Effects of sex and gonadectomy on cocaine metabolism in the rat.

The purpose of the current study is to determine whether sex differences in metabolism of cocaine (COC) exist that could contribute to the greater behavioral sensitivity of females to COC administration. To investigate this question, concentrations of COC and its two principle metabolites benzoylecgonine (BE) and ecgonine methyl ester (EME) were measured by gas chromatography/mass spectroscopy in brain and plasma collected from male and female rats that were sacrificed between 5 and 90 min after injection COC (15 mg/kg i.p.). COC concentrations did not differ in plasma or brain tissue of males and females, but sex-specific patterns of metabolite distribution were detected. BE was 2-fold higher in plasma and brain of males than females, whereas EME was much higher in brain and plasma of females. The influence of gonadal hormones on COC metabolite patterns were determined using gonadectomized and prepubertal rats. Castration of male or female rats did not alter brain or plasma COC, but did decrease BE concentrations. Seven-day-old pups injected with 15 mg/kg of COC had higher blood and brain COC than adults and relatively low levels of metabolites. No sex differences were found for COC, BE, or EME in brain or plasma of pups. These findings indicate that although gonadal steroids influence COC metabolism, these effects do not explain sex differences in COC-induced behaviors.

Ontogeny of the behavioral response to dopamine agonists after chronic cocaine.

The behavioral response to separate and combined administration of dopamine D1 and D2 receptor agonists was assessed acutely and after chronic cocaine exposure (30 mg/kg s.c. b.i.d. for 5 days) in infant (PND11) and weanling (PND20) rats. In infants, quinpirole (quin) and SKF-38393 (SKF) elevated locomotion, mouthing and sniffing acutely. Rearing was increased and mouthing decreased by decreased by combined administration. In weanlings, quin increased by locomotion, mouthing and sniffing in weanlings, while SKF increased only mouthing. SKF inhibited quin-induced rearing and locomotion. Infants treated chronically with cocaine showed sensitized quin- and quin/SKF-induced locomotion and quin/SKF stimulated rearing and sniffing. In weanlings, locomotion was sensitized with all drug combinations, and rearing with SKF alone. These results indicate a developmental progression in the psychopharmacological response to dopamine receptor stimulation. While both D1 and D2 receptors are active in infants, the full complement of acute responses and complete capacity for sensitization develop later.

Age-related differences in the chronic and acute response to cocaine in the rat.

Behavioral sensitization is known to occur in adult animals after the chronic intermittent administration of cocaine. Dopaminergic pathways in the brain, such as the nigrostriatal and mesoaccumbens projections play a vital role in this phenomenon. These pathways are rudimentary in the 1st week of life, indicating that the developing animal may be unable to respond to cocaine in the same manner as an adult. In the present study, we report that the acute response to cocaine is remarkably similar between week-old and adult rats. Pups do not, however, show locomotor sensitization to acute cocaine after chronic cocaine-administration as adults.

Isolation and purification of glutathione S-transferases from Brachionus plicatilis and B. calyciflorus (Rotifera).

1. The enzyme glutathione S-transferase (GST), a critical element in xenobiotic metabolism, was isolated from the marine rotifer Brachionus plicatilis and its freshwater congener B. calyciflorus. 2. In B. plicatilis, GST comprised 4.2% of cytosolic protein and was present as three separate isozymes with mol. wts 30,000, 31,400 and 33,700. Specific activity of crude homogenates was 56 nmol min-1 mg-1 protein, while that of affinity chromatography purified GST was 1850. 3. In B. calyciflorus, GST was present as two isozymes with mol. wts of 26,300 and 28,500, representing 1.0% of cytosolic protein. Crude GST specific activity was 1750 nmol min-1 mg-1 protein and purified was 72,400. 4. Rotifer GSTs are unusual because they are monomers whereas all other animals thus far investigated posses dimeric GSTs.