The 5-HT1A agonist 8-OH-DPAT increases attachment maintenance but decreases suckling-related intake in 17-18-day-old rat pups.

Deprived and nondeprived preweanling (17-18 days of age) Sprague-Dawley rat pups were injected with 0, 0.03, 0.06, 0.1, or 0.5 mg/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and observed in a suckling test using a milk replete anesthetized dam, with milk let-downs being intermittently precipitated via IV infusions of oxytocin. In experiment 1, the 0.5 mg/kg dose of 8-OH-DPAT was observed to increase the proportion of nondeprived animals which attached to a nipple; no dose effect was seen in deprived animals, who generally all attached. Deprived pups given the 0.5-mg/kg dose exhibited a lower frequency of nipple disattachment/reattachment following milk let-downs and had significantly lower percent body weight gains when compared with saline controls. In experiment 2a, the 0.5-mg/kg dose of 8-OH-DPAT was observed to decrease the overall incidence of nipple disattachment/reattachment as well as to suppress nipple shifting per se in both deprived and nondeprived 17-18-day-old rat pups; this dose also suppressed body weight gains in both the deprived and nondeprived pups. The suppression in weight gain by 8-OH-DPAT does not appear to be primarily related to a drug-induced reduction in nipple shifting. In experiment 2b, where pups were given access to only one nipple, an 8-OH-DPAT-related reduction in body weight gain was still evident. These experiments, which demonstrate that attachment maintenance and suckling ingestion are altered in opposite ways by 8-OH-DPAT, provide strong evidence that these two suckling-related phenomena are subject to different physiological controls.

Psychopharmacological responsiveness to the dopamine agonist quinpirole in normal weanlings and in weanling offspring exposed gestationally to cocaine.

The behavioral responsiveness to challenge doses of the D2 agonist quinpirole was examined in 21-day-old normal offspring (experiment 1) as well as offspring exposed gestationally to cocaine (experiment 2). In both experiments weanling rats received a subcutaneous injection of 0 (0.9% saline), 0.04, 0.08, 0.5, or 1.0 mg/kg/3 cc of the D2 agonist quinpirole and were placed in a divided glass testing apparatus containing either a dish of wet mash plus a food pellet or wood block (experiment 1) or both a food pellet and a wood block (experiment 2). Behaviors were recorded for 5 min via time-sampling at 30 and 60 min post-injection. In experiment 1 the three highest doses of quinpirole increased the amount of forward locomotion, rearing, sniffing and probing, as well as increasing directed oral movements at both the wood block and food pellet; in general these findings are reminiscent of those reported previously in adult animals. In experiment 2, cocaine-exposed weanlings exhibited an increased sensitivity to the stimulating effects of a low dose of the D2 agonist for forward locomotion and rearing as well as an increase in the overall incidence of sniffing behavior and chewing on food pellets. These data provide psychopharmacological evidence that the increase in striatal D2 binding previously observed in weanling offspring exposed gestationally to cocaine (Scalzo et al. 1990) may be associated with an increased behavioral sensitivity to the D2 agonist quinpirole.

Low doses of the 5-HT1A receptor agonist 8-OH-DPAT increase ingestive behavior in late preweanling and postweanling, but not neonatal rat pups.

Late preweanling (postnatal day 17-18; P17-18) and postweanling (P28-29) Sprague-Dawley rat pups were tested in the presence of both mash and liquid diets following s.c. administration of 0, 0.03, 0.06, 0.1 or 0.5 mg/kg of the 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT). Preweanling pups exhibited both a low dose stimulatory and high dose depressant effect of 8-OH-DPAT on mash-related ingestive behaviors, whereas postweanling rat pups were less sensitive to 8-OH-DPAT, exhibiting only an increase in mash ingestion within the dose range examined. In contrast, when neonatal (P3-4) rat pups were tested with milk across a dose range of 0.001-1.0 mg/kg 8-OH-DPAT, no increases in ingestion were seen, with lower doses in this range having no detectable effects and higher doses decreasing ingestion and mouthing. To the extent that low doses of 8-OH-DPAT increase feeding via preferential stimulation of 5-HT1A autoreceptors, these data suggest that neonates may lack functional 5-HT1A autoreceptors, with these receptors maturing by the late preweanling period.

Weanling rats exposed prenatally to cocaine exhibit an increase in striatal D2 dopamine binding associated with an increase in ligand affinity.

Prenatal exposure to cocaine can result in abnormal neurobehavioral development. This study found an increase in D2 dopamine receptor binding, associated with an increase in ligand affinity, in striatum of weanling rats exposed prenatally to cocaine. There were no changes in D2 receptor binding in nucleus accumbens nor D1 receptor binding in either striatum or nucleus accumbens. Alterations in D2 dopamine receptors may be associated with neurobehavioral alterations following prenatal cocaine exposure.

5-HT1A, 5-HT1B and 5-HT2 receptor agonists induce differential behavioral responses in preweanling rat pups.

Preweanling (postnatal day 17-18) Sprague-Dawley rat pups were tested in both the absence and presence of milk following administration of various doses of the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or ipsapirone, the 5-HT1B agonist 1-(3-chlorophenyl)piperazine (mCPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI). 8-OH-DPAT decreased mouthing while ipsapirone, mCPP and DOI had no effect upon this behavior. However, all four agonists significantly decreased grooming. Both 8-OH-DPAT and mCPP produced alterations in limb positioning, with 8-OH-DPAT administration resulting in a poor control of the hindlimbs and mCPP inducing a hindlimb straddle position. These functional responses to 5-HT1A, 5-HT1B and 5-HT2 agonists in preweanling pups vary from those observed previously in neonates. For instance, whereas inhibitory effects of 5-HT1A stimulation on mouthing are observed in both neonatal and preweanling pups, facilitory effects of 5-HT1B and 5-HT2 stimulation are only seen in neonates. These ontogenetic alterations may be related to the previously reported ontogenetic reversal in the effect of serotonergic activation upon mouthing and suckling that occurs during the neonatal to weanling age period.

Fetal and maternal brain and plasma levels of cocaine and benzoylecgonine following chronic subcutaneous administration of cocaine during gestation in rats.

The distribution of cocaine and the cocaine metabolite benzoylecgonine (BE) in brain and plasma of Sprague-Dawley rat dams and their near-term fetuses was assessed 0.5 and 2 h post-injection on gestational day 20 following chronic daily subcutaneous injections of 10, 20, or 40 mg/kg/3 ml cocaine hydrochloride beginning on gestational day 8. Plasma concentrations of cocaine reached in the dams were found to be in the range of, or to exceed, those reported in human cocaine users. Dose-related increases in plasma and brain levels of cocaine in the dams and the fetuses were observed, particularly at 2 h post-injection. Fetal concentrations of cocaine in brain and plasma were approximately 2-3-fold less than those of the dams, suggesting that the placenta may somewhat restrict cocaine entry into fetal circulation. Brain/plasma cocaine ratios, however, were generally equivalent in the dams and fetuses, suggesting that once cocaine enters the circulation, its affinity for brain tissue is similar in the fetus and dam. Whereas plasma levels of BE, like cocaine levels per se, were greater in the dams than fetuses, BE concentrations in fetal brain were greater than those observed in maternal brain. These high levels of BE may contribute to the production of neurobehavioral alterations in cocaine-exposed offspring, given that this active cocaine metabolite has been shown to form molecular complexes with calcium ions (Misra and Mule 1975), thereby having the potential to influence a multiplicity of calcium-regulated developmental events.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurobehavioral teratogenicity of gestational cocaine exposure.

Gestational cocaine exposure has an impact on a number of behavioral and physiological measures examined during the neonatal to weaning age period. Notable effects of early cocaine exposure include a disruption in cognitive function, along with a profile of DA alterations. Observed physiological differences do not appear to be restricted, however, to the DA system, or even the nervous system. Such data may have important implications regarding the prognosis for future development of human offspring exposed gestationally to cocaine.

Cocaine effects on the developing central nervous system: behavioral, psychopharmacological, and neurochemical studies.

IMPLICATIONS and FUTURE DIRECTIONS. The data we have collected thus far support the following conclusions: 1. Subcutaneous administration of cocaine results in dose-dependent increases in brain and plasma cocaine in both dams and fetuses, and maternal plasma levels in the range of or above those observed in human cocaine users. Fetal levels are lower than those of the dam, suggesting that the placenta may partially restrict cocaine entry into the fetus. Concentrations of the active cocaine metabolite benzoylecgonine, however, are greater in fetal than in maternal brain; this may have important implications for brain development given the calcium-binding properties of this metabolite. 2. Chronic subcutaneous administration of 10, 20 or 40 mg/kg cocaine from E8-E20 does not alter litter size, body weights at birth or weaning, or development of reflexes or physical landmarks in the offspring. 3. Offspring exposed gestationally to cocaine exhibit learning and/or retention deficits in some but not all conditioning situations. 4. Behaviorally and psychopharmacologically, there is evidence for a potential attenuation in DA activity in preweanling pups exposed gestationally to cocaine. There is, however, no sign of any alteration in DA turnover in treated offspring sacrificed at weaning, although preliminary data suggest that DA levels may be increased in exposed pups during the neonatal period. Possible alterations in DA receptor function are currently being assessed. We are still at the initial stages of our work, and the data we have collected thus far have raised as many questions as they have answered. We plan to assess further the cognitive deficits observed in cocaine-exposed offspring. Under what contingencies are these learning and/or retention deficits observed, and are they permanent deficits or does recovery eventually occur? Is there actually an attenuation in DA activity in treated offspring? If so, is this attenuation related to compensations at the presynaptic and/or postsynaptic level, and what is the time course for this effect on the DA system? What are the critical periods for the production of these alterations; is cocaine exposure during the second or third trimester alone sufficient? How do our results compare with those of other laboratories that are using other methods for administering cocaine during gestation? At some point in the future we also hope to examine potential therapeutic approaches to reduce the cognitive deficits observed in exposed offspring.(ABSTRACT TRUNCATED AT 400 WORDS)