Reduced Leukoaraiosis, Noncardiac Embolic Stroke Etiology, and Shorter Thrombus Length Indicate Good Leptomeningeal Collateral Flow in Embolic Large-Vessel Occlusion.

BACKGROUND AND PURPOSE: Acute leptomeningeal collateral flow is vital for maintaining perfusion to penumbral tissue in acute ischemic stroke caused by large-vessel occlusion. In this study, we aimed to investigate the clinically available indicators of leptomeningeal collateral variability in embolic large-vessel occlusion. MATERIALS AND METHODS: Among prospectively registered consecutive patients with acute embolic anterior circulation large-vessel occlusion treated with thrombectomy, we analyzed 108 patients admitted from January 2015 to December 2019 who underwent evaluation of leptomeningeal collateral status on pretreatment CTA. Clinical characteristics, extent of leukoaraiosis on MR imaging, embolic stroke subtype, time of imaging, occlusive thrombus characteristics, presenting stroke severity, and clinical outcome were collected. The clinical indicators of good collateral status (>50% collateral filling of the occluded territory) were analyzed using multivariate logistic regression analysis. RESULTS: Good collateral status was present in 67 patients (62%) and associated with independent functional outcomes at 3 months. Reduced leukoaraiosis (total Fazekas score, 0-2) was positively related to good collateral status (OR, 9.57; 95% CI, 2.49-47.75), while the cardioembolic stroke mechanism was inversely related to good collateral status (OR, 0.17; 95% CI, 0.02-0.87). In 82 patients with cardioembolic stroke, shorter thrombus length (OR, 0.91 per millimeter increase; 95% CI, 0.82-0.99) and reduced leukoaraiosis (OR, 5.79; 95% CI, 1.40-29.61) were independently related to good collateral status. CONCLUSIONS: Among patients with embolic large-vessel occlusion, reduced leukoaraiosis, noncardiac embolism mechanisms including embolisms of arterial or undetermined origin, and shorter thrombus length in cardioembolism are indicators of good collateral flow.

Perfusion Parameter Thresholds That Discriminate Ischemic Core Vary with Time from Onset in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: When mapping the ischemic core and penumbra in patients with acute ischemic stroke using perfusion imaging, the core is currently delineated by applying the same threshold value for relative CBF at all time points from onset to imaging. We investigated whether the degree of perfusion abnormality and optimal perfusion parameter thresholds for defining ischemic core vary with time from onset to imaging. MATERIALS AND METHODS: In a prospectively maintained registry, consecutive patients were analyzed who had ICA or M1 occlusion, baseline perfusion and diffusion MR imaging, treatment with IV tPA and/or endovascular thrombectomy, and a witnessed, well-documented time of onset. Ten superficial and deep MCA ROIs were analyzed in ADC and perfusion-weighted images. RESULTS: Among the 66 patients meeting entry criteria, onset-to-imaging time was 162 minutes (range, 94-326 minutes). Of the 660 ROIs analyzed, 164 (24.8%) showed severely or moderately reduced ADC (ADC ≤ 620, ischemic core), and 496 (75.2%), mildly reduced or normal ADC (ADC > 620). In ischemic core ADC regions, longer onset-to-imaging times were associated with more highly abnormal perfusion parameters-relative CBF: Spearman correlation, r = -0.22, P = .005; relative CBV: r = -0.41, P < .001; MTT: - r = -0.29, P < .001; and time-to-maximum: r = 0.35, P < .001. As onset-to-imaging times increased, the best cutoff values for relative CBF and relative CBV to discriminate core from noncore tissue became progressively lower and overall accuracy of the core tissue definition increased. CONCLUSIONS: Perfusion abnormalities in ischemic core regions become progressively more abnormal with longer intervals from onset to imaging. Perfusion parameter value thresholds that best delineate ischemic core are more severely abnormal and have higher accuracy with longer onset-to-imaging times.

Middle Cerebral Artery Plaque Hyperintensity on T2-Weighted Vessel Wall Imaging Is Associated with Ischemic Stroke.

BACKGROUND AND PURPOSE: Vessel wall imaging can identify intracranial atherosclerotic plaque and give clues about its components. We aimed to investigate whether the plaque hyperintensity in the middle cerebral artery on T2-weighted vessel wall imaging is associated with ischemic stroke. MATERIALS AND METHODS: We retrospectively reviewed our institutional vessel wall MR imaging data base. Patients with an acute ischemic stroke within 7-day onset in the MCA territory were enrolled. Patients with stroke and stenotic MCA plaque (stenosis degree, ≥50%) were included for analysis. Ipsilateral MCA plaque was defined as symptomatic, and contralateral plaque, as asymptomatic. Plaque was manually delineated on T2-weighted vessel wall imaging. The plaque signal was normalized to the ipsilateral muscle signal. The thresholds and volume of normalized plaque signal were investigated using logistic regression and receiver operating characteristic analysis to determine the association between normalized plaque signal and stroke. RESULTS: One hundred eight stenotic MCAs were analyzed (from 88 patients, 66 men; mean age, 58 ± 15 years), including 72 symptomatic and 36 asymptomatic MCA plaques. Symptomatic MCA plaque showed larger plaque hyperintensity volume compared with asymptomatic MCA plaque. The logistic regression model incorporating stenosis degree, remodeling ratio, and normalized plaque signal 1.3-1.4 (OR, 6.25; 95% CI, 1.90-20.57) had a higher area under curve in differentiating symptomatic/asymptomatic MCA plaque, compared with a model with only stenosis degree and remodeling ratio (area under curve, 0.884 versus 0.806; P =.008). CONCLUSIONS: The MCA plaque hyperintensity on T2-weighted vessel wall imaging is independently associated with ischemic stroke and adds value to symptomatic MCA plaque classification. Measuring the normalized signal intensity may serve as a practical and integrative approach to the analysis of intracranial atherosclerotic plaque.

Nonsphericity Index and Size Ratio Identify Morphologic Differences between Growing and Stable Aneurysms in a Longitudinal Study of 93 Cases.

BACKGROUND AND PURPOSE: Recent studies have strongly associated intracranial aneurysm growth with increased risk of rupture. Identifying aneurysms that are likely to grow would be beneficial to plan more effective monitoring and intervention strategies. Our hypothesis is that for unruptured intracranial aneurysms of similar size, morphologic characteristics differ between aneurysms that continue to grow and those that do not. MATERIALS AND METHODS: From aneurysms in our medical center with follow-up imaging dates in 2015, ninety-three intracranial aneurysms (23 growing, 70 stable) were selected. All CTA images for the aneurysm diagnosis and follow-up were collected, a total of 348 3D imaging studies. Aneurysm 3D geometry for each imaging study was reconstructed, and morphologic characteristics, including volume, surface area, nonsphericity index, aspect ratio, and size ratio were calculated. RESULTS: Morphologic characteristics were found to differ between growing and stable groups. For aneurysms of <3 mm, nonsphericity index (P < .001); 3-5 mm, nonsphericity index (P < .001); 5-7 mm, size ratio (P = .003); >7 mm, volume (P < .001); surface area (P < .001); and nonsphericity index (P = .002) were significant. Within the anterior communicating artery, the nonsphericity index (P = .008) and, within the posterior communicating artery, size ratio (P = .004) were significant. The nonsphericity index receiver operating characteristic area under the curve was 0.721 for discriminating growing and stable cases on the basis of initial images. CONCLUSIONS: Among aneurysms with similar sizes, morphologic characteristics appear to differ between those that are growing and those that are stable. The nonsphericity index, in particular, was found to be higher among growing aneurysms. The size ratio was found to be the second most significant parameter associated with growth.

The combination of baseline magnetic resonance perfusion-weighted imaging-derived tissue volume with severely prolonged arterial-tissue delay and diffusion-weighted imaging lesion volume is predictive of MCA-M1 recanalization in patients treated with endovascular thrombectomy.

INTRODUCTION: Indices of collateral flow deficit derived from MR perfusion imaging that are predictive of MCA-M1 recanalization after intravenous thrombolysis have been recently reported. Our objective was to test the performance of such MRI-derived collateral flow indices for prediction of recanalization after endovascular thrombectomy. METHODS: Fifty-seven patients with MCA-M1 occlusion evaluated with multimodal MRI prior to thrombectomy were included. Bayesian processing allowed quantification of collateral perfusion indices like the volume of tissue with severely prolonged arterial-tissue delay (>6 s) (VolATD6). Baseline DWI lesion volume was also measured. Correlations with angiographic collateral flow grading and post-thrombectomy recanalization were assessed. RESULTS: VolATD6 < 27 ml or DWI lesion volume <15 ml provide the most accurate diagnosis of excellent collateral supply (p < 0.0001). The combination of VolATD6 > 27 ml and DWI lesion volume >15 ml significantly discriminates recanalizers versus nonrecanalizers (whole cohort, p = 0.032; MERCI cohort (n = 50), p = 0.024). When both criteria are positive, 76.2 % of the patients treated with the MERCI retriever do not fully recanalize (p = 0.024). In multivariate analysis, the aforementioned combined criterion and the angiographic collateral grade are the only independent predictors of recanalization with the MERCI retriever (p = 0.015 and 0.029, respectively). CONCLUSION: Bayesian arterial-tissue delay maps and DWI maps provide a non-invasive assessment of the degree of collateral flow and a combined index that is predictive of MCA-M1 recanalization after endovascular thrombectomy. Further studies are needed to evaluate the accuracy of this index in patients treated with novel stent retriever devices.

Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects.

Neonatal rat pups exposed to repetitive acute pain show decreases in pain threshold and altered behavior during adulthood. A model using prolonged inflammatory pain in neonatal rats may have greater clinical relevance for investigating the long-term behavioral effects of neonatal pain in ex-preterm neonates. Neonatal rat pups were exposed to repeated formalin injections on postnatal (P) days 1-7 (P1-P7), with or without morphine pretreatment, and were compared with untreated controls. Behavioral testing during adulthood assessed pain thresholds using hot-plate (HP) and tail-flick (TF) tests, alcohol preference, and locomotor activity (baseline and postamphetamine). Adult rats exposed to neonatal inflammatory pain exhibited longer HP latencies than controls and male rats had longer HP thresholds compared to females. Male rats exposed to neonatal morphine alone exhibited longer TF latencies than controls. Both neonatal morphine treatment and neonatal inflammatory pain decreased ethanol preference, but their effects were not additive. During adulthood, male rats exposed to neonatal inflammatory pain exhibited less locomotor activity than untreated controls. We conclude that neonatal formalin and morphine treatment have specific patterns of long-term behavioral effects in adulthood, some of which are attenuated when the two treatments are combined.

Retinoic acid exposure on gestational days 11 to 13 impairs swallowing in rat offspring.

We have previously reported that exposure to 10 mg/kg of all-trans-retinoic acid (RA) daily on the 11th, 12th, and 13th days of rat gestation is lethal to all fetuses so exposed, due to an inability to suckle [R.R. Holson et al., Neurotoxicol Teratol 19 (1997) 347-353]. Because this lethal RA effect could be due to any of a variety of causes, from olfactory problems in locating the nipple to a motor problem in sucking or swallowing, we performed the following experiment. Albino dams were exposed to 10-mg/kg RA or vehicle daily over gestational days (GDs) 11 to 13. On the afternoon of GD 21 all pups were delivered by c-section. Tongue cannulae were inserted into the oral cavity of these offspring, and used to infuse a solution of condensed milk directly into the mouth. During and after each of four infusions, the behavioral response to the infusion (typically rolling and curling) was recorded. Controls responded well to this procedure, typically swallowing all milk so infused. In contrast, almost no RA-exposed neonates were able to swallow milk infused into the oral cavity. In such cases the milk simply dribbled out of the mouth, while the stomach was found to be empty at autopsy. However, the RA-treated animals did seem aware that milk was entering their mouths, because they showed a normal behavioral response to milk infusion. We conclude that GD 11-13 retinoid lethality is due to motor not sensory problems in the control of swallowing.

Can adverse neonatal experiences alter brain development and subsequent behavior?

Self-destructive behavior in current society promotes a search for psychobiological factors underlying this epidemic. Perinatal brain plasticity increases the vulnerability to early adverse experiences, thus leading to abnormal development and behavior. Although several epidemiological investigations have correlated perinatal and neonatal complications with abnormal adult behavior, our understanding of the underlying mechanisms remains rudimentary. Models of early experience, such as repetitive pain, sepsis, or maternal separation in rodents and other species have noted multiple alterations in the adult brain, correlated with specific behavioral phenotypes depending on the timing and nature of the insult. The mechanisms mediating such changes in the neonatal brain have remained largely unexplored. We propose that lack of N-methyl-D-aspartate (NMDA) receptor activity from maternal separation and sensory isolation leads to increased apoptosis in multiple areas of the immature brain. On the other hand, exposure to repetitive pain may cause excessive NMDA/excitatory amino acid activation resulting in excitotoxic damage to developing neurons. These changes promote two distinct behavioral phenotypes characterized by increased anxiety, altered pain sensitivity, stress disorders, hyperactivity/attention deficit disorder, leading to impaired social skills and patterns of self-destructive behavior. The clinical important of these mechanisms lies in the prevention of early insults, effective treatment of neonatal pain and stress, and perhaps the discovery of novel therapeutic approaches that limit neuronal excitotoxicity or apoptosis.

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors.

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.

The role of NMDA and sigma systems in the behavioral effects of phencyclidine in preweanling rats.

To determine the role of NMDA receptor blockade and sigma receptors in the behavioral effects of PCP during development, we assessed the behavioral effects of PCP, (+)-MK-801 and 1,3-Di(2-tolyl)guanidine (DTG) in preweanling rats. In the first experiment, rats were injected sc on postnatal day (PND) 19 with 0.5-4.5 mg/kg PCP, and locomotor activity and wall climbing behavior were scored. PCP induced high levels of locomotor activity on PND 19 in a dose dependent manner with the 2.0 mg/kg dose producing the greatest activity. In the second experiment, rats were injected on PND 12 or 19 with 1.0-4.0 mg/kg PCP or 0.1-0.4 mg/kg (+)-MK-801 and tested using the same procedures. Both PCP and (+)-MK-801 induced activity increases on PND 19 in a dose dependent manner, with 2.0 and 3.0 mg/kg PCP and 0.2 mg/kg (+)-MK-801 inducing the highest activity levels. Peak activity levels on PND 12 were approximately 30% of those observed on PND 19, with the lowest dose of PCP and (+)-MK-801 producing the greatest activity. Large amounts of wall climbing behavior were elicited by PCP on PND 12, whereas (+)-MK-801 induced only minor amounts of wall climbing. In the third experiment, the effects of 0, 1, 3, 6, or 12 mg/kg DTG were examined in PND 13-14 and 16-17 rats. DTG had little effect on locomotor activity on PND 13-14, although the highest dose did inhibit activity. On PND 16-17, all doses of DTG tended to increase locomotor activity. The results suggest (1) the robust locomotor effects of PCP on PND 19 are mediated in part by NMDA mechanisms (2) this period of increased sensitivity to both PCP and (+)-MK-801 might represent a critical period of development when systems mediating locomotor activity are vulnerable to neurotoxic insult (3) NMDA blockade alone does not mediate PCP-induced wall climbing behavior and (4) that at the doses of DTG and the ages tested, sigma receptors do not play a role in the locomotor-inducing effects of PCP.

Haloperidol effects on the developing dopamine system: conflicting results and implications for neurobehavioral teratology research.

In an attempt to further develop basic principles to guide research in neurobehavioral teratology, six experiments were conducted to examine the effects of prenatal haloperidol (a D2 dopamine antagonist) exposure on striatal D1 and D2 binding sites. Another laboratory has repeatedly reported that prenatal exposure to this dopamine antagonist reduces striatal dopamine binding sites in exposed offspring. Our initial studies were successful in replicating and extending these previously reported reductions in D2 dopamine binding sites in caudate of rats exposed prenatally to haloperidol. However, additional experiments in our laboratory, in which pups were exposed to a range of haloperidol doses over gestational periods when the dopamine system has been reported to be most vulnerable to prenatal haloperidol exposure effects, have repeatedly failed to replicate our initial findings. Three other laboratories have also failed to duplicate this effect. The results of these studies suggest that beyond "standard" confounding variables, neurobehavioral teratologists are faced with as yet poorly understood factors that influence replication of findings within and between laboratories. These findings also emphasize the importance of within- and between-laboratory replication of experimental findings.

Effects of labetalol on cocaine pharmacokinetics in neonatal piglets.

Developmental exposure to cocaine can produce adverse neurobehavioral and cardiovascular effects. Few animal models of human neonatal exposure have been established. A pharmacokinetic study was therefore conducted to characterize the disposition of cocaine and a major metabolite benzoylecgonine (BE) using piglets as an animal model. Eight piglets (postnatal days 8-9) were instrumented with a jugular cannula for drug administration and blood sampling. One group of subjects (controls) received 6.0 mg/kg of cocaine-HCl (i.v.) and blood samples were drawn over 0-24 h. In another group (labetalol), 0.25 mg/kg labetalol-HCl was coadministered 15 min following cocaine dosing. Plasma levels of cocaine and BE were determined using GC-MS methods. Pharmacokinetics were evaluated by using a model-independent approach and compartmental modeling. For controls model-independent results were as follows: AUC = 148.9 +/- 9.0 mg/l x min, systemic clearance = 0.041 +/- 0.003 liters/min/kg, volume of distribution = 1.543 +/- 0.470 liters/kg, and t1/2 beta = 29.4 +/- 6.8 min. Cocaine followed two-compartment model kinetics with distribution and elimination half-lives of 0.3 +/- 0.1 and 58.0 +/- 18.0 min, respectively. Labetalol significantly decreased systemic clearance to 0.029 +/- 0.004 liters/min/kg. BE kinetics revealed a elimination half-life of 230.0 +/- 83.2 min. The results demonstrate a rapid distribution and metabolism of cocaine to BE followed by a prolonged elimination phase which is extended by labetalol treatment.

The ontogeny of phencyclidine-induced wall climbing and locomotor activity.

Wall climbing behavior is an age-specific behavior that is elicited during postnatal Days 7 through 17 by various stimuli that include heat, odors, shock, and the catecholaminergic agonists apomorphine, amphetamine, and clonidine. In a previous study, a significant amount of wall climbing behavior was observed during ataxia and activity testing following phencyclidine (PCP) administration in Day 19 but not Day 40 rat pups. The present study describes the ontogeny of PCP-induced wall climbing behavior and locomotor activity. Frequency and duration of wall climbing bouts and locomotor activity were recorded on Days 5, 12, 19, 26, 33, or 40 following PCP treatment. On Day 12, all doses of PCP induced significant amounts of wall climbing behavior. A similar pattern of results was observed on Day 5 although these effects were not statistically significant. After Day 12, PCP-induced wall climbing behavior declined precipitously. PCP increased locomotor activity at all ages tested with maximum activities observed on Day 19. These results demonstrate that PCP-elicited wall climbing behavior follows an ontogenetic profile similar to that previously reported for other stimuli and that there are robust ontogenetic differences in the locomotor response to PCP.

Prenatal haloperidol exposure: effects on brain weights and caudate neurotransmitter levels in rats.

Monoamines may exert a trophic effect on early brain development. To assess the role of dopamine in prenatal neurological development of the rat, haloperidol (HAL) was given in daily 2.5 or 5 mg/kg SC doses to dams over gestational days 6 to 20. This treatment regime did not enhance fetal mortality, but did produce reliable, if modest, stunting of the body and brain weight of offspring. The 5 mg/kg HAL dose consistently reduced offspring brain weight to roughly 90% of controls. This effect was probably permanent, in that it was seen throughout maturation and in adults as late as 140 days of postnatal age. Appropriate controls showed that this effect was not due to drug-induced reductions in food intake, to the presence of HAL in maternal milk, or to behavioral abnormalities in HAL-exposed dams. These effects had, at best, modest regional specificity, in that most brain regions were affected, independently of degree of dopaminergic innervation. Closer investigation of HAL effects on the striatum suggested that this permanent weight reduction was not accompanied by alterations in striatal concentrations of monoamines, monoamine metabolites, amino acids, choline, acetylcholine, DNA, protein, or water. It is concluded that prenatal HAL does stunt growth, but that this effect may not involve a direct drug influence restricted to the fetal dopamine system in the brain.

Cardiovascular responses to feeding in newborn piglets.

Cardiovascular responses to feeding have been observed in several species during various periods of development and have been implicated in the development of cardiovascular regulation. In the rat, these responses are characterized by short-lasting, large increases in blood pressure (BP) and moderate increases in heart rate. These responses appear to be sympathetically mediated because pretreatment with ganglionic blockers eliminates the increase in BP associated with milk ingestion. The present study was designed to determine if similar cardiovascular responses occur during feeding in the newborn piglet. Piglets were obtained on postnatal d 2 and fed a milk diet via automatic feeder 6 times a day. On postnatal d 6, the piglets were instrumented with an external carotid artery catheter and an internal jugular vein catheter. On postnatal d 8 and 9, direct arterial BP and heart rate were recorded during feeding. BP responses to milk ingestion were immediate, and they reached a maximum increase of 50% above baseline on both test days and followed a response profile similar to that previously described in the 15-d-old rat. An increase in heart rate was also observed, reaching a maximum of 42% above baseline. The results show that early in life piglets have large cardiovascular responses to milk ingestion similar to those observed in young rats and human infants. These responses appear to model the cardiovascular responses to feeding observed in human infants and might be useful as a noninvasive method for assessing neonatal autonomic reactivity. These responses also have the potential to cause adverse effects in newborns already at risk for cardiovascular and cerebrovascular disease.

The ontogeny of behavioral sensitization to phencyclidine.

Repeated exposure of adult rats to a variety of psychoactive compounds can result in altered behavioral responsiveness to later exposures depending on the dose, route, and frequency of administration and time of testing. The ontogeny and mechanism of this altered responsiveness are not well understood. To determine when behavioral sensitization to phencyclidine (PCP) occurs, neonatal and early developmental exposure effects of PCP were assessed on later behavioral responsiveness to a PCP challenge. Rat pups were injected daily for nine days beginning on either postnatal days (PNDs) 1 or 22 with 0.9% saline, 5.0 or 10.0 mg/kg PCP-HC1 (s.c.). Ten days following the last injection, rats were given one of the following drug challenges: 0.9% saline, 5.0 or 10.0 mg/kg PCP-HC1 (s.c.). Locomotor activity, ataxia, and several other behaviors were measured for 1 h beginning 2-3 min after the challenge injection. Two major findings emerged from these studies. First, pups treated subchronically with PCP on PNDs 1-9 did not exhibit any difference in behavioral sensitivity to a PCP challenge when tested on PND 19 compared to subchronically treated saline controls. In contrast, pups subchronically treated with PCP on PNDs 22-30 exhibited an increased sensitivity to the behavioral effects of a PCP challenge. These data suggest that PCP has age-dependent exposure effects that occur sometime after the first postnatal week and that result in an enhanced behavioral responsiveness to PCP later in life.

Pharmacological blockade of blood pressure and heart rate increases following milk ingestion in 15-day-old SHR and WKY rat pups.

The effects of hexamethonium, a ganglionic blocker, on blood pressure (BP) and heart rate (HR) responses to milk ingestion were assessed in awake, 15-day-old spontaneously hypertensive rats (SHR) and their normotensive progenitor strain, Wistar-Kyoto rats (WKY) using two methods of milk delivery. SHRs had larger increases in BP compared to WKYs, but WKYs exhibited larger increases in HR following milk ingestion from an anesthetized dam. BP responses to milk ingestion from a tongue cannula were also larger in SHRs. Administration of hexamethonium prior to milk delivery resulted in a drop in BP following milk ingestion in both milk delivery situations for each strain. The results suggest that SHRs exhibit exaggerated sympathetic activation to milk ingestion compared to WKYs, and that in both strains, cardiovascular responses to feeding are modulated by the presence of the dam.

Behavioral and neurochemical effects of prenatal methylenedioxymethamphetamine (MDMA) exposure in rats.

MDMA is a hallucinogenic drug that is used by the general public as a recreational drug of abuse. The neurobehavioral consequences of prenatal MDMA exposure are unknown. Groups of pregnant rats were gavaged with 0, 2.5, or 10 mg/kg MDMA during gestation on alternate gestational days 6-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatments. Pregnancy weight gain was significantly reduced by MDMA treatment. Progeny growth, maturational parameters (eye opening and incisor eruption times), surface righting reflex, swimming performance, forelimb grip strength, milk-induced behaviors, passive avoidance behavior, figure-8 maze activity over 48 hours, the density of brain serotonin (5-HT) uptake sites, and brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were unaffected by MDMA treatments. Olfactory discrimination on postnatal days (PND) 9-11 was enhanced in both male and female MDMA-treated progeny, while negative geotaxis (PND 7-10) was delayed in female pups. In contrast to progeny, MDMA caused dose-dependent decreases in 5-HT and 5-HIAA levels in discrete brain areas of the dam. It is concluded that prenatal exposure to MDMA at the levels used here produces only subtle behavioral alterations in developing rats. The dam is more at risk for MDMA-induced 5-HT depletion than is the conceptus.

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.