Postnatal methadone exposure doe not prevent prenatal methadone-induced changes in striatal cholinergic neurons.

On postnatal day 4, rats exposed to methadone prenatally but fostered to control dams, as well as those fostered to dams treated with methadone, exhibited significant reductions in striatal acetylcholine (ACh) content. This suggests that neonatal withdrawal from methadone is not responsible for the effects of prenatal exposure on cholinergic development in the early perinatal period. The effects of perinatal exposure to methadone on serotonin (5HT) and dopamine (DA) metabolism do not appear to be strictly related to changes in ACh content. Although prenatal exposure reduces 5-hydroxyindole acetic acid (5HIAA) content, changes in 5HT content prevent significant changes in the ratio 5HIAA/5HT. Pups exposed to methadone only prenatally (withdrawal group) exhibited a decreased DOPAC/DA ratio, whereas pups in the treatment group exposed to methadone both pre- and postnatally exhibited an increased DOPAC/DA ratio.

Effects of cocaine and the cocaine analog CFT on glutamatergic neurons.

The effects of cocaine and the cocaine analog methyl-3-beta-(p-fluorophenyl)-1 alpha H, 5 alpha H-tropane-2b-carboxylate (CFT) on glutamate turnover rate were studied in the nucleus accumbens, striatum, frontal cortex, and parietal-cingulate cortex of the rat, using neurotransmitter turnover rate as an estimate of the activity of the glutamatergic neurons. Both cocaine [15 or 30 mg/kg, intraperitoneally (IP)] and CFT (2.2 mg/kg, IP) increased glutamate turnover in the nucleus accumbens, although the time course of their actions differed. These effects on glutamate turnover appeared at times after maximal motor activation of the animals had occurred. On the other hand, neither cocaine nor CFT affected glutamate turnover in the frontal cortex, parietal-cingulate cortex, or striatum. Neither cocaine nor CFT affected the content of glutamate or glucose in any brain region studied. Thus, although cocaine and CFT affect glutamatergic neurons in the CNS, these actions are not generalized across the CNS, but are restricted to a specific brain region.

Maternal and fetal brain and plasma levels of cocaine and benzoylecgonine after acute or chronic maternal intravenous administration of cocaine.

The effect of repeated i.v. administration of cocaine HCl (1.5, 3 or 6 mg/kg daily) from gestational day 8 through gestational day 18 was studied on maternal and litter parameters in the pregnant female Sprague-Dawley rat. These doses of cocaine had no significant effect on maternal weight gain or nutritional intake and did not significantly affect litter size. Levels of cocaine and its metabolite benzoylecgonine in the brain and plasma of the dams and their fetuses were measured on gestational day 18 at 1, 5, 20 or 60 min after a single injection or 11 daily i.v. injections of cocaine (6 mg/kg). The shape of the time courses for cocaine differed somewhat between dams and fetuses, with fetal plasma concentrations of cocaine initially being lower than those of their dams and then by 5 min becoming equivalent to those of their dams. Although plasma concentrations of cocaine soon equilibrated between dams and fetuses, plasma concentrations of benzoylecgonine did not. Interestingly, brain concentrations of cocaine did not differ between dams and fetuses. The most remarkable finding was that the relative distribution of cocaine between brain and plasma differed after chronic vs. acute treatment, with a relative shift in the distribution of cocaine from plasma to the brain in the fetuses, and with the exception of the earliest time point measured, in the dams after repeated dosing.

Blockade of acute hypertensive response does not prevent changes in behavior or in CSF acetylcholine (ACH) content following traumatic brain injury (TBI).

There is evidence that the blood-brain barrier (BBB) is breached following traumatic brain injury (TBI), allowing the unregulated entry of circulating neuroactive substances into the central nervous system. As the traumatic episode is typically associated with an acute hypertensive event, which in itself may alter BBB status, the effects of the blockade of TBI-associated hypertension on injury-associated behavioral and cerebrospinal fluid (CSF) neurochemical changes were assessed in rats. Animals were injected with either saline or hexamethonium 15 min prior to a moderate fluid percussion injury while under light methoxyflurane anesthesia. This dose of hexamethonium was demonstrated to block the hypertensive response to TBI. Pretreatment with hexamethonium prevented neither acute nor more enduring behavioral deficits observed after TBI. Hexamethonium did not prevent TBI-associated increases in CSF acetylcholine (ACh) content in separate group of rats sampled 12 min following TBI. Furthermore, histological inspection indicated that hexamethonium did not prevent TBI-induced disruption of the BBB, as assessed by intravascular horseradish peroxidase (HRP). Thus, blockade of the hypertensive response to TBI does not afford behavioral protection nor does it prevent changes in the BBB or CSF ACh content following TBI. TBI is in itself sufficient to modify behavior, neurochemistry and BBB function in the absence of hypertension.

Prenatal exposure to methadone affects central cholinergic neuronal activity in the weanling rat.

The effect of prenatal exposure to methadone via maternal osmotic minipumps was studied on brain regional acetylcholine (ACh) turnover and dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT) and their metabolites in 21-day-old female and male rats. ACh content was not affected in any region studied. However, the turnover rate of ACh (TRAch) was increased significantly in the striata and parietal cortices of both sexes. Two gender-specific changes were observed: a profound decrease in hypothalamic TRACh in the females and an increase in hippocampal TRACh in the males. No changes were observed in TRACh in the medulla-pons or the frontal cortex of either sex. The reduction in TRACh was accompanied by a threefold increase in DA content in the hypothalamus of the methadone-exposed females. No other changes were observed in DA, NE, or 5-HT, save for increased 5-HT content in the medulla-pons of the male methadone-exposed rats. Thus, prenatal methadone exposure produces several lingering changes in cholinergic function, many of which were not apparent in the immediate postnatal period. Although striatal ACh content was no longer reduced in methadone-exposed rats, striatal cholinergic function remains disrupted. It remains to be proven whether these differences are a direct effect of methadone exposure or are a consequence of neonatal withdrawal.

The effect of prenatal exposure to methadone on neurotransmitters in neonatal rats.

The effect of prenatal exposure to methadone via maternal osmotic minipumps was studied on neurotransmitter content of 4-day-old male and female rats. Several sex-related differences were observed in brain regional neurotransmitter content. Prenatal exposure to methadone produced only selective changes in brain regional neurotransmitter content. Exposure to methadone in doses sufficient to produce maternal and fetal dependence selectively reduced striatal acetylcholine content and produced a sex-dependent change in hindbrain acetylcholine.