Effects of prenatal cocaine on hearing, vision, growth, and behavior.

The illicit use of cocaine has increased dramatically over the last 10-12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of "cocaine babies." According to some estimates, these children make up more than half of the drug-associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre- and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.

Effects of prenatal alcohol exposure and aging on auditory function in the rat: preliminary results.

This study investigated select aspects of peripheral and central auditory dysfunction, as well as the pathological effects of aging, In an animal model of fetal alcohol syndrome (FAS). Pregnant rats consumed liquid alcohol diets containing 0, 17.5, or 35% ethanol-derived calories, from gestation day 7 to parturition. A fourth group was untreated. Offspring of these mothers were tested for auditory and neurological function, using the auditory brainstem response at 6, 12, and 18 months of age. Some animals in the alcohol-exposed groups showed a peripheral auditory disorder in the form of congenital sensorineural hearing loss. This was correlated with punctate lesions and malformed stereocilia on the auditory sensory receptor cells of the inner ear. Alcohol-exposed animals also showed a central auditory processing disorder characterized by prolonged transmission of neural potentials along the brainstem portion of the auditory pathway. Animals in the highest dose group also showed an augmentation in the age-related deterioration of auditory acuity. Thus, increased peripheral and central auditory dysfunctions and pathological deterioration of auditory function in old age may be sequelae of FAS. Such morbidities have important implications for the long-term clinical assessment and management of FAS patients.

Effects of tone burst frequency and intensity on the auditory brainstem response (ABR) from albino and pigmented rats.

Young adult male Sprague-Dawley (SD) and Long-Evans (LE) rats were evaluated using the auditory brainstem response (ABR). ABRs were evoked by stimuli with intensities ranging from 15 to 100 dB peSPL. Stimuli were tone bursts of 2000, 4000 and 8000 Hz. As stimulus intensity decreased from 100 to 15 dB, the ABR peak latencies prolonged, interpeak latencies (IPLs) shortened and amplitudes decreased. As stimulus frequency decreased from 8000 to 2000 Hz, ABR latencies prolonged, amplitudes decreased and ABR thresholds increased. The longest IPLs were in response to the 4000 Hz tone bursts. SD rats had ABRs with shorter peak latencies, larger amplitudes and lower thresholds than LE rats. The IPLs usually did not show significant strain-dependent differences. Our observations on stimulus intensity and frequency are consistent with previous reports. Our observations also suggest that the SD (albino) rat has better auditory acuity than the LE (pigmented) rat over the frequency range of 2000 to 8000 Hz. This implies that previous concerns about the use of albino animals in audiological research are somewhat overstated.

Interactive effects of prenatal alcohol and cocaine exposures on postnatal mortality, development and behavior in the Long-Evans rat.

Polydrug abuse has increased substantially in recent years amongst obstetric patients. One of the most common drug combinations is alcohol and cocaine. To better understand the adverse consequences of this drug combination on pregnancy and the offspring, alcohol (2 g/kg, b.i.d.) and cocaine HCl (30 mg/kg, b.i.d.) were administered individually and in combination to separate groups of pregnant Long-Evans rats from gestation days 7-20. The pregnant dams were evaluated for maternal weight gain, food and water consumption, mortality, and gestational length. The offspring were evaluated for physical maturation, mortality, and behavior. The drug combination was found to have greater effects regarding decreased birth weight, increased postnatal mortality, and delayed physical maturation than either drug alone. Drug treatments also influenced activity monitor behavior in that prenatal cocaine exposure was associated with hypoactivity while the alcohol and the alcohol-plus-cocaine treatments were associated with hyperactivity in periweanling pups. Drug treatments had no significant effects on passive or active avoidance behaviors. These results suggest that combining alcohol and cocaine increases the risk to the offspring.

Sensorineural hearing loss as evidenced by the auditory brainstem response following prenatal cocaine exposure in the Long-Evans rat.

Prenatal cocaine exposure has been associated with a variety of adverse neurological effects. Three recent studies found evidence that prenatal cocaine exposure is associated with abnormal auditory electrophysiology, suggesting abnormal processing of auditory information. The present study used the auditory brainstem response to evaluate the effects of prenatal cocaine exposure on hearing in an animal model (Long-Evans rat). We report that prenatal cocaine exposure can cause elevated ABR thresholds and latency-intensity curves consistent with a recruitment-type sensorineural hearing loss.

Prenatal cocaine exposure in the Long-Evans rat: I. Dose-dependent effects on gestation, mortality, and postnatal maturation.

Pregnant Long-Evans rats were injected daily with 40, 60, 80, or 100 mg/kg cocaine HCl (SC, 2% solution) from gestational days 7-20 (sperm positive = day 0). Daily doses were split evenly with half given between 9:00-10:00 a.m. and half between 3:00-4:00 p.m. An ad lib-fed group as well as nutritional control groups that were pair-fed to the 80 and 100 mg/kg cocaine dams were also evaluated (N = 11-18 liters/group). Cocaine had no effect on gestational length but did cause dose-dependent decreases in maternal food consumption and weight gain and increases in maternal mortality. Interestingly, cocaine-treated dams shows a significant increase in water consumption. In terms of offspring variables, there was a dose-dependent decrease in birth weight and postnatal weight gain in both the cocaine and pair-fed groups. There were also dose-dependent effects on litter size, stillbirths and postnatal mortality in the cocaine-treated groups as compared to the control groups. High dose cocaine treatment caused delays in several indices of physical maturation (pinna detachment, fur growth, ear opening, eye opening, vaginal opening) but not in others (incisor eruption, testicular descent). Physical anomalies and postnatal morbidity, while uncommon, were observed in animals prenatally exposed to the higher cocaine doses. Collectively, these data suggest that prenatal cocaine exposure can increase postnatal morbidity as well as increase pre-and postnatal mortality in animal offspring.

Prenatal cocaine exposure in the Long-Evans rat: II. Dose-dependent effects on offspring behavior.

Pregnant Long-Evans rats were injected daily with 40, 60, 80 or 100 mg/kg cocaine HCl (SC, 2% solution) from gestational days 7-20 (sperm positive = day 0). Daily doses were split with half given between 9:00-10:00 a.m. and half between 3:00-4:00 p.m. An ad lib-fed group as well as nutritional control groups that were pair-fed to the 80 and 100 mg/kg cocaine dams were also evaluated (N = 11-18 litters/group). The negative geotactic reaction of the offspring, evaluated from day 2-14 (birth = day 0), showed no group differences. Spontaneous alternation behavior in a T-maze showed no evidence of perseveration in any group on either day 21 or day 80. Most cocaine-treated offspring showed an altered preference in turning right versus left on day 21. Activity monitor behavior showed that the cocaine-treated and pair-fed offspring were hypoactive on day 20. Some degree of hypoactivity was still evident on day 49, but absent on day 80. The passive avoidance behavior of day 19 offspring showed no group differences in acquisition of task learning. The 100 mg/kg cocaine offspring did show significantly poorer retention of task learning 48 hr later. On day 80, no group differences were seen in passive avoidance behavior. Acquisition of an active avoidance behavior on day 80 was significantly poorer in the 100 mg/kg cocaine group.

Prenatal cocaine exposure in the Long-Evans rat: III. Developmental effects on the brainstem auditory-evoked potential.

Prenatal cocaine exposure has been associated with a variety of adverse neurological effects in infants and laboratory animals. Of particular interest, one group of investigators reported that exposed neonates have an abnormality in the brainstem auditory-evoked potential (BAEP). The particular abnormality, a prolongation in the wave I-V interpeak latency, suggested delayed or desynchronized transmission of subcortical auditory information. To further investigate this possible consequence of prenatal cocaine exposure, pregnant Long-Evans rats were injected daily with 60, 80 or 100 mg/kg cocaine HCl (SC, 2% solution) with half the daily dose given in the morning and the other half given in the afternoon. Treatment was given from gestation days 7 to 20 (sperm positive = GD 0). Ad lib-fed and pair-fed control groups were also used. Offspring were evaluated at the age of 35 days (birth = PD 0) and as adults (6-10 months). BAEPs were elicited by click stimuli presented over a broad range of intensities and repetition rates. Prolongation of the interpeak latencies and a reduction in BAEP amplitudes were observed only in the highest dose (C100) group, only at the age of 35 days, and only at the highest stimulus intensity. While these results support those found in exposed neonates, our data suggest a) that the effects are developmental delays which dissipate with aging and b) that the effects require high cocaine exposure.

An improved microelectrode resistance meter.

A device is described for measuring the resistance of micropipette electrodes. The useful range of electrode resistances that it can measure is 100 k omega to 1 G omega. It is more convenient to use than previously described or commercially available meters, especially for very high-resistance electrodes. Resistance of even the finest microelectrodes can be measured accurately while their tips are inserted by hand into a test solution. This eliminates the need for special holders, speeding and simplifying the screening of large numbers of electrodes. Test solutions are stored in interchangeable reservoirs, making it easy to characterize the resistance of an electrode in solutions of different resistivity. Test solutions can also be capped and removed when not in use to prevent evaporation. To protect very high-resistance electrodes from damage during measurement, the measuring current is low (only 300 pA on the highest resistance range) and the test voltage across the electrode is limited to +/- 1 V.