Ethanol-diazepam interactions on delayed match-to-sample performance in baboons.

Four juvenile male baboons were trained on a delayed match-to-sample (MTS) discrimination task. Single administration of 0.25, 0.5, 1.0, 2.0, 4.0, and 6.0 mg/kg diazepam (DZ) resulted in a dose-related increase in mean response time (MRT), with a maximum effect at 2.0 mg/kg. Administration of 0.25 mg/kg of DZ had no effect. Response time was increased significantly by 1.0 g/kg of ethanol (EtOH) but was not affected by 0.5 g/kg EtOH. There were no significant effects on the number of correct responses. Combined treatment of 0.5 g/kg of EtOH with 1.0 mg/kg DZ produced the same increase in MRT as the DZ alone. When 1.0 g/kg EtOH was administered with 0.25 mg/kg DZ. MRT decreased which was a significant improvement in performance as compared to the increase in MRT observed with either the EtOH or the DZ alone. Combined doses of 1.0 g/kg EtOH and 0.5 mg/kg DZ produced essentially the same increases in MRT as either dose alone. Similar results were obtained when 1.0 g/kg EtOH and 1.0 mg/kg DZ were combined and the increase in MRT was about the same for DZ alone and more than twice as great for the EtOH alone. Combined administration of the drugs had no significant effects on the number of correct choices. Since the administration of a combination of a low dose of DZ with EtOH appeared to prevent the increases in MRT observed with either drug alone and there were no observable effects on the number of correct response, these effects do not appear to involve cognitive processes but might be related to excitability changes in motor systems.

Ethanol and chronic diazepam interactions on conflict behavior in rats.

Four groups of five rats each received training on the Geller-Seifter procedure and then received 0.5, 1.0 or 2.0 mg/kg diazepam (DZ) or vehicle, respectively, 15 min prior to the behavior sessions for 14 days. On Day 14 of DZ treatment rats also were administered 2.0 g/kg of ethanol (EtOH) 30 min prior to testing. Significant dose-related decreases in lever pressing occurred between groups over the 13 days of DZ treatment during the pre- and posttone periods. However, a significant effect attributable to days occurred only in the pretone period. During the tone period, the dose-related effects were greater but the variability also increased and specific contrasts between individual means were not significant. The largest increases in lever pressing associated with an anxiolytic effect occurred with 1.0 mg/kg of DZ at Day 6. On Day 14, all animals received 2.0 g/kg of EtOH and their performance was compared to performance on Day 13. During the pre- and posttone periods, the EtOH resulted in significantly less lever pressing in the control, 0.5 and 2.0 mg/kg DZ groups, indicating a sedative effect. Rats treated with 1.0 mg/kg of DZ did not exhibit this EtOH reduction in lever pressing. During the tone or conflict period, a significant dose-related increase in lever pressing due to the EtOH was observed. The increase in the control group was not significant. During repeated exposure to DZ there was a small but significant decrease in number of reinforcements which was enhanced by the EtOH at the 0.5 and 2.0 mg/kg DZ doses but not at 1.0 mg/kg DZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactive effects of diazepam and ethanol on baboon match-to-sample performance.

Four juvenile male baboons were trained to perform a match-to-sample (MTS) discrimination task. Diazepam (DZ) at doses of 0.5, 1.0, 2.0, 4.0, or 6.0 mg/kg resulted in a significant (p less than 0.05) increase in the mean response times (MRT) during the 2 hr test session in terms of percent change from baseline performance under nondrug conditions measured the day prior to drug treatment. Effects were maximal at 2.0 mg/kg diazepam and no further effects were observed at 4.0 or 6.0 mg/kg. Administration of 0.25 mg/kg of diazepam had no effect on MTS performance. Exposure to 0.5 g/kg of ethanol (EtOH) had no effect on response time, while 1.0 g/kg EtOH significantly (p less than 0.05) increased response time. Baboons receiving combined treatment with 0.5 or 1.0 g/kg EtOH plus 1.0 mg/kg diazepam displayed a significant (p less than 0.05) percent increase in mean response time compared to that observed under baseline conditions on the day prior to drug treatment. The 0.5 g/kg EtOH and 1.0 mg/kg diazepam combination increased MRT to an extent comparable to the effect observed at the same dose of diazepam alone. Effects observed with 1.0 mg/kg diazepam and 1.0 g/kg EtOH were similar to those produced by the DZ alone. Combinations of 0.5 g/kg EtOH and 0.5 mg/kg diazepam, 1.0 g/kg EtOH and 0.25 mg/kg diazepam, and 1.0 g/kg EtOH and 0.5 mg/kg diazepam had no significant effect on response times.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol and diazepam interactions on conflict behavior in rats.

Twenty-four adult male rats trained on the Geller-Seifter conflict procedure received: 1.0, 2.0, or 4.0 mg/kg diazepam at 15 min, 0.25, 0.5, 1.0, 2.0, or 4.0 g/kg of ethanol (EtOH) at 30 min prior to the test session, or combinations of the same diazepam doses and 0.5 g/kg of EtOH. Ethanol administration produced a significant (p less than 0.05) dose-related decrease in lever pressing during the periods prior to the introduction of the tone stimulus, compared to lever pressing during the corresponding control periods on the day prior to drug treatment. During the posttone periods 0.25 g/kg increased lever pressing (p less than 0.05), while doses of EtOH from 0.5 to 4.0 g/kg resulted in significantly lower levels of lever pressing in periods following the discontinuation of the tone. In the presence of the conflict evoking tone stimulus, rats treated with 2.0 g/kg of EtOH increased their rate of lever pressing, while animals receiving the other EtOH doses exhibited lever pressing comparable to that observed during the corresponding control periods. Administration of EtOH had no effect on the number of reinforcements received during the entire test session, except for a significant (p less than 0.05) reduction at the highest dose of 4.0 g/kg. Diazepam increased the number of reinforcements received during the entire test session as compared to those obtained during control sessions. Lever pressing was not affected by diazepam treatment during pretone or tone periods. During the posttone periods responses were significantly (p less than 0.05) increased in rats receiving the lowest dose of 1.0 mg/kg of diazepam but the other doses were without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic action of delta-9-tetrahydrocannabinol to inhibit the release of prolactin and growth hormone in the rat.

The site of action of delta-9-tetrahydrocannabinol (THC) to inhibit the release of prolactin (PRL) and growth hormone (GH) was examined by in vivo and in vitro experiments. In conscious freely moving animals bearing implanted third ventricular (3V) and external jugular cannulae, THC or the diluent was microinjected into the 3V and blood samples were removed to determine the effect on plasma PRL and GH. Both the 0.4- and 4-micrograms dose injected intraventricularly resulted in a suppression of PRL and GH release as indicated by declines in plasma levels within 40-80 min which were highly significant statistically but not dose-related. The higher dose evoked a pulse of GH and/or PRL in most animals which preceded the lowering of hormonal levels. In the in vitro experiments dipersed anterior pituitary cells were incubated with 5 x 10(-8) or 5 x 10(-9)M THC or the diluent for 5 days. Fresh culture medium was added to the cells after 3 days and the cells cultured for an additional 2 days. After this period, the cells were incubated for an additional 2 h in culture medium with or without THC plus a near maximal dose of thyrotropin-releasing hormone and GH-releasing factor (50 and 10 ng/ml, respectively) or the diluent to evaluate the response of PRL and GH release, respectively. Neither dose of THC altered the release or storage of the two hormones during culture or affected the response to the releasing hormones which is suggestive that there is no direct effect of THC on either GH or PRL release.(ABSTRACT TRUNCATED AT 250 WORDS)

Testicular Ca++ ATPase activity in mice: effects of age and gonadotropin administration.

These studies describe a high affinity calcium (Ca++)-dependent ATPase in purified testicular plasma membranes, which exhibits increased activity from weaning age to adulthood. Administration of human chorionic gonadotropin (hCG; 5 IU) increased enzyme activity in 21-day old and pubertal (35 to 40-day old), but not in adult mice. In pubertal mice, these increases in testicular Ca++-ATPase activity were dose-related and evident 60 min after hCG administration. A second challenge dose of 5 IU hCG administered either 24, 48 hrs, or 5 days later, had no additional effect on Ca++ ATPase in purified testicular plasma membranes in these pubertal animals. The present findings indicate that testicular plasma membrane Ca++ATPase activity exhibits a developmental pattern concomitant with increased testicular steroidogenic activity during sexual maturation. Furthermore, enzyme activity is increased by gonadotropic stimulation and exhibits a refractoriness similar to that of androgen biosynthesis to repeated hCG stimulation.

Effects of delta-9-tetrahydrocannabinol on the hypothalamic-pituitary control of luteinizing hormone and follicle-stimulating hormone secretion in adult male rats.

The main psychoactive component of marihuana, delta-9-tetrahydrocannabinol (THC) was injected into the 3rd cerebral ventricle. A single dose of THC (2 microliter of 10(-6) M) decreased serum LH temporarily but did not alter serum follicle-stimulating hormone (FSH) levels. The mediobasal hypothalamic (MBH) luteinizing hormone-releasing hormone (LHRH) content was elevated by 30 min after the injection. The elevation persisted for 1 h. Then, the LHRH content returned towards the preinjection level. In contrast, the LHRH in the organum vasculosum of the lamina terminalis did not change after a single dose of THC. The results indicate that THC alters pituitary LH release by inhibiting the release of LHRH which then increases in the MBH by continued synthesis or transport from rostral areas. In addition, the data support the existence of an FSH releasing factor, the release of which is not suppressed by this dose of THC. THC did not alter the release, storage or responsiveness to LHRH of cultured anterior pituitary cells, which further supports the view that its principal site of action is on the hypothalamus.

LHRH-receptor-regulated Ca2+-ATPase activity in murine pituitary gland.

Addition of luteinizing hormone releasing hormone (LHRH) in vitro (10(-5) -5 X 10(-9) M) to murine pituitary membranes resulted in a dose-related decrease in Ca2+-ATPase activity within 15 min. Inhibitory effects of LHRH (10(-7) M) occurred after 90 sec, and appeared maximal by 120 sec. Eadie-Hofstee analysis at 10(-7) M LHRH, at varying [Ca2+]free, resulted in a Km = 0.89 +/- 0.06 microM and a Vmax = 18.8 +/- 0.71 nmol/mg per 2 min, compared to a Km = 0.69 +/- 0.06 microM and a Vmax = 32.8 +/- 1.21 nmol/mg per 2 min for controls. Pre-incubation for 5 min with LHRH antagonist (10(-8) M) significantly attenuated (50%) the inhibitory effects of 10(-7) M LHRH on pituitary Ca2+ ATPase activity with a Km = 0.97 +/- 0.24 microM and a Vmax = 28.1 +/- 2.8 nmol/mg per 2 min. The addition of LHRH (10(-7) M) to pituitary homogenates significantly increased luteinizing hormone (LH) release already at 10 and up to 40 sec compared to basal LH release. Systemic administration of 50 ng LHRH (i.p.), significantly (P less than 0.05) reduced pituitary Ca2+-ATPase after 30, 60 and 90 min, with a return to control levels by 120 min. Pituitary LH content was reduced slightly at 15 min, but was increased significantly at 90 and 120 min post-treatment. Plasma LH levels were elevated by 5 min, reached a peak by 15 min and returned to control within 60 min. The present findings indicate that LHRH receptor activation may influence cytosolic Ca2+ transport through effects on membrane Ca2+-ATPase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute delta 9-tetrahydrocannabinol exposure alters Ca2+ ATPase activity in neuroendocrine and gonadal tissues in mice.

Acute administration of delta 9-tetrahydrocannabinol (THC) (50 mg/kg) at puberty (35-40 days) significantly (P less than 0.05) reduced Ca2+ ATPase activity in hypothalamic plasma membranes but increased, although not significantly, enzyme activity in hypothalamic tissue obtained from adult mice. In contrast, testicular Ca2+ ATPase activity was increased in pubertal THC-treated males, and significantly reduced in adults. Pituitary Ca2+ ATPase activity exhibited a dose-related decrease after acute THC administration at 0.5, 5 or 50 mg/kg, but there were no differential effects of age. Pituitary plasma membranes obtained from THC-treated males did not respond to in vitro exposure to luteinizing hormone releasing hormone (LHRH, 10(-7) M) with the marked reduction (approximately 40%) in Ca2+ ATPase activity observed in pituitaries from oil-treated controls. In addition, effects of THC appear specific for Ca2+ ATPase activity, since Mg2+ ATPase and Na+/K+ ATPase activities were not affected. These findings indicate that acute in vivo administration of THC influences Ca2+ membrane transport, in particular Ca2+ ATPase activity. These effects occur at each level of the hypothalamic-pituitary-gonadal (HPG) axis, are related to dose and developmental age at exposure, and also appear specific for Ca2+-dependent ATPase activity. Furthermore, THC exposure modulates pituitary sensitivity to LHRH receptor-mediated effects on Ca2+ ATPase activity. Therefore, effects on Ca2+ membrane transport may be involved in acute THC actions on hormonal activity at these HPG sites.

Acute delta 9-tetrahydrocannabinol exposure: effects on hypothalamic-pituitary-testicular activity in mice.

The endocrine functions of the median eminence, pituitary and testes were examined in male mice after exposure to delta 9-tetrahydrocannabinol (THC) either in vivo or in vitro. The secretion of luteinizing hormone-releasing hormone (LHRH) under basal conditions, and in the presence of norepinephrine (NE; 60 microM), was significantly enhanced in median eminence fragments obtained 1 hr post-treatment with THC (50 mg/kg), while addition of THC (250 ng/ml) to the incubation media enhanced clonidine, as well as NE-stimulated LHRH release, but did not affect basal LHRH release. In vitro exposure to THC also enhanced LHRH-stimulated LH release by pituitaries, but did not affect basal secretion rates. In vivo THC exposure tended to enhance pituitary responsiveness to LHRH, although this effect was not statistically significant. In testicular perifusions, addition of THC at a concentration of 250 ng/ml completely blocked hCG-stimulated T secretion within 30 min. The suppressive effects of a lower dose of THC, 25 ng/ml, required 60 min to inhibit T production, an effect which persisted for 60-80 min post-THC. These findings indicate that THC exposure enhances responsivity at neuroendocrine target sites, but attenuates gonadotropin-stimulated testicular steroidogenesis.

Maternal cannabinoid exposure. Effects on spermatogenesis in male offspring.

Maternal exposure to cannabinoids influenced spermatogenesis and fertility in their male offspring examined at 60-80 days of age. Approximately 20% less spermatozoa were found in males whose mothers had received either the non-psychoactive cannabinol (CBN) or cannabidiol (CBD) on day 1 postpartum. Males exposed to the major psychoactive component of marihuana, delta 9-tetrahydrocannabinol (THC) appeared to have spermatozoa in number comparable to controls. This finding may be consistent with the additional observation that CBN or CBD, but not THC, reduced the percentage of successful impregnations by cannabinoid-exposed males. However, males exposed to each of these cannabinoids produced significantly less live offspring compared to controls. Plasma levels of testosterone and luteinizing hormone (LH) were reduced significantly in mice exposed to THC on day 12 of gestation, while testicular weight was reduced in adult mice exposed either on day 12 of gestation to CBD or on day 1 post-partum to THC. These results indicate that perinatal exposure to psychoactive and non-psychoactive components of marihuana can produce long-term disruption of testicular function including the spermatogenic as well as the steroidogenic components.

Cannabinoid exposure: effects on development.

The literature concerning the teratologic effects of cannabinoids is reviewed, and some methodological issues associated with perinatal cannabinoid exposure are discussed. The long-term consequences of perinatal cannabinoid exposure on brain, endocrine, immune, and hepatic functions are considered. In our studies, perinatal cannabinoid exposure affected the long-term development of body weight regulation, neuroendocrine function, and adult sexual behaviors. In addition, the immune system and hepatic cytochrome P-450 levels were also influenced in adult male mice perinatally-exposed to cannabinoids. It is hypothesized that these effects may be mediated by cannabinoid-induced alterations in the fetal and/or neonatal hormonal milieu. In addition, the possibility that perinatal cannabinoid administration affects the subsequent ability of the exposed offspring to adapt to the environment is discussed. Finally, possible mechanisms of cannabinoid action in altering development are evaluated. It is concluded that the evidence to date indicates that cannabinoids can be embryocidal, affect gestational length and labor, induce maturational delays, and that these substances affect a myriad of physiological processes in the developing offspring, including effects on behavioral parameters, not only in laboratory animals, but also in the human neonate. Consequences of perinatal cannabinoid exposure on development are described and possible mechanisms of action of cannabinoids are discussed.

Perinatal cannabinoid exposure: demasculinization in male mice.

Maternal exposure to psychoactive or non-psychoactive cannabinoids produces long-term changes in body weight regulation, pituitary-gonadal feedback, testicular function, and also affects adult sexual behavior in male offspring. Alterations in brain biogenic amine concentration and metabolism have also been observed in adult males perinatally-exposed to cannabinoids. The possibility that these effects are mediated by cannabinoid-induced suppression or interference with fetal and/or neonatal androgen production is discussed. In addition, data are presented showing that exposure to the major psychoactive component of marihuana, delta 9-tetrahydrocannabinol (THC), on day 12 of gestation significantly increased hepatic cytochromes P-450 levels. In contrast, cytochromes P-450 levels were significantly decreased in adult males exposed to these cannabinoids on day 1 post-partum. The response of these animals to the negative feedback effects of exogenous androgen was also influenced by perinatal cannabinoid exposure. One hr after injection of 20 micrograms testosterone (T), plasma levels of luteinizing hormone (LH), were markedly increased in castrated males exposed to CBD on day 12 of gestation, while the THC and control mice showed no response to T injection. In contrast to the reduced plasma LH levels in the controls, the levels of LH were significantly increased in postnatal THC-exposed males, while the CBN and CBD-exposed mice exhibited no reduction in plasma LH in response to exogenous androgen. Prenatal exposure to THC resulted in a greater suppression of plasma follicle-stimulating hormone (FSH) levels in mice receiving 20 micrograms T, compared to the effects in the castrated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of follicle-stimulating and luteinizing hormones on testosterone production by mouse testes.

In adult mice, direct intratesticular injection of ovine follicle-stimulating hormone (o-FSH-13; AFP 2846-C, from NIAMDD, less than 1% LH contamination) at 10, 100 or 1000 ng significantly elevated concentrations of testosterone (T) within the testis. These effects were rapid, with peak values attained by 15 min, and transient, with return to values comparable to that in the contralateral, saline-injected testis within 90 min. Intratesticular injection of FSH (1 microgram) significantly increased testicular T levels in 15- and 60-day old mice. This contrasted with the effects of intratesticular administration of human chorionic gonadotropin (hCG), which stimulated T production significantly at 30 days of age through adulthood. In adult mice, the equivalent LH to the possible contamination in the FSH preparation (1 ng) had no effect. Intratesticular injection of 10 ng LH produced comparable stimulation to that by 100 ng FSH (approximately 7-fold). Systemic pre-treatment with a charcoal-treated porcine follicular fluid (PFF) extract for 2 days reduced plasma FSH levels [86 +/- 17 (5) vs 700 +/- 8 (6); P less than 0.05], but had no effect on plasma LH. Twenty-four hours after the last treatment, the response to intratesticular injection of hCG (2.5 mIU), FSH (100 ng) or LH (10 ng) was also significantly attenuated in these mice. Intratesticular injection of PFF had no direct effect on testicular T levels. In vitro T production in the presence of hCG, LH or FSH were differentially affected by the concentrations of calcium (Ca2+) or magnesium (Mg2+) in the incubation media. The stimulatory effects of FSH were apparent at significantly lower levels of Ca2+ or Mg2+, than were those of LH or hCG. The results of these studies indicate that FSH is capable of stimulating testicular T production. Furthermore, the responsiveness to FSH is qualitatively different than that to LH/hCG in terms of the age pattern, as well as the dependence on Ca2+ or Mg2+. In addition, plasma FSH levels appear to influence testicular responsiveness to direct exogenous administration of gonadotropins. These studies indicate that FSH stimulation of T production can be differentiated from those of LH, and that these effects of FSH can be observed under physiological conditions.

Perinatal cannabinoid exposure: effects on hepatic cytochrome P-450 and plasma protein levels in male mice.

Maternal exposure to the major psychoactive delta 9-tetrahydrocannabinol (THC), or to the nonpsychoactive cannabinol (CBN) or cannabidiol (CBD) on day 12 of gestation, or on day 1 postpartum, affected the concentrations of hepatic cytochromes P-450 in adult male offspring. Levels of P-450 were significantly increased in adult males prenatally exposed to cannabinoids, but were reduced after postnatal exposure. The response to exogenous testosterone was also differentially affected by perinatal cannabinoid exposure, with reduced plasma androgen in males prenatally exposed to THC, but increased levels of hormone in mice exposed postnatally to THC or CBN. There was a concomitant decrease in plasma albumin and increased gamma-globulin in adult males postnatally exposed to CBN. Beta-globulin levels were also significantly increased in adult males exposed to cannabichromene (CBC) on day 1 postpartum. Cannabinoid exposure during perinatal periods of development exert effects on hepatic function, plasma androgen levels, and on the immune system. These effects may reflect the ability of perinatal cannabinoid exposure to interfere with androgen-mediated processes of differentiation.

Effects of delta 9-tetrahydrocannabinol on testosterone production in vitro: influence of Ca++, Mg++ or glucose.

The major psychoactive component of marihuana, delta 9-tetrahydrocannabinol (THC), influences testicular function. In the present experiments, the addition of THC to incubations of whole decapsulated mouse testes altered testosterone (T) production differentially, depending on the specific gonadotropin used, the dose of THC and/or the amount of divalent cation present in the media. In the presence of luteinizing hormone (LH; 10 ng/ml), and a dose of 25 micrograms THC/ml, T production was significantly decreased, compared to that by testes incubated with LH and vehicle at all Ca++ levels, except at 0.127 or 1.0 mM Ca++. The production of T by these paired testes exposed to either THC or vehicle (ethanol; ETOH), increased as Ca++ concentration approached physiological levels. In contrast, in the presence of follicle-stimulating hormone (FSH; 1 microgram/ml), THC-induced suppression of T production was significant in the absence of Ca++ from the media, and at 12.7 mM Ca++. However, it appeared that the levels of Ca++ did not differentially affect T production in the presence of FSH, whether or not THC was also added. In the presence of human chorionic gonadotropin (hCG; 12.5 mIU/ml), a lower dose of THC (25 ng/ml), stimulated T production at 0.25 to 1 mM Ca++, but had no effect as Ca++ reached 2.5 mM. Without additional Ca++ in the media, this dose of THC significantly reduced T secretion. In contrast, in the presence of hCG, a higher THC dose (25 micrograms/ml), suppressed T accumulation at 0.127, and from 1.0 to 12.7, but had no effect at 0.25 mM, or in the absence of Ca++. In the presence of hCG, the high 25 micrograms/ml dose of THC stimulated T production, in the absence of additional Mg++, and at 0.01 mM Mg++, but THC had no effect at 0.1 mM Mg++, but inhibited T production at 1.1 mM Mg++. In the presence of hCG, 25 micrograms THC/ml produced a consistent suppression of T production across glucose concentrations examined. These findings suggest that the mechanisms by which THC effects testicular steroidogenesis may involve Ca++- and/or Mg++-dependent processes. Differential requirements for these divalent cations by the gonadotropins may explain the interactive effects of THC with LH, hCG or FSH.

Neonatal exposure to DES in BALB/c male mice: effects on pituitary-gonadal function.

Neonatal male BALB/c mice were injected with diethylstilbestrol (DES), estradiol benzoate (E2B), testosterone propionate (TP), progesterone or DES, in combination with E2B, TP or progesterone and examined in adulthood. Body weight was reduced in males exposed to DES, TP or DES + TP, while testicular weight was reduced in animals injected with DES, E2B, TP, DES + TP or DES + progesterone. Exposure to DES and/or E2B also produced reproductive tract abnormalities and concomitant progesterone exposure did not further affect this parameter. Concomitant DES did not further alter the reduced plasma luteinizing hormone (LH) levels attributable to neonatal TP or E2B treatment. Plasma follicle-stimulating hormone (FSH) levels in intact males were increased by DES, DES + progesterone or progesterone alone. Assessment of the feedback effects of exogenous gonadal steroids on pituitary gonadotropin release in castrated adults indicated that injection of 125 micrograms TP further increased the already elevated post-castration levels of LH and FSH in mice neonatally exposed to progesterone. The increase in testosterone (T) concentration after intratesticular human chorionic gonadotropin (hCG) administration was significantly attenuated in mice neonatally exposed to DES plus E2B or to progesterone. Basal testicular T levels were significantly elevated in males exposed to DES, alone, or in combination with progesterone. Exposure to DES and TP increased hypothalamic serotonin (5-HT) levels in intact mice, while levels of 5-HT were lower after castration compared to controls. DES + E2B-treated mice had higher norepinephrine (NE) levels, and E2B-treated mice also had higher 5-HT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of psychoactive and non-psychoactive cannabinoids on neuroendocrine and testicular responsiveness in mice.

Repeated oral administration of the non-psychoactive cannabinol (CBN; 5 or 50 mg/kg) significantly reduced the concentration of norepinephrine (NE) in median eminence and greatly reduced NE levels 1 and 2 hrs after administration of alpha-methylparatyrosine (alpha-MPT). The levels of dopamine (DA) in median eminence were significantly different, as indicated by the differences in slopes obtained in CBN- treated and control mice before and after alpha-MPT. Plasma levels of luteinizing hormone (LH) were significantly reduced in CBN-exposed mice before alpha-MPT, elevated at 1 hr post-injection, but were also reduced 2 hrs post-injection at 50 mg/kg CBN. Follicle-stimulating hormone (FSH) levels were increased at 1 hr post-alpha-MPT in mice receiving 50 mg/kg CBN. Oral administration of CBN at 50 mg/kg for 4 days enhanced testicular testosterone (T) production in response to intratesticular in vivo injection of 2.5 or 25 mIU human chorionic gonadotropin (hCG). A single oral dose of the psychoactive delta 9-tetrahydrocannabinol (THC) enhanced the production of T 15 min after intratesticular LH (10 ng) injection. However, at 45 or 60 min post-THC treatment, the response to LH was significantly attenuated. These studies demonstrate that both psychoactive and non-psychoactive components of marihuana alter testicular responsiveness to gonadotropins in vivo. These effects may be biphasic, involving stimulation and inhibition of responsiveness, and appear to be correlated with alterations in plasma LH levels. Alterations in plasma gonadotropins may be mediated by cannabinoid effects on catecholamine concentrations in median eminence and THC-induced alterations in testicular responsiveness to gonadotropin probably also involve direct effects of THC at the gonadal level.

Supersensitivity to norepinephrine induced by prenatal exposure to ethanol.

Pregnant random bred mice were treated with ethanol (ETOH) (0.33 g/kg) for 1 or 2 days prior to parturition. When compared to saline controls, ETOH-treated adult males had vasa deferentia that were supersensitive to norepinephrine (NE). Tissues from mice prenatally treated for 1 day with ETOH showed a decreased response to electrical stimulation whereas vas deferens obtained from 2-day-treated ethanol showed no significant difference in the response compared to that of controls. These findings indicate that prenatal exposure to ETOH can influence the subsequent sensitivity of the vas deferens to adrenergic stimulation. These changes appear to reflect effects of ETOH during critical periods.

Perinatal dopamine-related drugs demasculinize rats.

Administration of haloperidol, a common neuroleptic, to pregnant or lactating rats impaired the masculine sex behavior of their male offspring. Prenatal haloperidol did not affect testosterone concentrations in fetuses. Maternal administration of apomorphine, a dopamine agonist, and of alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, also demasculinized male offspring. In both experiments other behaviors and developmental milestones were unaffected. Perinatal haloperidol, apomorphine, and alpha-methyl-p-tyrosine did not lower testosterone in adulthood. These drugs may act directly on neurons that control masculine behavior without lowering testosterone prenatally or in adulthood.