Prenatal cocaine exposure adversely affects development of the primate cerebral cortex

This study was conducted to determine whether prenatal exposure to cocaine interferes with the development of the primate cerebral cortex. For this purpose, pregnant rhesus monkeys received cocaine orally (20 mg/kg/day in fruit or candy treats), twice a day from the 40th-102nd days of pregnancy (E40-E102), which is a period of corticogenesis in this species. The control group of pregnant animals received fruit or candy treats only. On E64 and E65, all animals received intravenous injections of [³H]thymidine. Monkeys were allowed to deliver at term. The offspring were sacrificed at age 2 months, and their brains were processed for histology and autoradiography. The analysis of cresyl violet-stained sections showed that prenatal treatment with cocaine significantly altered lamination of the primate cerebral cortex, in some cases completely blending distinction between individual layers. In addition, autoradiographic analysis revealed that in the control animals, [³H]thymidine labeling concentrated in cortical layers V and/or IV depending on the cytoarchitectonic area observed. In contrast, drug- treated animals displayed labeled cells in the white matter and cortical layer VI in addition to layers V and IV, suggesting inability of cortical cells to reach proper cortical layers. The number of labeled cells was also much lower in these animals. Finally, immunocytochemical studies with antisera directed toward glial fibrillary acidic protein showed that prenatal exposure to cocaine had dramatic effect on the glial fibers normally observed in the upper cortical layers. In many cortical regions of cocaine-treated animals, we observed practically no such fibers. This study demonstrates that cocaine administered during pregnancy can significantly affect the development of the primate cerebral cortex. © 1995 Wiley-Liss, Inc.     

Prenatal cocaine produces signs of neurodegeneration in the lateral habenula

The lateral habenula is a nucleus in the dorsal thalamus that innervates midbrain dopaminergic and serotonergic nuclei via projections through its major efferent pathway, the fasciculus retroflexus (FR). It was previously demonstrated that cocaine administered continuously to adult rats over several days produces neurodegeneration in the lateral habenula and FR. Because exposure to cocaine during pregnancy reportedly can cause neurobehavioral deficits, we examined whether rat fetuses exposed to continuous cocaine during the last week of gestation would similarly demonstrate selective neurodegeneration in the lateral habenula. On day 17 of gestation, dams were implanted with two silicone pellets, each containing either vehicle or one of 2 doses of cocaine (80 mg or 55 mg per pellet). Degenerating neurons containing silver deposits were counted in lateral habenula and in the striatum. Cocaine-exposed pups had significantly more silver-stained cells in the lateral habenula than vehicle-treated pups, but similar numbers of silver-stained cells were present in the striatum of all three groups. When similarly treated vehicle- and cocaine-exposed animals were tested behaviorally at 60 days of age, they did not differ on measures of open field activity, open arm avoidance on the elevated plus-maze or conditioned place preference for cocaine, although a linear trend analysis indicated some hyperactivity of the cocaine-pretreated pups during the place preference test. These results indicate that continuous cocaine exposure has selective neurotoxic effects on the habenula of the developing fetus similar to cocaine's effects in the adult.     

Primates exposed to cocaine in utero display reduced density and number of cerebral cortical neurons.

This study examined the effects of cocaine use during the second trimester of pregnancy on cerebral neocortical volume and density, and total number of neocortical neurons and glia in offspring. We also evaluated the extent of postnatal recovery of cytoarchitectural abnormalities previously observed in the neocortex of two-month-old primates born from cocaine-treated mothers (Lidow [1995] Synapse 21:332-334). Pregnant monkeys received cocaine orally (20 mg/kg/day) from the 40th to 102nd days of pregnancy (embryonic day [E]40-E102). On E64 and E65, the animals were injected with [(3)H]thymidine. Cerebral hemispheres of the offspring were examined at three years of age. We found a reduction in the neocortical volume and density and total number of neocortical neurons. The observed reduction in neuronal number within the neocortex was not accounted for by the increase in the number of neurons in the white matter of cocaine-exposed animals, because the number of these "extra" neurons was equal to only half that of missing neurons. We detected no significant changes in the number of neocortical glia. The cytoarchitectural abnormalities in the neocortex of prenatally cocaine-exposed three-year-old monkeys closely resembled previously described neocortical abnormalities in similarly exposed two-month-old animals: the neocortex lacked a discernible lamination; the majority of the cells labeled by [(3)H]thymidine injected during neocortical neurogenesis did not reach their proper position within the cortical plate. Therefore, postnatal maturation is not associated with significant improvement in neocortical organization in primates prenatally exposed to cocaine. There was, however, a postnatal recovery of low glial fibrillary acidic protein (GFAP) immunoreactivity previously observed in 2-month-old cocaine-exposed animals.     

Prolactin serum levels correlate with inflammatory status in drug-naïve first-episode schizophrenia

Objectives. The present study was to examine the relationship between serum levels of prolactin and the inflammatory status in drug-naïve, first-episode schizophrenia patients with normal weight. Methods. Patients with normal weight, drug-naïve, first-episode schizophrenia and healthy controls were enrolled in the study. Serum levels of prolactin (PRL) were measured using electrical chemiluminescence immunoassay. Serum levels of interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were examined using enzyme-linked immunosorbent assay (ELISA). Results. Sixty patients with normal weight, drug-naïve, first-episode schizophrenia and 60 healthy controls were enrolled. The schizophrenia group had higher serum levels of PRL, IL-1β, IL-6 and TNF-α compared with the control group. There was a gender difference of hyperprolactinemia in schizophrenia group. There were positive relationships between serum levels of PRL and serum levels of IL-1β, IL-6 and TNF-α within the schizophrenia group. Within the schizophrenia group, TNF-α was the strongest predictor among the three cytokines for serum levels of prolactin after controlling for gender, age, education, smoking status and disease duration. Conclusions. Patients with normal weight, drug-naïve, first-episode schizophrenia present elevated serum levels of PRL, which might be related to the up-regulated inflammatory status in this patient population.     

Restless legs syndrome in Korean patients with drug-naïve Parkinson's disease: A nation-wide study

BackgroundRestless legs syndrome is a common neurologic disorder, and there is increasing evidence for a dopaminergic link between Parkinson's disease and restless legs syndrome. However, most previous studies did not take into account the effects of dopaminergic medication. We conducted a nation-wide, cross-sectional study to determine the prevalence and clinical characteristics of restless legs syndrome in Korean drug-naïve Parkinson's disease patients.MethodsOne hundred and fifty-one drug-naïve patients with Parkinson's disease were enrolled from 18 centers in South Korea over the course of one year. Clinical profiles of parkinsonism, restless legs syndrome, psychiatric symptoms, and laboratory data were collected. The findings of subjects with and without restless legs syndrome were compared.ResultsThe prevalence of restless legs syndrome in drug-naïve patients with Parkinson's disease was 16.5%. Subjects with restless legs syndrome had a higher mean Hoehn and Yahr stage and more severe limb parkinsonism, especially tremor. There was, however, no difference in iron metabolism between patients with and without restless legs syndrome. Analysis demonstrated that Beck's depression inventory score was associated with the severity of restless legs syndrome.ConclusionOur study demonstrated an increased prevalence of restless leg syndrome in drug-naïve patients with Parkinson's disease than in the general population. Based on the association between parkinsonism and restless legs syndrome, and the unique characteristics of restless legs syndrome in patients with Parkinson's disease, we suggest that the pathophysiology of restless legs syndrome in Parkinson's disease differs from that in patients without Parkinson's disease.     

Prevalence and factors related to orthostatic syndromes in recently diagnosed,drug-naïve patients with Parkinson disease

Clinical Autonomic Research - The aim of this study was to explore the prevalence of and factors related to orthostatic syndromes in recently diagnosed drug-naïve patients with Parkinson...     

Gender differences in non-motor symptoms in early, drug naïve Parkinson’s disease

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson’s disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ ² exact test; multiple comparisons were corrected with the Benjamini–Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.     

Quantitative synthetic MRI reveals grey matter abnormalities in children with drug-naïve attention-deficit/hyperactivity disorder

Brain Imaging and Behavior - To investigate the quantitative profiles of brain grey matter (GM) in pediatric drug-naïve ADHD patients using synthetic magnetic resonance imaging (SyMRI). A...     

Cocaine-induced alterations in the density of monoaminergic receptors in the embryonic guinea pig cerebral wall.

Quantitative receptor autoradiography was used to examine the effect of chronic cocaine exposure on the density of alpha1-, alpha2- and beta-adrenergic, 5-HT1A- and 5-HT2-serotonergic, and D1- and D2-dopaminergic receptors in the fetal guinea pig cerebral wall which contained forming motor area of the cerebral cortex. The pregnant guinea pig received two daily subcutaneous injections of 20 mg/kg cocaine beginning on the 20th day of pregnancy (E20). The control animals received injections of equivalent volume of saline. The receptor densities were examined between days 5-30 of the treatment, which corresponds to E25-E50. By the fifth day of treatment (E25), cocaine produced downregulation of all receptors studied throughout the entire depth of the fetal cerebral wall. More extended treatment, however, resulted in recovery of receptor levels. Finally, from days 20-30 of treatment (E40-E50) there was a significant upregulation of noradrenergic and dopaminergic receptor sites. These findings demonstrate that exposure to cocaine in utero can influence adrenergic, serotonergic, and dopaminergic receptors in the embryonic cerebral wall, which may lead to alteration in corticogenesis. Furthermore, the present study reveals that, in the course of chronic treatment, cocaine may completely reverse its receptor regulatory activity in the fetal brain.     

Withdrawal following cocaine self-administration decreases regional cerebral metabolic rate in critical brain reward regions

The quantitative [¹⁴C]-2-deoxyglucose autoradiographic method was utilized to assess regional cerebral metabolic rate for glucose (rCMR_glc) in rat brain during withdrawal from cocaine self-administration. RCMR_glc was determined in 62 regions from brains of naïve rats which were placed into an empty operant chamber for 12 hr continuously, and rats trained to self-administer cocaine during 3 hr training sessions and subsequently placed into the operant chamber for 12 hr continuously with or without access to cocaine. Animals placed into the chamber without access to cocaine were examined 6 hr later, while animals allowed access to the 12 hr cocaine binge were examined either 6 or 72 hr post-cocaine. Metabolic activity was reduced during withdrawal in the nucleus accumbens, olfactory tubercle, islands of Calleja region, basolateral and central amygdaloid nuclei, medial septum, piriform and cingulate cortices, rostral caudatoputamen, entopeduncular nucleus and the adjacent lateral hypothalamus, somatosensory, auditory, and motor cortices compared to the naïve state. These effects were usually more severe at 72 than at 6 hr after binge exposure, with intermediate values observed in cocaine trained animals without binge exposure. The response was negatively correlated with the amount of cocaine consumed during binge exposure in the striatum, olfactory tubercle, piriform, cingulate, somatosensory, and motor cortices. Thus, the amount of cocaine consumed can affect the extent of metabolic depression after sustained drug exposure. The pattern of regional effects suggests that mesolimbic and rostral extrapyramidal dopamine terminal regions and certain of their efferent pathways are preferentially affected during cocaine withdrawal. The reduction of basal metabolic rate observed in these brain regions during cocaine withdrawal may become more severe with time despite the apparent recovery of certain behavioral-motivational responses. © Wiley-Liss, Inc.     

Inflammatory cytokines,complement factor H and anhedonia in drug-naïve major depressive disorder

ObjectiveAnhedonia is a core symptom of major depressive disorder (MDD) and often associated with poor prognosis. The main objective of the present study was to explore the relationship between complement factor H (CFH), inflammatory cytokines and anhedonia in drug-naïve MDD patients.MethodsA total of 215 participants (61 MDD patients with anhedonia, 78 MDD patients without anhedonia, and 76 control subjects) were included. Severity of depression and levels of anhedonia were evaluated by Hamilton Rating Scale for Depression-17 (HAMD-17) and SHAPS (Snaith-Hamilton Pleasure Scale). Plasma levels of CFH, interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) were measured.ResultsThe plasma levels of CFH, IL-10 and TNF-α were higher in drug-naïve MDD patients than control subjects. Compared to MDD patients without anhedonia, patients with anhedonia showed higher levels of CFH and IL-6. The stepwise regression analysis revealed that IL-10, TNF-α, as well as IL-10 × TNF-α were associated with depressive symptoms measured by HAMD-17 in drug-naïve MDD patients, while only CFH levels were identified as a mediator factor for the severity of anhedonia in the patients.ConclusionMDD patients with anhedonia showed different inflammatory characteristics compared to patients without anhedonia. Our results provide novel evidence suggesting that increased plasma CFH levels may be a potential biomarker of anhedonia of subtyping MDD.     

Serum brain-derived neurotrophic factors in Taiwanese patients with drug-naïve first-episode schizophrenia: Effects of antipsychotics

Objectives: Brain-derived neurotrophic factors (BDNF) are known to be related to the psychopathology of schizophrenia. However, studies focussing on drug-naïve first-episode schizophrenia are still rare.

Methods: Over a 5-year period, we investigated the serum BDNF levels in patients with first-episode drug-naïve schizophrenia and compared them to age- and sex-matched healthy controls. We also explored the association between antipsychotic doses, positive and negative syndrome scale (PANSS) scores, and serum BDNF levels before and after a 4-week antipsychotic treatment.

Results: The baseline serum BDNF levels of 34 patients were significantly lower than those of the controls (df?=?66, P?=?.001). Although the PANSS scores of 20 followed-up patients improved significantly after antipsychotic treatment, the elevation of the serum BDNF levels was not statistically significant (P?=?.386). In addition, Pearson’s correlation test showed significant correlations between pre-treatment negative scale scores and percentage changes in BDNF (P?=?.002).

Conclusions: The peripheral BDNF levels in Taiwanese patients with drug-naïve first-episode schizophrenia, compared with healthy controls, did not elevate after antipsychotic treatment, and pre-treatment negative symptoms played a pivotal role in trajectories of serum BDNF levels. Large samples will be needed in future studies to verify these results.     

Transcranial direct current stimulation on primary sensorimotor area has no effect in patients with drug-naïve restless legs syndrome: a proof-of-concept clinical trial

ObjectiveTo evaluate the efficacy of transcranial direct current stimulation (tDCS) in people with drug-naïve restless legs syndrome (RLS).MethodsA two-week, double-blind, randomized, sham-controlled trial was performed. Thirty-three females with RLS were recruited. Participants received five sessions of tDCS using cathodal, anodal or sham stimulation. They were assessed at baseline (T0), three days (T1) and 13 days (T2) after the end of tDCS. Primary outcomes included the International RLS Group Rating Scale (IRLS) and the Clinical Global Impressions-Improvement (CGI-I). Secondary outcomes included the Patient Global Impression scale, the Pittsburgh Sleep Quality Index, the Medical Outcome Study sleep subscales, and the Beck Depression Inventory. Objective neurophysiological changes were assessed using event-related desynchronization/synchronization (ERD/ERS) of electroencephalography.ResultsThe changes in the IRLS scores, as well as the responder rate in the CGI-I scale, did not differ significantly among the groups. There was also no significant difference in any of the secondary outcome measures and ERD/ERS among the groups.ConclusionsTranscranial direct current stimulation with electrodes on the sensorimotor areas showed no significant effect in people with drug-naïve RLS.     

Adverse effect of maternal caffeine ingestion on fetal cerebrum in rat

This study was undertaken to determine whether maternal caffeine ingestion is or is not a risk factor in fetal cerebral development using experimental rat models. Pregnant rats of the Wistar strain were given 0.04% caffeine in drinking water before and/or during pregnancy for various numbers of days. Control rats received water for the same periods. There was no reduction of maternal body weight, fetal body weight or fetal total brain weight. Low fetal cerebral weight and placental weight were observed when dams were given caffeine before mating for long times and/or throughout pregnancy. DNA, RNA and protein contents per cerebrum were also reduced in fetuses from dams given caffeine throughout pregnancy or for the last 6 gestational days. Cerebral DNA and protein contents as expressed per wet weight were higher and significantly lower respectively in the fetuses from dams given caffeine throughout pregnancy when compared to controls. Activity of thymidine kinase was not significantly decreased in caffeine-treated fetuses. There was a positive correlation between maternal serum and fetal cerebral caffeine levels. Additionally a negative correlation between maternal caffeine levels and fetal survival rates which decreased in litters from dams given caffeine throughout pregnancy was demonstrated. Our rat model indicates maternal caffeine ingestion during pregnancy is associated with reduction of fetal cerebral weight and protein content without reduction of body weight.     

Dual-isotope SPECT imaging of striatal dopamine: a comparative study between never-treated and haloperidol-treated first-episode schizophrenic patients

The aim of this dual-isotope SPECT imaging study was to evaluate striatal dopamine transporter (DAT) and D2 receptor availability in first-episode never-treated and haloperidol-treated schizophrenic patients and whether the availability is associated with psychopathology. Twenty-four inpatients with a first acute schizophrenic episode were enrolled in the study; 12 of these patients were treated with haloperidol for 2 weeks before dual-isotope SPECT was performed, whereas the other 12 patients underwent the SPECT evaluation directly after enrollment. Twelve healthy control persons were also recruited and evaluated with the dual-isotope SPECT protocol. Psychopathology was assessed by the Positive and Negative Syndrome Scale and other scales. D2-radioligand binding did not differ between drug-naïve patients and the control group but was significantly lower in the haloperidol-treated group. DAT availability was also significantly lower in the haloperidol patients than in the other two groups and differed significantly between drug-naïve, positive-syndrome-type patients and healthy controls. The data obtained with the new dual-isotope SPECT technique reveal a direct effect of haloperidol at the D2 and DAT receptor level.     

Intrauterine cocaine exposure of rabbits: persistent elevation of GABA-immunoreactive neurons in anterior cingulate cortex but not visual cortex

The effects of prenatal cocaine exposure on the development of the rabbit cerebral cortex were studied. Two cortical areas were compared: primary visual cortex (VC) and anterior cingulate (ACC). ACC was selected because behavioral deficits observed in cocaine-exposed infants suggest the involvement of ACC. In addition, ACC receives dense dopaminergic innervation and cocaine's action in inhibiting the re-uptake of dopamine is believed to underly the rewarding properties of cocaine. VC was selected as a control area because there is no evidence of behavioral deficits associated with visual perception in cocaine-exposed infants, and because VC receives minimal dopaminergic innervation. Two aspects of cortical development was studied: (i) cortical morphology, growth and cytoarchitectonic organization; and (ii) the development of the GABAergic neurotransmitter system. Measures of postnatal cortical growth, including cortical lamination, cell number and soma size, were compared in cocaine-exposed or control (saline) rabbits aged P5–P60. There was no difference between cocaine and saline animals in any of these parameters, and cortical cytoarchitecture appeared normal. However, despite the absence of major abnormalities in cortical development, we found that the number of GABA-immunoreactive neurons in cocaine-exposed animals was significantly higher than normal in ACC. This effect was highly consistent, was present in all laminae and at all ages studied, and persisted into maturity (P60). In contrast, in VC, the number of GABA-immunoreactive neurons in cocaine-exposed animals did not differ from normal. We suggest that increased GABA immunoreactivity may reflect a compensatory response to excessive excitatory input to ACC. A change in the balance of excitation and inhibition in ACC, reflecting ‘noisy’ or dysfunctional intracortical circuitry, may underly the emotional lability and attentional deficits characteristically described in infants exposed in utero to cocaine.     

Serum cortisol and BDNF in patients with major depression—effect of yoga

Abstract

Depression is associated with low serum Brain Derived Neurotrophic Factor (BDNF) and elevated levels of serum cortisol. Yoga practices have been associated with antidepressant effects, increase in serum BDNF, and reduction in serum cortisol. This study examined the association between serum BDNF and cortisol levels in drug-naïve patients with depression treated with antidepressants, yoga therapy, and both. Fifty-four drug-naïve consenting adult outpatients with Major Depression (32 males) received antidepressants only (n?=?16), yoga therapy only (n?=?19), or yoga with antidepressants (n?=?19). Serum BDNF andcortisol levels were obtained before and after 3 months using a sandwich ELISA method. One-way ANOVA, Chi-square test, and Pearson’s correlation tests were used for analysis. The groups were comparable at baseline on most parameters. Significant improvement in depression scores and serum BDNF levels, and reduction in serum cortisol in the yoga groups, have been described in previous reports. A significant negative correlation was observed between change in BDNF (pre–post) and cortisol (pre–post) levels in the yoga-only group (r?=??0.59, p =?0.008). In conclusion, yoga may facilitate neuroplasticity through stress reduction in depressed patients. Further studies are needed to confirm the findings and delineate the pathways for these effects.     

Sex hormone levels in drug-naïve,first-episode patients with psychosis

Abstract

Aim: Sex differences have long been reported in schizophrenia leading to the hypothesis that sex hormones may be implicated in the pathophysiology of the disorder. We assessed gonadal hormones during the fasted state in drug-naïve patients with psychosis.

Method: Fasting serum concentrations of follicular-stimulating hormone (FSH) and luteinizing hormone (LH), testosterone, free-testosterone, Sex Hormone Binding Globulin (SHBG) and oestradiol (E₂) were compared between a group of 55 newly diagnosed, drug-naïve, first-episode men with psychosis and a group of 55 healthy controls, matched for age, smoking status and BMI. Testosterone, free-testosterone and SHBG were compared between a group of 32 drug-naïve, first-episode females with psychosis and a group of 32 healthy controls matched for age, smoking status and BMI.

Results: Testosterone and free-testosterone levels were significantly lower in the patients’ group and SHBG levels significantly higher in the patients’ group compared to those in healthy controls. The two female groups had similar values in the hormones which were measured.

Conclusion: Our findings provide evidence of lower testosterone and free-testosterone levels and increased SHBG levels in drug-naïve, first-episode males with psychosis.

• KEY POINTS

• Reduced testosterone and free-testosterone levels in drug-naive, first-episode males with psychosis.

• Increased SHBG levels in drug-naive first-episode males with psychosis.

• No difference in FSH, LH and E2 levels between drug-naive first episode males with psychosis and controls.

• No difference in testosterone, free-testosterone and SHBG levels between drug-naive, first-episode women with psychosis and controls.

     

Consequences of maternal cocaine on cerebral microvascular functions in piglets

Maternal cocaine abuse is associated with fetal and neonatal neurological abnormalities. Prolonged exposure to cocaine can induce blood flow disorders, growth restriction, and hypoxia in the newborn. We investigated the impact of chronic fetal cocaine exposure on cerebral microvascular reactivity and autonomic function in the piglets. Pregnant pigs received cocaine (1 mg/kg i.v.; twice weekly) or saline throughout the last trimester. Prenatal exposure to cocaine did not have any significant effect on the birth weight of the piglets as compared to the control. Following delivery, effects of recurrent prenatal cocaine exposure on cerebral microvascular functions were examined in piglets (3-6 days old). Pial arteriolar responses to applications of 5-hydroxytryptamine (5-HT), endothelin-1 (ET-1), and clonidine were examined using closed cranial windows. Functional effects of prenatal cocaine exposure on changes in mean arterial pressure (MAP) and pial arteriolar diameter induced by intracisternal injection (i.c.) of clonidine (1 microg/kg) were also determined. Topical applications of 5-HT, ET-1, and clonidine dose-dependently decreased pial arteriolar diameter in the control and these constrictions were significantly enhanced in the in utero cocaine-exposed piglets. Prenatal cocaine exposure did not have any significant effects on the resting MAP and heart rate as there were no differences between the groups. IC clonidine caused sustained decrease in MAP in both groups but the decrease was more pronounced in the cocaine than the control group. IC clonidine causes cerebral microvascular dilation coincident with the development of hypotension. Such dilation was severely attenuated in the cocaine group, even though the hypotension was much more pronounced than in the control. In conclusion, prenatal cocaine exposure resulted in attenuated autoregulatory vasodilation and potentiated responses to vasoconstrictor agents. The mechanisms behind the effects of in utero cocaine exposure on alteration of newborn cerebral functions need further investigation. Such actions may be important in development of cerebral pathologies associated with recurrent prenatal cocaine exposure.