Justin M. Joffe

Increased neonatal mortality in offspring of male rats treated with methadone or morphine before mating

METHADONE ((±)-4, 4-diphenyl-6-dimethylamino-3-heptanone hydrochloride) is a potent (addictive) analgesic with pharmacological effects which are qualitatively similar to those of morphine, although it is far more effective than morphine when given orally. Its ability to diminish the severity of the abstinence syndrome resulting from heroin withdrawal led to the introduction of methadone in the chemotherapy of narcotic addiction1–3. Little is known, however, about its long term toxicity effects. We report that treatment of male rats with either (±)-methadone HCl (METH) or morphine sulphate (MS), given orally, for 24 h before mating to untreated females increases the neonatal (21-d) mortality of their offspring.

Lethal and sublethal effects on the progeny of male rats treated with methadone

Fifteen male rats were treated with methadone-HCl (Meth) at 10 mg/kg sc per day for 12 days and an equal number received injections of sterile distilled water. Each male was caged with four untreated females each night. A necropsy was performed on male rats following the period of mating and the litter sizes, birth and weaning weights, and survival to 21 days (neonatal mortality) of their progeny were evaluated. METH-treated males had a reduction in body and seminal vesicle weights and in mating frequency, confirming prior studies. Progeny of METH-treated males (507 pups) were of lower average birth weight than the 276 controls. In addition, it was found that prior copulation had a differential effect, resulting in slightly heavier control pups but significantly decreased birth weights in the METH group. Neonatal mortality of the METH progeny was significantly increased, with 18.2% dead by 21 days compared to 9.5% of the controls (p < 0.01). The present data indicated that mortality was related in a complex fashion to number of drug exposures and previous sexual experience of the sire and that male offspring were particularly affected. Ponderal growth of survivors from litters with high neonatal death rates was inhibited, with females being significantly lighter at 75 and 132 days of age. Open-field defecation scores were significantly different at 2 but not at 4 months of age, but no differences in acquisition of a conditioned avoidance response were noted. No differences in litter size, neonatal mortality, or birth or weaning weights as a result of METH administration were found in the F2 generation. These results, together with previous data from our laboratory, establish that there are lethal, sublethal, and possibly delayed effects on the progeny of male rats treated with methadone.

Modification of prenatal stress effects in rats by adrenalectomy, dexamethasone and chlorpromazine

This study was designed as a 4 (maternal treatments) by 2 (prenatal stress) factorial. The 4 treatment groups were: chlorpromazine (CPZ) 2.1 mg/kg; dexamethasone (DEX) 38.7 mug/kg; adrenalectomy (ADX); and controls (CON). Half of the females in each group were stressed prior to mating and during gestation. Stress significantly reduced birth and weaning weights of CON offspring but did not affect the weight of CPZ, DEX or ADX offspring. At birth, DEX and ADX offsrping, as well as offspring of partially adrenalectomized females, were significantly lighter than controls; at weaning, only the DEX animals displayed a weight deficit. Stress increased open field activity of ADX offspring but decreased the activity of DEX offspring while the performance of CON and CPZ offspring was not affected. In a food deprivation test at 42 days there were significantly more deaths among male offspring of no stress (32 percent) than of stress (4 percent) females and stress offspring in all groups lost less weight than unstressed offspring in a food deprivation test at 69 days. Avoidance conditioning tests showed effects only in female offspring. Stress significantly decreased avoidances made by CON offspring and increased avoidances made by DEX offspring. Treatment with ADX, CPZ or DEX can prevent the effects of prenatal stress on some characteristics of the offspring, but in other cases the effects are potentiated by these manipulations.

Effects of adrenalectomy on open-field behavior in rats

Abstract Two experiments investigated the effects of adrenalectomy (Adx) on open-field defecation and activity in Long-Evans hooded rats. In the first it was found that Adx females defecated significantly more than unoperated controls. In Expt 2 both males and females were included, as well as the appropriate sham-operated groups. Adrenalectomy significantly increased defecation in both sexes as compared to either sham-operated or intact controls. The significantly lower home-cage defecation of Adx groups appears to rule out a general increase in defecation as an explanation of this effect. Adx rats were also significantly less active than controls on Days 3 and 4 of testing as a result of a greater drop in activity over the four days of testing. The defecation scores and activity pattern displayed by Adx animals is characteristic of more “emotional” rats.

Modification of prenatal stress effects in rats by dexamethasone and adrenocorticotrophin

Abstract To determine if effects of prenatal stress on offspring are mediated by the maternal pituitary-adrenocortical (PAC) system, female rats were stressed during gestation while manipulating their PAC output and the growth and behavior of their offspring examined. Specifically, females were injected with ACTH, dexamethasone (DEX), or saline (SAL) during pregnancy or were untreated (CON). Half the females in each group received daily electric shock sessions from Day 7 to Day 21 of gestation. Significantly more females in the ACTH and SAL groups delivered their litters late. Although DEX produced a significant reduction in birth and weaning weights of offspring whereas ACTH did not, both DEX and ACTH blocked the increase in birth weights produced by prenatal stress in offspring of SAL treated females. However, the significant effect of stress on mortality from birth to weaning was potentiated by ACTH and mortality was increased by either DEX or ACTH alone (compared to SAL). In addition, ACTH reversed the effect of stress on open-field activity of 86–96 day old offspring: stress reduced activity of SAL offspring but increased that of ACTH offspring. DEX itself significantly increased activity of female, but not male, offspring and ACTH significantly decreased activity of unstressed offspring of both sexes. Open-field behavior of 32–38 day offspring and active and passive avoidance conditioning of 86–96 day offspring were unaffected by prenatal drug or stress treatments. Attenuation of the maternal PAC response to stress consistently blocks the effects of prenatal stress on birth weights of offspring but can potentiate, reverse, or fail to modify the effects of stress on behavior. It thus seems unlikely that prenatal stress effects on offspring behavior are mediated by the maternal PAC system.

Chronic methadone administration to male rats: Tolerance to adverse effects on sires and their progeny

Previous studies have shown that acute administration of methadone to male rats prior to mating results in adverse effects on their progeny, particularly decreased birth weights and increased neonatal mortality. Rather than chronic administration accentuating these effects, results of the present study indicate that tolerance developed so that no adverse effects were found in offspring sired after 21--32 days of methadone administration. In the sire, maintenance of normal weights of accessory sex glands after 4 months of daily methadone suggests that tolerance developed to the CNS effect(s) responsible for the depressed serum LH and testosterone levels found after acute administration of narcotics. In contrast, tolerance did not develop to the inhibition of weight gain produced by methadone administration. No evidence for a dominant lethal effect could be found after chronic methadone administration, in contrast to suggestive evidence for this effect found in previous experiments after acute methadone administration.

Sex difference in the effect of dexamethasone on open-field behavior in rats: Gonadal hormones ☆

A study was undertaken to determine whether or not the sex differences in the effect of dexamethasone (DEX) on open-field defecation depended on the difference in circulating gonadal hormones in normal male and female rats. The experiment involved ovariectomized females, ovariectomized females given supplementary male hormones, and sham-operated females. In comparison to control groups, all the DEX-treated groups showed a suppression of plasma corticosterone levels, a decrease in weight levels, and reduced adrenal weights. Open-field defecation increased in the DEX-treated female rats but open-field activity was not affected. No differences in behavior or physiological changes were evident between the 3 differently treated groups. These results indicate that sex differences in the response of open-field defecation to DEX-treatment is not the result of sex differences in circulating sex hormones. The response may spring from the organizing effects of the gonadal hormones during the perinatal stage rather than the activating effect of gonadal hormones during adulthood.

Looking for the Causes of the Causes

In the context of research on adverse developmental outcomes it is argued that focusing on the factors correlated with such outcomes—the “causes of the causes”—is likely to suggest more effective approaches to prevention, than focusing on proximate causes of such outcomes. Some reasons are suggested as to why we shy away from the implication that social change will often be needed for effective prevention.

Effects of prenatal stress procedures on maternal corticosterone levels and behavior during gestation

Exposing pregnant rats to a signal previously paired with electric shock has frequently been used to examine the effects of prenatal stress on their offspring. To determine to what extent this procedure affects the females themselves, their defecation in the shuttlebox and plasma corticosterone levels in their home cages or after shuttlebox exposure were measured. Defecation was significantly more frequent in females that had received premating avoidance conditioning only on the first 2 days of gestation. There were no indications that avoidance conditioning before mating affected plasma corticosterone levels of rats in their home cages or following reexposure to the shuttleboxes or their response to the stress of the first blood sample. Levels were raised in all groups placed in the boxes, whether they had received avoidance conditioning or only CS exposures before mating. Implications for hypotheses concerning the way in which prenatal stress effects are mediated are discussed.

You'd Have to Be Sick Not to Be Crazy

Stress can cause a variety of biological and psychological alterations in an organism, including behaviors and neurological changes that are characteristic of certain “mental illnesses.” Many stress-related disorders (e.g., cardiovascular damage, ulceration, and neuronal degeneration) occur when an organisms natural response to stress continues for an extended period of time, often due to the prolonged duration of the stressful event itself. It is during this time that stress-related disorders occur. Those prolonged stressors are more likely to occur in some populations in others—a primary example is the stressors that accompany lower SES. We propose that, similar to other stress-induced changes, many “mental illness” are normal responses to stressful situations.