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Abstract: Many studies have shown that developmental cocaine exposure alters brain function and behavior; the present study examined the relationship between brain metabolism and behavioral responses to drug challenge. SKF 82958, a selective D1 dopamine agonist, was administered to preweaning cocaine-exposed (50 mg/kg/day) rats and controls at 60 days of age. Deoxyglucose was administered 30 min later, during the peak behavioral response, to measure brain functional activity Pearson product-moment correlations of behavior (locomotor activity and Stereotypic behavior) with rates of glucose metabolism in components of the nigrostriatal and mesolimbic circuits were analyzed. The analysis revealed that under saline-challenge conditions in control animals, rates of metabolism in mesolimbic regions are positively correlated to rates of locomotor activity, whereas in cocaine-treated rats, these correlations were absent. Following SKF challenge, a different pattern was seen; locomotor activity or Stereotypic behavior was not correlated with mesolimbic or nigrostriatal metabolism, respectively,in controls but was positively correlatedin cocaine-treatedrats. Therefore, cocaine exposure during development enhances the coupling of metabolism in components of the mesolimbic and nigrostriatal dopamine systems with the behavioral output associated with these systems under drug-challenge conditions. This may be due to loss of inhibitory influences within the mesolimbic and nigrostriatal systems. Thus, the correlation of behavior and cerebral glucose metabolism provides a unique way of examining the effect of developmental cocaine exposure.

The distribution of 3'-azido-3'-deoxythymidine (AZT, zidovudine), an antiviral drug used in the treatment of human immunodeficiency virus, was investigated in gestation day-20 (G-20) fetuses and in postnatal day-20 (PND-20) rats. At both ages, a single dose of 150 mg/kg (1.78 mmol/kg) AZT was administered orally along with tracer amounts of ¹⁴C-AZT, and rats were randomly killed at 15, 30, 60, 120, or 240 min after dosing. The fetuses, brains, and spinal cords were processed for autoradiography. The peak concentrations of AZT in plasma of G-20 and PND-20 rats were 92.2 μg/mL (0.345 μmol/mL) and 56.6 μg/mL (0.21 μmol/mL) at 15 and 30 min after intubation, respectively. The peak concentration of fetal tissue occurred in the colon at 60 min and was 205.8 μg/g tissue. In the G-20 rats, the brain showed higher levels of AZT than spinal cord only at the 30-min sample time, whereas in the PND-20 rats, greater radioactivity was found in the spinal cord up to the 240-min sample time. This pattern of AZT distribution in the central nervous system may hypothetically be attributed to the postnatal development of an organic anion carrier system believed to be responsible for transporting AZT from the brain to the blood, resulting in relatively greater overall exposure of the spinal cord to AZT than observed in the brain. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1964–1971, 2001

The distribution of 3′‐azido‐3′‐deoxythymidine (AZT, zidovudine), an antiviral drug used in the treatment of human immunodeficiency virus, was investigated in gestation day‐20 (G‐20) fetuses and in postnatal day‐20 (PND‐20) rats. At both ages, a single dose of 150 mg/kg (1.78 mmol/kg) AZT was administered orally along with tracer amounts of 14C‐AZT, and rats were randomly killed at 15, 30, 60, 120, or 240 min after dosing. The fetuses, brains, and spinal cords were processed for autoradiography. The peak concentrations of AZT in plasma of G‐20 and PND‐20 rats were 92.2 μg/mL (0.345 μmol/mL) and 56.6 μg/mL (0.21 μmol/mL) at 15 and 30 min after intubation, respectively. The peak concentration of fetal tissue occurred in the colon at 60 min and was 205.8 μg/g tissue. In the G‐20 rats, the brain showed higher levels of AZT than spinal cord only at the 30‐min sample time, whereas in the PND‐20 rats, greater radioactivity was found in the spinal cord up to the 240‐min sample time. This pattern of AZT distribution in the central nervous system may hypothetically be attributed to the postnatal development of an organic anion carrier system believed to be responsible for transporting AZT from the brain to the blood, resulting in relatively greater overall exposure of the spinal cord to AZT than observed in the brain. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1964–1971, 2001

Protein kinase C (PKC) is a multigene family of at least ten isoforms, nine of which are expressed in brain (α, βI, βII, γ, δ, ϵ, η, ζ, ι/λ). Our previous studies have shown that many of these PKCs participate in synaptic plasticity in the CA1 region of the hippocampus. Multiple isoforms are transiently activated in the induction phase of long‐term potentiation (LTP). In contrast, a single species, ζ, is persistently activated during the maintenance phase of LTP through the formation of an independent, constitutively active catalytic domain, protein kinase Mζ (PKMζ). In this study, we used immunoblot and immunocytochemical techniques with isoform‐specific antisera to examine the distribution of the complete family of PKC isozymes and PKMζ in rat brain. Each form of PKC showed a widespread distribution in the brain with a distinct regional pattern of high and low levels of expression. PKMζ, the predominant form of PKM in brain, had high levels in hippocampus, frontal and occipital cortex, striatum, and hypothalamus. In the hippocampus, each isoform was expressed in a characteristic pattern, with ζ prominent in the CA1 stratum radiatum. These results suggest that the compartmentalization of PKC isoforms in neurons may contribute to their function, with the location of PKMζ prominent in areas notable for long‐term synaptic plasticity. J. Comp. Neurol. 426:243–258, 2000. © 2000 Wiley‐Liss, Inc.

This study investigated whether exposure to cocaine during the postnatal period affects the acoustic startle response (ASR) following administration of the serotonin (5-HT) agonists, 8-OH-DPAT and mCPP, in adulthood. To test the hypothesis that alterations in reactivity may be due to cocaine's effects at the 5-HT carrier, another group of rats was given fluoxetine, a specific 5-HT uptake inhibitor, during the same postnatal period and tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg/day cocaine HCl, fluoxetine HCl, or vehicle SC during postnatal days 11–20. At 75 days of age, subjects were ASR tested for 30 min on 2 consecutive days. On the first test day, there was a significant effect of treatment and gender with post hoc analysis indicating that, overall, the males were more reactive than the females and that the fluoxetine-treated males showed a pattern of reactivity resembling sensitization. On the second test day, subjects received a dose of the 5-HT1A agonist 8-OH-DPAT, the 5-HT1B2C agonist, mCPP, or saline prior to being placed in the startle chamber. Cocaine-exposed males showed an enhanced response to 8-OH-DPAT and a reduction in the depression produced by mCPP administration compared to their response to saline. Fluoxetine exposed males showed a significant increase in startle response following saline administration compared to the rats receiving vehicle during the postnatal period and 8-OH-DPAT produced an insignificant enhancement of that startle response. mCPP reduced startle in fluoxetine-treated males as it did in the postnatal vehicle-treated controls. In females, the postnatal cocaine and fluoxetine treatments did not alter the response to 8-OH-DPAT or mCPP compared to females receiving vehicle during the postnatal period. Together these data indicate that, in males, whereas postnatal cocaine alters the development of the 5-HT system as evidenced by an altered startle response to 5-HT agonists, cocaine does not produce the same alteration as that produced by the administration of a specific 5-HT uptake inhibitor during the same period of development.

APPLEWHITE-BLACK, L. E., D. L. DOW-EDWARDS AND H. L. MINKOFF. Neurobehavioral and pregnancy effects of prenatal zidovudine exposure in Sprague–Dawley rats: Preliminary findings. NEUROTOXICOL TERATOL 20(3)251–258, 1998.—In 1994, the Public Health Service made prenatal zidovudine (ZDV, AZT) the standard of care to prevent mother-to-child transmission of HIV. The current study was undertaken to determine if prenatal exposure to ZDV has an impact on pregnancy outcomes, birth anomalies, or offspring behavior in an animal model using Sprague–Dawley (SD) rats. Thirty-one virgin female SD rats were mated and randomly assigned to receive either ZDV at 150 mg/kg/day or vehicle via gastric intubation for 22 days starting on gestation day (G) 1. On G 22, teratologic examination of 12 litters showed no gross structural malformations. There were no significant differences between the groups for maternal food and water consumption or maternal weight gain across pregnancy. However, ZDV treatment significantly reduced litter size and increased birth weights for both male and female pups. One developmental milestone, pinna detachment, occurred significantly earlier in the ZDV-exposed male pups compared to the vehicle-intubated male controls. On day 21–22 of life, pups in each litter were injected with one of four doses of amphetamine and were observed for behavioral activity in a photobeam-based activity monitor for 1 h. Overall amphetamine increased activity and decreased thigmotaxis or wall-hugging behavior. ZDV treatment increased the locomotor response to amphetamine in females only and dampened the action of amphetamine to decrease thigmotaxis in both genders. Further studies are warranted to determine the threshold dose at which these changes occur, the duration of the effects, as well as the neurochemical system(s) responsible for the altered amphetamine responses.

Studies involving body fluid homeostasis were carried out in adult Long-Evans rats whose mothers received liquid diets containing 35% of the calories derived from ethanol between the 6th and the 20th day of gestation. Control rats were offspring of pair-fed dams given isocaloric liquid diets containing no ethanol. Plasma levels of arginine vasopressin (AVP), plasma osmolality, urine production and urine osmolality were determined in both the water-sated (WS) and water-deprived (WD) conditions. Fetal alcohol exposure (FAE) induced a seven-fold increase in plasma AVP levels in the WS condition. Water consumption was significantly greater in the FAE animals but plasma osmolality, urine osmolality, and urine production were within the normal range. In the control rats, 24 hours of WD produced the expected increase in plasma AVP, plasma and urine osmolality. The FAE rats, however, showed only an increase in plasma osmolality and no significant change in plasma AVP or urine osmolality with WD.These data suggest that fetal alcohol exposure causes a long-term disruption in the central mechanisms regulating vasopressin release and therefore fluid homeostatic responses.