Prenatal methamphetamine attenuates serotonin mediated renin secretion in male and female rat progeny: Evidence for selective long-term dysfunction of serotonin pathways in brain

In adult rats, methamphetamine produces biochemical alterations in brain serotonin (5-HT) neurons. Since 5-HT is critical to the development of fetal 5-HT neurons and target tissues, we hypothesized that in utero exposure to methamphetamine could result in long-term alterations in postnatal 5-HT systems. Pregnant Sprague-Dawley rats, administred either saline or (±)methamphetamine (5 mg/kg, s.c., b.i.d.) from gestational day 13 to 20, were divided into three treatment groups: Saline-injected/Ad Lib Fed (VEH); Saline-injected/Pair Fed (PF); and methamphetamine injected (METH). Prenatal methamphetamine exposure did not alter litter size, gender number, or progeny birth weights. Functional alterations in serotonergic systems were determined in postnatal day (PD) 70 male progeny and in PD 30 female progeny by measuring changes in 5-HT mediated increases in plasma hormones following a single injection of the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg). Prenatal metham-phetamine produced long-term marked (?30 to ?62%) attenuation of plasma renin responses to PCA in male and female progeny. In contrast, no alterations were observed in the ACTH, corticosterone, or prolactin responses to PCA in male and female progeny. Prenatal methamphetamine did not alter basal levels of any hormones measured regardless of gender. No significant differences were observed in the density of cortical or hypothalamic 5-HT uptake sites, or in the density of cortical 5-HT₁ or 5-HT₂ receptors in male progeny. The lack of significant differences in cortical 5-HT uptake sites observed between PF and METH treated dams 2 days post-parturition indicates that methamphet-amine was not neurotoxic to the pregnant dams. These data, which demonstrate long-term postnatal deficits in 5-HT mediated renin secretion, suggest selective functional alterations of brain 5-HT systems in male and female progeny exposed in utero to methamphetamine. © 1993 Wiley-Liss, Inc.     

Cocaine-induced deficits in ACTH and corticosterone responses in female rat progeny

The objective of this study was to determine whether prenatal exposure to cocaine could produce functional changes in central serotonergic systems mediating neuroendocrine responses in female progeny. Pregnant rats were administered either saline or (−) cocaine (15 mg/kg, SC b.i.d.) from gestational day 13–20. Progeny were fostered to nontreated lactating dams at birth. Central serotonergic function was determined by the ability of a serotonin releaser, p-chloroamphetamine (PCA), to stimulate plasma adrenocorticotropin (ACTH), corticosterone, and renin secretion in female progeny at postnatal day (PD) 30. Prenatal cocaine did not alter basal levels of ACTH, corticosterone, or renin. In contrast, ACTH and corticosterone responses to the 5-HT releaser PCA were significantly attenuated (−28 to 43%) in cocaine progeny, while the renin response to PCA was unaffected. These data suggest that cocaine administration during pregnancy can produce long-term selective alterations in neuroendocrine responses mediated by central serotonergic systems in prepubescent female progeny.     

Prenatal cocaine exposure potentiates 5-HT(2a) receptor function in male and female rat offspring

We have reported previously prenatal cocaine-induced functional deficits in serotonergic terminals, and gender-specific supersensitivity of postsynaptic 5-HT(1A) receptor-mediated hormone responses in offspring. This study investigates the effects of prenatal exposure to cocaine on postsynaptic 5-HT(2A) receptor-mediated responses in prepubescent male and female offspring. Pregnant rats were administered saline or (-)cocaine (15 mg/kg, s.c., b.i.d) from gestational day 13 through 20. Changes in 5-HT(2A) receptor function in offspring were assessed by differences in the ability of DOI [4-iodo, 2,5-dimethoxyphenyl-isopropylamine; 2. 0 mg/kg, s.c.] to elevate plasma levels of the hormones ACTH, corticosterone and renin. Basal hormone levels in male and female progeny were unaffected by prenatal cocaine exposure. However, prenatal exposure to cocaine significantly potentiated the magnitude of the ACTH response to DOI in both male (+19%) and female (+43%) progeny. Similarly, the DOI-induced elevation of plasma renin was markedly potentiated in male (+51%) and female (+83%) cocaine-exposed offspring. Although DOI significantly elevated corticosterone levels in both male and female offspring, the magnitude of corticosterone responses was not altered by prenatal exposure to cocaine. Densities of agonist ((125)I-DOI)-labeled receptors in hypothalamus and cortex were unaltered by prenatal exposure to cocaine. These data indicate prenatal cocaine-induced supersensitivity of postsynaptic 5-HT(2A) receptor function in male and female offspring without changes in receptor density. Synapse: 35:163-172, 2000.     

Repeated injections of cocaine inhibit the serotonergic regulation of prolactin and renin secretion in rats

Alterations in serotonergic function following repeated cocaine injections were examined using neuroendocrine responses to a serotonin (5-HT) releaser and 5-HT agonists.Forty-two hours following administration of cocaine (1–15 mg/kg i.p.) twice daily for 7 or 30 days, male Sprague-Dawley rats were injected with the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg i.p.) and blood samples were collected 1 h later for radioimmunoassays of plasma prolactin, plasma renin activity (PRA) and plasma renin concentration (PRC). PCA significantly increased secretion of prolactin and renin. These responses were attenuated in rats pretreated with cocaine for 30 days. In rats receiving cocaine for 7 days, the attenuation of PCA-induced secretion of prolactin and renin was less consistently observed. To determine whether these alterations were due to pre- or postsynaptic effects, rats were injected with cocaine (15 mg/kg i.p.) twice daily for 7 days, and the neuroendocrine responses to the direct 5-HT agonists RU 24969 and m-CPP were examined, 42 h after the last cocaine injection. Pretreatment with cocaine potentiated RU 24969-induced stimulation of plasma prolactin concentration. However, cocaine did not alter the ability of m-CPP to increase plasma prolactin concentrations. The stimulation of renin secretion in response to both 5-HT agonists was not altered by cocaine pretreatment. The data suggest that repeated cocaine impairs the function of serotonergic nerve terminals that regulate these endocrine responses. Furthermore, the 5-HT receptors that mediate prolactin secretion may exhibit supersensitivity.     

Effect of cocaine injections on the neuroendocrine response to the serotonin agonist MK-212.

This study was undertaken to examine whether several of the hormones that can be released by activation of serotonin receptors will be affected by long-term cocaine administration. Male rats received cocaine injections (15 mg/kg, IP) twice daily for 7 days. Forty-two hr after the last cocaine injection, the rats were challenged with increasing doses (0, 1, 5, 10 mg/kg, IP) of the 5-HT1/5-HT2 agonist MK-212 (6-chloro-2-[1-piper-azinyl]-pyrazine). The following observations were made: (1) cocaine reduced the rate of body weight gain; (2) cocaine inhibited the stimulatory effect of MK-212 on plasma vasopressin, oxytocin, and prolactin concentrations and on plasma renin activity and concentration; (3) cocaine did not inhibit the stimulatory effect of MK-212 on plasma ACTH or corticosterone concentrations. The data indicate that a wide-spectrum 5-HT (serotonin) agonist such as MK-212 can reveal differential neuroendocrine responses. This effect could be related to cocaine-induced changes in the different 5-HT receptor subtypes that regulate the secretion of these hormones.     

Neurochemical changes in brain serotonin neurons in immature and adult offspring prenatally exposed to cocaine

The present study investigates the age-dependent effects of prenatal cocaine exposure on changes in the neurochemical and functional status of brain serotonin neurons. Pregnant rats were administered either saline or (−)cocaine HCl (15 mg/kg, subcutaneously), twice daily from gestational days 13 through 20. Neurochemical changes in frontal cortex, hypothalamus, hippocampus, striatum and midbrain of prepubescent and adult offspring were determined by measuring: (1) the content of serotonin (5-HT) and its major metabolite 5-hydroxyindolacetic acid (5-HIAA), and (2) the ability of the serotonin releasing drug p-chloroamphetamine (PCA) to reduce brain serotonin levels. Brain catecholamine content was determined in progeny for comparative purposes. Prior to maturation, prenatal exposure to cocaine did not alter basal levels of brain 5-HT or 5-HIAA in any brain region examined. However, in adult progeny prenatally exposed to cocaine, basal 5-HT content was significantly reduced in the frontal cortex (−32%) and hippocampus (−40%), suggesting maturation-dependent effects of prenatal cocaine exposure on brain 5-HT neurons. Consistent with the maturational onset of changes in 5-HT, striatal dopamine was significantly reduced (−10%) by prenatal exposure to cocaine only in adult offspring. Reductions in 5-HT in most brain regions, produced by pharmacological challenge with p-chloroamphetamine (PCA), were comparable in prenatal saline versus cocaine offspring. One notable exception was the markedly greater reduction (−40%) in 5-HT in the midbrain of immature offspring prenatally exposed to cocaine, suggesting alterations in midbrain 5-HT neurons prior to maturation. Overall, these data demonstrate prenatal cocaine exposure produces region-specific changes in 5-HT neurons in offspring with some deficits occurring only following maturation.     

Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity'') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT_2C receptor (5-HT_2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT_2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT_2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT_2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.     

Cocaine and serotonin: a role for the 5-HT(1A) receptor site in the mediation of cocaine stimulant effects.

Cocaine induced locomotor stimulant effects are generally attributed to cocaine effects on brain dopamine. In this report, we present evidence that the 5-hydroxytryptamine(1A) (5-HT(1A)) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and the 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cycylhexanecarboxaminde maleate (WAY 100635) can enhance or block, respectively, the locomotor stimulant effects induced by cocaine. In two separate experiments, rats administered cocaine (10 mg/kg) exhibited a locomotor stimulant effect and decreased grooming behavior compared to saline treated rats. Pretreatment with the 5-HT(1A) agonist, 8-OHDPAT (0.2 mg/kg) enhanced and pretreatment with the 5-HT(1A) antagonist, WAY 100635 (0.4 mg/kg) eliminated the locomotor stimulant effect of cocaine. Neither the 8-OHDPAT nor WAY 100635 effects were attributable to effects on the behavioral baseline. The 8-OHDPAT and WAY 100635 had opposite effects on grooming behavior. 8-OHDPAT decreased and WAY 100635 increased grooming. Neither treatment, however, affected the grooming suppression induced by cocaine. Ex vivo biochemical measurements indicated that neither 8-OHDPAT or WAY 100635 affected brain dopamine metabolism or cocaine availability in brain. Both treatments affected 5-HT metabolism and altered the effect of cocaine on 5-HT metabolism. 8-OHDPAT increased and WAY 100635 decreased cocaine effects on 5-HT metabolism. Cocaine and 8-OHDPAT but not WAY 100635 increased corticosterone. Altogether, these findings indicate that the 5-HT(1A) receptor site may be an important target for the development of pharmacotherapies for the treatment of cocaine abuse.     

Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding.

Repeated cocaine intoxication can result in the development of behavioral sensitization in animals and psychosis in humans, phenomena that have been associated with alterations in dopamine (DA) function. Using electrophysiologic and autoradiographic techniques, modifications of central serotonin (5-hydroxytryptamine; 5-HT) systems were investigated in rats treated with a regimen of cocaine administration that produced behavioral sensitization. The inhibitory response of single 5-HT neurons in the dorsal raphe (DR) to (-)-cocaine, the 5-HT uptake inhibitor fluoxetine or the 5-HT1A agonist 8-hydroxy-2-[di-N-propylamino]tetralin (8-OHDPAT) was significantly enhanced in cocaine-treated rats. Furthermore, several brain areas that contain either cell bodies (DR) or terminals for 5-HT (medial and sulcal prefrontal cortex, frontal cortex) showed cocaine-induced elevations in [3H]imipramine-labeled 5-HT uptake sites, while [3H]-8-OHDPAT-labeled 5-HT1A receptors were decreased only in the central medial amygdala. These results suggest that modifications of autoregulatory mechanisms secondary to alterations of 5-HT uptake processes may contribute to the development of cocaine sensitization.     

Reduced serotonin release and serotonin uptake sites in the rat nucleus accumbens and striatum after prenatal cocaine exposure

This study was designed to assess the effects of prenatal cocaine exposure on the development of the serotonergic system. Pregnant Sprague-Dawley rats received daily sc injections of either cocaine (30 mg/kg) or saline from gestation day 7 (GD 7) to GD 20. At 1 week postnatal, all pups were killed and tissues containing the striatum and nucleus accumbens dissected out. In superfusion experiments, tissue slices were incubated with [3H]serotonin ([3H]5-HT) for 30 min and then superfused. The [3H]5-HT release was induced by exposures to the following treatments: electrical stimulations (20 mA or 40 mA, 0.5 Hz, 4 min), the medium containing 15 or 30 mM potassium (2 min), fenfluramine (1 or 2 microM for 2 min), para-chloroamphetamine (1 or 2 microM for 2 min), methiothepin (1 or 2 microM for 2 min), and fluoxetine (1 or 2 microM for 2 min). The results showed that the treatment-induced [3H]5-HT releases were all significantly less pronounced in the pups prenatally exposed to cocaine than in those prenatally exposed to saline regardless of the mechanisms by which the treatment increases extracellular 5-HT. Saturation analysis showed that the Bmax of [3H]citalopram binding sites was also significantly lower in the pups prenatally treated with cocaine than in those prenatally treated with saline. The results are consistent with the concept that less serotonergic innervation may exist in the examined brain areas of cocaine-treated offspring at 1 week postnatal, and support the hypothesis that prenatal cocaine exposure affects the postnatal development of the serotonergic system.     

Infant rats with chronic neonatal isolation experience show decreased extracellular serotonin levels in ventral striatum at baseline and in response to cocaine

Previously, we demonstrated that the early life stress of neonatal isolation enhances extracellular dopamine (DA) levels in ventral striatum in response to psychostimulants in infant rats. Yet, neonatal isolation does not alter baseline DA levels. DA levels are affected by serotonin (5-HT) and striatal levels of this transmitter are also enhanced by cocaine. Other early life stresses are reported to alter various 5-HT neural systems. Thus, the purpose of this study is to test whether neonatal isolation alters ventral striatal 5-HT levels at baseline or in response to cocaine. Litters were subjected to neonatal isolation (1-h individual isolation/day on postnatal days 2-9) or to non-handled conditions and pups assigned to one of three cocaine doses (0, 2.5, or 5.0 mg/kg) groups. On postnatal day 10, probes were implanted in the ventral striatum. Dialysate samples obtained over a 60-min baseline period and for 120 min post cocaine injections were assessed for levels of 5-HT and its metabolite, 5-HIAA. ISO decreased ventral striatal 5-HT levels at baseline and after cocaine administration but did not alter 5-HIAA levels. These data add to the literature on the immediate effects of early life stress on 5-HT systems by showing alterations in the ventral striatal system. Because serotonergic effects in this neural area are associated with reward and with emotion and affect regulation, the results of this study suggest that early life stress may be a risk factor for addiction and other psychiatric disorders.     

The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety

Substantial evidence has suggested that the activity of the bed nucleus of the stria terminalis (BNST) mediates many forms of anxiety-like behavior in human and non-human animals. These data have led many investigators to suggest that abnormal processing within this nucleus may underlie anxiety disorders in humans, and effective anxiety treatments may restore normal BNST functioning. Currently some of the most effective treatments for anxiety disorders are drugs that modulate serotonin (5-HT) systems, and several decades of research have suggested that the activation of 5-HT can modulate anxiety-like behavior. Despite these facts, relatively few studies have examined how activity within the BNST is modulated by 5-HT. Here we review our own investigations using in vitro whole-cell patch-clamp electrophysiological methods on brain sections containing the BNST to determine the response of BNST neurons to exogenous 5-HT application. Our data suggest that the response of BNST neurons to 5-HT is complex, displaying both inhibitory and excitatory components, which are mediated by 5-HT_1A, 5-HT_2A, 5-HT_2C and 5-HT₇ receptors. Moreover, we have shown that the selective activation of the inhibitory response to 5-HT reduces anxiety-like behavior, and we describe data suggesting that the activation of the excitatory response to 5-HT may be anxiogenic. We propose that in the normal state, the function of 5-HT is to dampen activity within the BNST (and consequent anxiety-like behavior) during exposure to threatening stimuli; however, we suggest that changes in the balance of the function of BNST 5-HT receptor subtypes could alter the response of BNST neurons to favor excitation and produce a pathological state of increased anxiety.     

Changes in the postnatal development on nitric oxide system induced by serotonin depletion

Serotonin (5-HT) is expressed early during central nervous system (CNS) development and plays an important role during this period. Nitric oxide (NO) is also involved in neuronal development. Morphological and functional relationships between NO and 5-HT, demonstrated as alterations of the nitrergic system, were observed after a 5-HT depletion. It has been hypothesized that NO may be related to the neuronal damage induced by some 5-HT neurotoxins. A parachloroamphetamine (PCA) treatment is able to damage ascending 5-HT fibers proceeding from the dorsal raphe nucleus (DRN) and depletes 5-HT storage in neuronal somata. In order to study the effects of a 5-HT depletion on the nitrergic system during postnatal development, Wistar rat pups were injected subcutaneously twice, on postnatal day (PND) 3 and PND4 with PCA. Neuronal nitric oxide synthase (nNOS) immunoreactivity and NADPH diaphorase reactivity were performed on brain sections from PND5, 7, 12, 19, 29 and 62 animals. After the treatment, we found an increased NADPH-d staining and nNOS immunoreactivity in striatum, frontal cortex and hippocampus along the different studied time periods. Interestingly, the expression of both NO markers was higher when 5-HT depletion was more evident, suggesting a very close relationship between 5-HT and NO systems during postnatal development.     

Polymorphism in the serotonin transporter gene and moderators of prolactin response to meta-chlorophenylpiperazine in African-American cocaine abusers and controls

Serotonin (5-HT) function is altered in several psychiatric disorders, including cocaine dependence (CD), and its role in impulsive-aggressive behaviors has been widely studied. However, the relationship between psychopathological and behavioral dimensions and mechanisms of 5-HT alterations remains unclear. We investigated the relationship of a polymorphism in the 5' promoter region of the serotonin transporter gene (5-HTTLPR) with prolactin (PRL) response to meta-chlorophenylpiperazine (m-CPP) in a sample of 68 African-American individuals, 35 CD subjects and 33 controls. We also examined whether measures of impulsivity, hostility and sensation seeking influenced the relationship between the 5-HTTLPR polymorphism and PRL response to m-CPP in this sample. Individuals with the SS genotype showed significantly heightened PRL response to the challenge compared with the LL and LS genotypes. No influence of gender or substance abuse condition was observed. Hostility was associated with blunted PRL response in the total sample. Cocaine abuse was the most significant moderator of DeltaPRL (peak PRL-baseline PRL), and the interaction of genetic, behavioral and psychopathological measures helped predict most of the observed DeltaPRL (62.5%). Although these results need replication, variation in the 5-HTTLPR gene appears to influence measures of 5-HT function and interact with disease state and personality dimensions to account for 5-HT disturbances in African-American populations.     

Increased tyrosine hydroxylase immunoreactivity in the rat cortex following prenatal cocaine exposure.

Cocaine has been found to be a neurobehavioral teratogen in both animals and humans. In this study the effects of cocaine on the developing catecholamine systems were examined. Rats were treated gestationally with cocaine (40 mg/kg s.c.) or saline from gestational day 13 until parturition. On postnatal day 28, tyrosine hydroxylase immunocytochemistry was performed. Increases in catecholamine fiber densities were observed in the hippocampus, anterior cingulate cortex, and parietal cortex in cocaine-treated animals. These findings may explain some of the behavioral alterations seen following prenatal cocaine exposure.     

The Excitatory Effects of the Amygdala on Hypothalamo-Pituitary-Adrenocortical Responses Are Mediated by Hypothalamic Norepinephrine, Serotonin, and CRF-41

The hypothalamic neural mechanisms that are involved in the facilitatory effects of the amygdala (AMG) on the hypothalamo-pituitary-adrenocortical (HPA) axis have been investigated in rats. Stimulation of the central AMG nucleus caused a depletion of hypothalamic CRF-41, presumably due to its release into the portal circulation, and a subsequent rise in plasma ACTH and corticosterone (CS) levels. These effects were inhibited in rats in which hypothalamic norepinephrine (NE) or serotonin (5-HT) was depleted by catecholamine or serotonin neurotoxins, respectively. Furthermore, the administration of prazosin, an α1, but not of atenolol, which is a β-blocker, as well as administration of the 5-HT₂ blocker ketanserin inhibited the ACTH and CS responses to AMG stimulation. These results indicate that the facilitatory effects of the AMG on the HPA axis are mediated by hypothalamic NE via α1 receptors and by 5-HT via 5-HT₂ receptors, as well as by CRF-41 in the paraventricular nucleus.     

In utero ethanol exposure decreased the density of serotonin neurons. Maternal ipsapirone treatment exerted a protective effect.

Prior studies from this laboratory showed that in utero ethanol exposure severely retards the development of the serotonin (5-HT) system; we demonstrated a reduced concentration of 5-HT and 5-HT reuptake sites and alterations in the concentration of 5-HT(1A) receptors in ethanol-exposed offspring. These investigations also found that maternal treatment with a 5-HT(1A) agonist, buspirone, prevented most of the ethanol-associated damage to the developing 5-HT system. In the present investigation, we investigated whether the ethanol-associated changes in the 5-HT system are due to a reduction of 5-HT neurons and whether any changes in the density of 5-HT neurons can be prevented by maternal treatment with another 5-HT(1A) agonist, ipsapirone. Using immunocytochemistry, we found that in utero ethanol exposure reduced the density of 5-HT immunopositive neurons in the dorsal raphe, median raphe and B9 neurons of postnatal day 5 (PN5) rats. In all three brain areas, the offspring of ethanol-fed, saline-treated dams exhibited a 28%-40% reduction in 5-HT neurons. Ipsapirone prevented the ethanol-induced reduction in 5-HT immunopositive neurons in the dorsal raphe, median raphe and B9 neurons. In the dorsal and median raphe of control offspring, ipsapirone did not alter the concentration of 5-HT neurons. However, this drug did reduce 5-HT neurons in the B9 region of the offspring of control-fed rats.     

Effects of heavy in utero cocaine exposure on adolescent caudate morphology

We assess the effects of in utero cocaine and polysubstance exposure on the adolescent caudate nucleus through high-resolution magnetic resonance imaging. Cocaine exposure may compromise the developing brain through disruption of neural ontogeny in dopaminergic systems, effects secondary to fetal hypoxemia, or altered cerebrovascular reactivity. Cocaine exposure may also lead to neonatal lesions in the caudate. However, long-term or latent effects of intrauterine cocaine exposure are rarely found. We use T(1)-weighted magnetic resonance imaging to quantify caudate nucleus morphology in matched control and exposed groups. The literature suggests that in utero cocaine exposure consequences in adolescents may be subtle, or masked by other variables. Our comparison focuses on contrasting the control group with high-exposure subjects (mothers who reported 2 median of 117 days of cocaine use during pregnancy; 82% tested positive for cocaine use at term). We use advanced image registration and segmentation tools to quantify left and right caudate morphology. Our results indicate that the caudate is significantly larger in controls versus subjects (P < 0.0025), implying cocaine exposure-related detriments to the dopaminergic system. The right (P < 0.025) and left (P < 0.035) caudate, studied independently, show the same significant trend. Permutation testing and the false discovery rate were used to assess significance.     

Relationship of increased food intake and plasma ACTH levels to 5-HT1A receptor activation in rats

Various putative agonists of the 5-HT_1A receptor subtype induce feeding in rats, probably by activating raphé somatodendritic 5-HT autoreceptors. These drugs also produce a marked increase in plasma concentrations of corticotropin (ACTH). In the present experiment we attempted to localize the site of action of 5-HT_1A agonists on the secretion of ACTH and examined the relationship between 5-HT_1A agonist-induced feeding and ACTH secretion. Rats were injected with either the high affinity 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.016-1.0 mg/kg, s.c.) or the novel anxiolytics buspirone, gepirone or ipsapirone (2.0–16.0 mg/k/g, s.c.), and either had their food intake measured 2 hr post injection or were sacrificed 30–40 min post injection for measurement of plasma ACTH. Plasma ACTH also was measured in rats pretreated with the serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) for three days (150 mg/kg, i.p. per day) and subsequently injected with 8-OH-DPAT (0.3 mg/kg, s.c.).As previously reported, the 5-HT_1A agonists increased both food agonists increased both food intake and plasma ACTH concentrations. After 8-OH-DPAT, ipsapirone and gepirone the amount of food consumed was positively correlated with the concentration of plasma ACTH. No such correlation was evident following buspirone. PCPA pretreatment resulted in near total depletion of brain 5-HT content but had no effect on the ACTH rise induced by 8-OH-DPAT. Therefore, in contrast to the presynaptic site previously proposed for 5-HT_1A agonist-induced feeding, the present results suggest a agonist-induced feeding, the present results suggest a postsynaptic location for the 5-HT_1A receptor mediating ACTH release.