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P M Whitaker-Azmitia

Publications and source records attributed to P M Whitaker-Azmitia.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effects of gestational exposure to monoamine oxidase inhibitors in rats: preliminary behavioral and neurochemical studies.

Monoamine neurotransmitters are important in the development of the immature mammalian brain, prior to assuming their role as neurotransmitters. The endogenous levels of these transmitters are highly regulated by the enzyme monoamine oxidase (MAO). Thus, any change in this enzyme should have a profound effect on brain development. In order to test this hypothesis, we treated developing rat pups with the monoamine oxidase inhibitors (MAO-Is), clorgyline (MAO-A, 3 mg/kg), and deprenyl (MAO-B, 3 mg/kg) throughout gestation (MAO-I-birth), or throughout gestation and to sacrifice (MAO-I-sac). The animals were analyzed for serotonin and dopamine terminal density, using 3H-paroxetine and 3H-GBR 12935, respectively. Whereas there were no changes in the development of the dopamine system, the serotonin system was severely affected, particularly in the cortex that showed a significant reduction of innervation at 30 days postnatal. The animals reached all normal development milestones on schedule, and had no changes in measures of anxiety (% light/dark); however, the animals showed increased open field activity and deficits in a passive avoidance paradigm, which may be a measure of impulsivity. The MAO-I-sac animals were severely impaired, showing stereotypic behavior, seizures, and eventually visual impairments. Our results are discussed in terms of relevance to human disease states, such as atypical Norrie's disease, impulsivity, and hyperactivity. As well, our results should be used to caution against the use of MAO-Is in women of child-bearing age.

Animals↗
PubMed1994

Astroglial 5-HT1a receptors and S-100 beta in development and plasticity.

The work described in this article is concerned with the role of the 5-HT1a receptor in mediating the neurotrophic effects of serotonin, principally through the release of the substance S-100 beta from astroglial cells. These receptors are also present in astrocytes of the mature brain and may play a role in the synaptic plasticity necessary for certain experience-driven brain changes, such as memory or learning. The presence of these receptors on astroglial cells of the adult brain also has interesting implications for the mechanism of action of many psychotropic drugs acting through the serotonergic system.

Aging↗
PubMed1993

Localization of 5-HT1A receptors to astroglial cells in adult rats: implications for neuronal-glial interactions and psychoactive drug mechanism of action.

Although tissue culture studies have shown a variety of neurotransmitter receptors on astroglial cells, verifying these observations in adult animals has been difficult and rarely accomplished. In the current study we have used double immunocytochemistry to localize 5-HT1a receptors to astroglial cells in fixed sections of adult rat brain. The astroglial cells were identified using an antibody raised against the astroglial-specific protein glial fibrillary acidic protein (GFAP). To label the 5-HT1a receptor, we used an antibody we recently raised against a unique peptide sequence occurring in the second extracellular loop of the receptor. Our results show that the 5-HT1a receptor occurs in relatively high abundance on astroglial cells. There is regional specificity, the receptor being much more commonly found in septum and hippocampus than striatum. There are also intraregional differences in that even within a single brain region one astrocyte may have very high levels of the receptor while an adjacent cell has none. We propose that the cellular localization of this receptor could have significance in understanding the mechanism of action of 5-HT1a receptor active drugs in alleviating anxiety and depression. The mechanism may be through the release of a neurotrophic agent, S-100 beta, from astrocytes. This factor may then cause regeneration or sprouting of neuronal terminals which have been lost due to a disease process.

Animals↗
PubMed1992

Prenatal cocaine exposure disrupts the development of the serotonergic system.

Prenatal cocaine exposure has been found to result in a number of neurobehavioral abnormalities in both clinical and laboratory studies. We have previously shown that cocaine inhibits the growth of developing serotonin neurons in culture. This study examines the effects of cocaine on the developing serotonin system in vivo. Pregnant rats were injected with cocaine (40 mg/kg s.c.) from gestational day 13 to parturition. One group of rats was additionally injected on postnatal days 1-5 with cocaine (10 mg/kg s.c.). [3H]Paroxetine, a selective ligand for the serotonin uptake carrier, was used to quantify serotonin terminal fiber density at one day, one week, and four weeks postnatal. Cocaine exposure was found to significantly decrease [3H]paroxetine-labelled sites and thus the density of serotonin fibers in the cortex and hippocampus at one day and one week postnatal. By four weeks postnatal, no significant effect was observed, indicating that a recovery had occurred. Serotonin immunocytochemistry performed at one month revealed normal fiber distribution in the cortex but a loss of fibers in the CA1 and CA2 hippocampal fields. Postnatal treatment alleviated the effects of prenatal cocaine exposure, resulting in [3H]paroxetine binding levels at one week which were comparable to and, in the cortex, even higher than those of saline controls. We conclude that cocaine delays the maturation of the serotonin system when administered prenatally but may accelerate maturation when administered both pre- and postnatally.

Animals↗
PubMed1992

5-HT3 receptor-active drugs alter development of spinal serotonergic innervation: lack of effect of other serotonergic agents.

Our work has focused on identifying the type of serotonin receptor through which serotonin acts as a developmental signal in the central nervous system. Previously, we have found that the regulation of development of ascending serotonergic neurons is through the balance of two serotonin receptors. One, the 5-HT1a receptor, releases a growth factor from astroglial cells. The other receptor is related to a release-regulating autoreceptor and can be stimulated indirectly by serotonin releasers such as fenfluramine. In the present study, we examined the receptors which regulate development of the descending neurons by treating pregnant rats with selective serotonergic drugs, from gestation day 12 until birth. Pups were subsequently tested for alterations in development by nociceptive testing (tail-flick latency) and by determining the binding of 3H-paroxetine, an indicator of serotonin terminal density, in spinal cord. Our results show that agents stimulating the 5-HT1a receptor (8-OH-DPAT) or the 5-HT1b receptor (TFMPP) or substances which release serotonin (fenfluramine) had no effect on the development of spinal serotonergic pathways. However, agents acting on the 5-HT3 receptor did--the agonist phenylbiguanide (PG) increased latency on tail-flick testing (postnatal days 10 and 30), while the antagonist, MDL 72222, decreased latency (postnatal days 10 and 18). Interestingly, both the agonist and the antagonist significantly increased 3H-paroxetine binding on postnatal day 18. Our results are discussed in terms of a possible mechanism by which 5-HT3 receptors may influence development.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Dose-related effects of prenatal 5-methoxytryptamine (5-MT) on development of serotonin terminal density and behavior.

Our previous studies with a tissue culture model of neuronal development have shown that the development of serotonin neurons is dependent, at least in part, on the stimulation of high affinity serotonin receptors. One receptor inhibits the outgrowth of neurons, while the other promotes it. The present study was therefore undertaken to replicate these findings in a whole animal model system. Pregnant Sprague-Dawley rats were treated from gestational day 12 until birth with 0.1, 1.0 or 3.0 mg/kg 5-methoxytryptamine (5-MT). The pups were assessed for serotonin outgrowth by the selective synaptosomal uptake of [3H]serotonin at postnatal days 1, 15 and 30 (D1, D15, D30). In addition, the pups were tested behaviorally for the neonatal serotonin syndrome at D5 (induced by quipazine), spontaneous alternation and open field activity at day 15 and lick suppression at day 30. At 1.0 mg/kg, the terminal outgrowth of serotonin neurons was inhibited, while the highest dose, 3.0 mg/kg, showed stimulation of outgrowth. The highest dose caused behavioral alterations which had abated by 30 days, while the intermediate dose (1.0 mg/kg) showed behavioral changes throughout. Interestingly, the lowest dose, 0.1 mg/kg, showed changes in uptake only at D1 and behavioral changes only at later timepoints, principally at D30. This suggests that serotonin not only plays a role in regulating the development of the neurons which produce it, but that it may also play a role in neurochemical imprinting--that is, changes in behavior in the adult may be due to changes in neurochemistry during development, even though that neurochemistry may have been corrected by the time the animal becomes an adult.

5-Methoxytryptamine↗
PubMed1991

Activity of hippocampal extract on development of [3H]5-HT high-affinity uptake in dissociated microcultures.

Specific and localized lesions of the 5-HT fibers in the hippocampus induce homotypic collateral sprouting and enhance serotonergic fiber outgrowth from adult neurons and transplanted fetal tissue. In this study, hippocampal extracts were prepared and applied to primary cultures of fetal serotonergic neurons. The effects of plating density and serum additives were examined. The growth of the serotonergic neurons in the rostral brainstem dissociated cultures were estimated by measuring the specific uptake of [3H]5-HT. The results indicate the presence of a trypsin-sensitive factor which is active when prepared fresh at dilutions up to 1/10,000. The factor is higher in hippocampus than cerebellum. Young male tissue contained more activity than either female or aged hippocampus. Although both positive and negative effects are described, higher dilutions of factor (1/1,000) were generally stimulatory in high density cultures while lower dilutions (1/10) were inhibitory in low density cultures. Specific removal of 5-HT hippocampal afferents with fornix-fimbria microinjections of 5,7-dihydroxytryptamine resulted in an initial loss of activity (2 days and 2 weeks) followed by an enhanced activity (2 months) compared to normal hippocampal extract. Several possibilities are discussed as to the identity of the serotonergic growth factor from hippocampal supernatant.

5,7-Dihydroxytryptamine↗
PubMed1991

Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system.

The serotonergic neurons of the mammalian brain comprise one of the most expansive chemical systems known. The cell bodies are largely confined to the midline (raphe) region of the brain stem in two general clusters: a superior group that consists of the dorsal raphe nucleus (B-7 and B-6), median raphe nucleus (B-8 and B-5), caudal linear nucleus (rostral B-8), and supralemniscal nucleus (B-9), and an inferior group that consists of nucleus raphe obscurus (B-2), nucleus raphe pallidus (B-1), nucleus raphe magnus (B-3), ventral lateral medulla (B-1/B-3), and the area postrema. The axons from these cells project throughout the neuroaxis from the spinal cord to the olfactory bulb and from the cerebral cortex to the hypothalamus. The development of this giant system begins very early in gestation and is influenced by a variety of growth regulatory factors, including the astroglial protein S-100 beta. Evidence will be presented that the serotonergic system plays a major role in the maturation of the brain by interacting with the 5-HT1A receptors which are most dense during these early developmental periods. The 5-HT1A receptor is located on both neurons and astrocytes, and in the latter cells may serve to stimulate release of S-100 beta. The developmental role of 5-HT appears to become dormant as the brain matures, and during aging and Alzheimer's disease, 5-HT receptors are significantly depressed. However, specific damage to 5-HT fibers in the adult brain by 5,7-dihydroxytryptamine produces a sharp fall in the levels of 5-HT which seems to reactivate the developmental signals in the brain. Not only are the serotonergic fibers encouraged to sprout and expand their territory, but the stimulation of the astrocytic growth factor by a 5-HT1A agonist is reinstated. The ability to recall developmental processes in the adult brain by interrupting the 5-HT fibers may provide important tools for understanding and treating the aged brain.

Adult↗
PubMed1990

Prenatal treatment with a selective D1 receptor agonist (SKF 38393) alters adult [3H]paroxetine binding and dopamine and serotonin behavioral sensitivity.

We have previously shown that the development of serotonin neurons can be affected by various pharmacological agents acting on the serotonin system. Receptor stimulation by high doses of 5-methoxytryptamine (5-MT) causes increased outgrowth, through release of an astroglial growth factor, while a low concentration of 5-MT has a direct inhibitory effect on neuronal outgrowth. Since 5-MT is known to be a release-regulating autoreceptor agonist, the present study was aimed at testing the hypothesis that inhibition of serotonin release causes the inhibition of outgrowth. We used the D1 receptor agonist SKF 38393 as an inhibitor of serotonin release. Pregnant Sprague-Dawley rats were treated with SKF 38393 (1 mg/kg; subcutaneously) from gestational day 12 until parturition. Development of serotonin terminal outgrowth was evaluated in the offspring using the selective uptake marker [3H]paroxetine in brainstem and frontal cortex. In saline and SKF 38393 treated animals, the developmental pattern in the frontal cortex showed the highest terminal density at day 60 and a return to normal by day 90, with no statistically significant differences between the groups. Conversely, in the brainstem, [3H]paroxetine binding developed normally until postnatal day 90, when the SKF 38393 pretreated animals showed only 58% of the binding observed in saline animals. In a fixed interval responding task, given at day 90, both dopamine and serotonin receptor systems have significantly decreased sensitively after the SKF 38393 pretreatment. In conclusion, our results show that the inhibitory effects of serotonin on the growth of serotonin neurons, may be through inhibition of neurotransmitter release. Moreover, we propose a means by which serotonin and dopamine systems could be interdependent during development.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Stimulation of astroglial 5-HT1A receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology.

Stimulation of astroglial 5-HT1A receptors causes astroglial cells to acquire a more mature morphology and to release a factor (or factors) which promotes growth of serotonergic neurons. By using an antibody-blocking approach, we have shown that at least one of the growth-promoting factors thus released is the astroglial-specific protein S-100. This may be a particularly important observation, in view of studies implicating S-100 in both Down's syndrome and Alzheimer's disease.

Animals↗
PubMed1990

S-100B but not NGF, EGF, insulin or calmodulin is a CNS serotonergic growth factor.

The effects of S-100B, nerve growth factor (NGF), epidermal growth factor (EGF) and insulin were tested in cultured mesencephalic neurons. Only chronic S-100B showed enhancement (maximal at 3.2 ng/ml is 171%) after 3 days of incubation of the [3H]5-HT uptake capacity by serotonergic neurons. A single application at initial plating of S-100B (maximal at 5 ng/ml is 185%), but not calmodulin, increased the development of the [3H]5-HT uptake capacity by the cultured serotonergic neurons. Morphometric analysis of cultured 5-HT immunoreactive (IR) neurons showed an increase (135 and 147%) in neurite length 30 h after S-100B application of 16 and 3.2 ng/ml (respectively). These results suggest that S-100B is a serotonergic growth factor in the mammalian brain.

Animals↗
PubMed1990

Serotonergic agents restore appropriate decision-making in neonatal rats displaying dopamine D1 receptor-mediated vacillatory behavior.

A number of studies in the past have indicated that certain types of dopamine receptor-mediated behaviours can be reversed by serotonin agonists. We have recently described a behavior in neonatal rats induced by the selective D1 receptor agonist SKF 38393, which we termed vacillatory behavior. The current study was aimed at determining the effectiveness of several serotonin-specific agents at reversing this behavior. Behaviors measured on day 15 revealed that SKF 38393-mediated behavior was effectively blocked by SCH 23390 (a selective D1 antagonist), serotonin receptor agonists specific for the 5-HT1A receptor (buspirone and ipsapirone), and the serotonin uptake inhibitor clomipramine. However, the behavior was not reversed by diazepam. These data suggest that the serotonergic and dopaminergic neurotransmitter systems must be in a proper balance for appropriate decision-making behaviors to occur.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for Ca2(+)-dependent toxicity linked to release.

Animal studies have established a correlation between release of 5-hydroxytryptamine (5-HT) and the long-term reduction of 5-HT (toxicity) by 3,4-methylenedioxymethamphetamine (MDMA) with the S(+) enantiomer being more active than the R(-). Using a microculture system of fetal raphe neurons, the enantiomers of MDMA were tested to determine if a similar difference in potency existed. The results showed that the development of the uptake capacity of [3H]5-HT in 4-day cultures was half-maximally inhibited by a single application at time of plating of 5 X 10(-6) M S(+)-MDMA and 5 X 10(-5) M R(-)-MDMA. In order to determine if the Ca2(+)-independent release (chemically induced through the transporter protein and inhibited by reuptake blockers) or the Ca2(+)-dependent release (K(+)-induced and inhibited by presynaptic receptors) contributed to the toxicity, fluoxetine and D1 and alpha 2 agonists were studied. The results showed that both forms of release were involved in the loss of [3H]5-HT uptake capacity, with the direct MDMA-induced Ca2(+)-independent (fluoxetine-sensitive) release being the first step. Evidence from binding studies indicates that MDMA has a micromolar affinity for the 5-HT2 receptor, and our studies in culture showed that ketanserin, a specific 5-HT2 antagonist, was effective at attenuating the effects of S(+)-MDMA on the development of the [3H]5-HT uptake capacity by the cultured raphe neurons. The 5-HT2 receptor is linked to increased intracellular Ca2+ through a second messenger phosphatidylinositol (PI)-hydrolysis mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1990

5-HT1A and 5-HT1B agonists play a differential role on the respiratory frequency in rats.

The effect of the putative 5-HT1A agonists 8-OH-DPAT and ipsapirone and 5-HT1B agonists TFMPP and m-CPP on respiratory activity in rats has been examined. In chloral hydrate-anesthetized rats, respiratory counts were decreased in a dose-dependent manner by both TFMPP and m-CPP, with an ED50 of 0.30 mg/kg (1.1 mumol/kg) and 3.0 mg/kg (11.0 mumol/kg) respectively. In contrast, both 5-HT1A agonists tested, 8-OH-DPAT and ipsapirone, produced an increase in respiratory rate at all doses tested. Moreover, the TFMPP-induced decrease in respiratory rate was antagonized by 8-OH-DPAT. The 5-HT2 antagonist ketanserin had no effect on the TFMPP-induced decrease in respiratory activity. However, methylsergide (5-HT1/5-HT2 antagonist) and (-)-cyanopindolol (5-HT1B antagonist) antagonized the TFMPP-induced respiratory rate decrease. The results of these experiments, coupled with the predominant presence of 5-HT1B receptors in the lower brainstem, pons, and medulla, as established by autoradiography studies, suggest a possible involvement of the 5-HT1B receptor subtype in the control of respiratory mechanisms, especially those involved in respiratory rhythmicity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗