta(9)-THC) or vehicle during the perinatal period. In the first experiment, we evaluated the sensitivity of hypothalamic dopaminergic neurons to amphetamine (AMPH), which causes enhancement of dopaminergic activity by a variety of mechanisms. The most interesting observation was that both adult males and females, when perinatally exposed to delta(9)-THC, showed a more marked AMPH-induced decrease in the production of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite of dopamine (DA), although this did not affect the prolactin (PRL) release. In the second experiment, we evaluated the in vivo synthesis of DA by analyzing the magnitude of L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation caused by the blockade of L-DOPA decarboxylase with NSD 1015. As expected, NSD 1015 increased L-DOPA accumulation and decreased DOPAC production, with a parallel increase in PRL release, all of similar magnitude in both delta(9)-THC- and oil-exposed adult animals. In the last experiment, we tested the magnitude of the increase in PRL release produced by the administration of either SKF 38393, a specific D1 agonist, or sulpiride, a specific D2 antagonist. Both compounds increased plasma PRL levels in adult animals of both sexes, the effects in females being significantly more marked. The perinatal exposure to delta(9)-THC also modified the degree of increase in plasma PRL levels induced by both compounds, with opposite responses as a function of sex. Thus, delta(9)-THC-exposed females responded more intensely to SKF 38393 and, particularly, to sulpiride than oil-exposed females, whereas delta(9)-THC-exposed males responded to SKF 38393 lesser than oil-exposed males, although both responded equally to sulpiride. In summary, our results are consistent with the possible existence of subtle changes in the activity of hypothalamic dopaminergic neurons in adulthood caused by the exposure to delta(9)-THC during perinatal development. These silent changes could be revealed after the administration of drugs such as: (i) AMPH, whose effect producing a decreased DOPAC accumulation was more marked in delta(9)-THC-exposed males and females; and (ii) SKF 38393 and sulpiride, whose stimulatory effects on PRL secretion were of different magnitude in delta(9)-THC-exposed animals, with an evident sexual dimorphism in the response. The neurochemical basis for these differences remains to be determined.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗