Recent observations indicate that drugs of abuse, including alcohol and opiates, impair adult neurogenesis in the hippocampus. We have studied in rats the impact of cocaine treatment (20 mg/kg, daily, i.p.) on cell proliferation, survival and maturation following short-term (8-day) and long-term (24-day) exposure. Using 5'-bromo-2-deoxyuridine (BrdU) and Ki-67 as mitotic markers at the end of the drug treatments, we found that both short- and long-term cocaine exposures significantly reduced cell proliferation in the dentate gyrus (DG) of the hippocampus. By labelling mitotic cells with BrdU pulses before or during the early stages of the drug treatment, we determined that long-term cocaine exposure did not affect the survival of newly generated cells. In register with this finding, cocaine chronic exposure did not increase the number of apoptotic cells labelled by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling). Using doublecortin (DCX) immunocytochemistry and electron microscopy, we next examined the effects of cocaine exposure on the maturation of the neural precursors and on synaptic output to CA3. DCX immunocytochemistry showed that immature hippocampal cells of rats exposed to cocaine displayed normal arborization patterns and similar degrees of colocalization with BrdU at two different developmental stages. Moreover, cocaine did not produce significant morphological alterations of the mossy fibre projection system to stratum lucidum in the CA3 area of the hippocampus. The results presented demonstrate that chronic cocaine exposure impairs proliferation dynamics in the DG without significantly altering either the survival and growth of immature cells or the structural features of terminal projections to CA3.

Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus.

A total of 45 male Sprague-Dawley rats were employed to determine whether cocaine or cocaine methiodide (CM) administration can induce a significant increase in mean arterial blood pressure (MABP) in rats, and whether such an increase in MABP can produce a global increase in blood oxygenation level-dependent (BOLD) contrast in the rat brain detectable by functional magnetic resonance imaging (fMRI) Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier (BBB) Experimental results demonstrated that both CM (with doses of 25 and 75 mg/kg) and cocaine (with doses of 125 and 50 mg/kg) can induce a significant MABP change (30-80%) It was found that CM can only produce scattered, weak, and transient BOLD signals in a few voxels of the rat brain, and that these MABP-induced BOLD signals are not dose-dependent In contrast, the administration of cocaine induced dose-dependent biphasic BOLD signals that were consistent with pharmacologically-induced cerebral vascular constriction and neuronal activity in the mesolimbic systems of the rat brain The potential confounding factor of the MABP changes had little effect on the interpretation of drug-induced BOLD signal changes These results confirm that the BOLD-weighted fMRI method can be extended to map drug-induced neuronal activity

Characterization of effects of mean arterial blood pressure induced by cocaine and cocaine methiodide on BOLD signals in rat brain

Neuropeptide Y (NPY) potentiates the effect of luteinizing hormone-releasing hormone (LHRH) on luteinizing hormone secretion in several species, including human. In addition to the pituitary sites, the interactions of the NPY and LHRH systems may involve diencephalic loci. However, the morphologic basis of this putative communication has not yet been elucidated in the human brain. To discover interaction sites, the distribution and connections of LHRH and NPY-immunoreactive (IR) neuronal elements in the human hypothalamus were investigated by means of light microscopic single- and double-label immunocytochemistry. NPY-IR perikarya and fibers were found to be widely distributed in the ventral diencephalon, with high densities in the preopticoseptal, periventricular, and tuberal regions. Small neuronal cell groups were infiltrated with a dense network of varicose NPY-IR fibers in the lateral preoptic area. The LHRH-IR perikarya were located mainly in the preopticoseptal region, diagonal band of Broca, lamina terminalis, and periventricular and infundibular nuclei. A few LHRH-IR neurons and fibers were scattered in the mamillary region. The overlap between the NPY and LHRH systems was apparent in the periventricular, paraventricular, and infundibular nuclei. Double-labeling immunohistochemistry showed NPY-IR axon varicosities in contact with LHRH-IR perikarya and main dendrites. The putative innervation of LHRH neurons by NPY-IR fibers was also seen in 1-microm-thick plastic sections and with confocal laser scanning microscope, thus further supporting the functional impact of NPY-IR terminals on LHRH-IR neurons. The present findings suggest that the hypophysiotropic LHRH-synthesizing neurons may be innervated by intrahypothalamic NPY-IR fibers. Confirmation by ultrastructural analysis would demonstrate that the LHRH system in the human hypothalamus is regulated by NPY, as has been demonstrated in nonhuman species.

Topography and associations of luteinizing hormone-releasing hormone and neuropeptide Y-immunoreactive neuronal systems in the human diencephalon.

Many important physiological, behavioral, and psychoemotional effects of intravenous (IV) cocaine (COC) are too fast and transient compared with pharmacokinetic predictions, suggesting a possible involvement of peripheral neural mechanisms in their triggering. In the present study, we examined changes in cortical electroencephalogram (EEG) and neck electromyogram (EMG) induced in freely moving rats by IV COC administration at low, reinforcing doses (0.25–1.0 mg/kg) and compared them with those induced by an auditory stimulus and IV COC methiodide, which cannot cross the blood-brain barrier. We found that COC induces rapid, strong, and prolonged EEG desynchronization, associated with decrease in alpha and increase in beta and gamma activities, and EMG activation and that both begin within 2–6 s following the start of a 10-s injection; immediate components of this effect were dose independent. The rapid COC-induced changes in EEG and EMG resembled those induced by an auditory stimulus; the latter effects had shorter onset latencies and durations and were fully blocked during urethane anesthesia. Although urethane anesthesia completely blocked COC-induced EMG activation and rapid components of EEG response, COC still induced EEG desynchronization that was much weaker, greatly delayed (∼60 s), and associated with tonic decreases in delta and increases in alpha, beta, and gamma activities. Surprisingly, IV saline delivered during slow-wave sleep (but not quite wakefulness) also induced a transient EEG desynchronization but without changes in EMG activity; these effects were also fully blocked during anesthesia. Peripherally acting COC methiodide fully mimicked rapid EEG and EMG effects of regular COC, but the effects at an equimolar dose were less prolonged than those with regular COC. These data suggest that in awake animals IV COC, like somato-sensory stimuli, induces cortical activation and a subsequent motor response via its action on peripheral neural elements and involving rapid neural transmission. By providing a rapid neural signal and triggering transient neural activation, such an action might play a crucial role in the sensory effects of COC, thus contributing to the learning and development of drug-taking behavior.

Rapid EEG desynchronization and EMG activation induced by intravenous cocaine in freely moving rats: a peripheral, nondopamine neural triggering

Neuropeptide Y (NPY) is a sympathetic cotransmitter and a platelet-derived factor which causes vasoconstriction, potentiation of norepinephrine (NE) action, and vascular mitogenic effects. Reciprocally, NE markedly enhances the actions of NPY. We studied vasopressor effects of NPY and sources of peptide release during the development of hypertension in spontaneously hypertensive rats (SHR). Conscious SHR (4 and 16 weeks old) had higher resting plasma levels of NE and epinephrine than age-matched Wistar-Kyoto (WKY) rats, but similar NPY immunoreactivity (NPY-ir) levels in platelet-poor plasmas (PPP). In both strains, NPY-ir levels in PPP were higher in 4-week-old than in older rats. However, at all ages (4-24 weeks) SHR had markedly elevated NPY-ir content in platelet-rich-plasmas than WKY rats, although levels declined with age and hypertension. In the superior mesenteric artery, NPY-ir content (per mg) was significantly higher in 4-week-old but lower in 16-week-old SHR than in WKY rats, suggesting greater sympatho-neural NPY stores and release (leading to depletion) during the development of hypertension. Four-week-old SHR also tended to have higher NPY-ir content in the adrenal medullae and coeliac ganglia but a lower content in the kidney than WKY rats; these differences disappeared with age. Pressor responsiveness to alpha-agonists and NPY were similar in both strains at 4 weeks. While unchanged by age in WKY rats, adrenergic and NPY-mediated vasopressor responses became augmented in 16- to 24-week-old SHR (compared with WKY rats); this hyperresponsiveness was not completely abolished by ganglionic blockade and not observed with vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of vascular function by neuropeptide Y during development of hypertension in spontaneously hypertensive rats

The effects of various doses of intravenously (i.v.) infused (5-min duration, 0.1-3.2 nmol/kg/min) or bolus-injected (0.1-3.2 nmol/kg) porcine and/or rat/human neuropeptide Y (NPY) on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of porcine NPY-like immunoreactivity (pNPYir) were examined in conscious, unrestrained spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats of various ages. When administered as an infusion to 12- to 17-week-old SHR, WKY, and SD rats, porcine NPY (pNPY) was more potent in increasing MAP in SHR than in either WKY or SD rats. Infusions of rat/human NPY instead of pNPY resulted in similar increases in potency in 12- to 17-week-old SHR as compared with WKY. This potency-associated hyperresponsiveness to infused pNPY was also observed when 36- to 41-week-old and 6-week-old SHR and WKY were examined, but infused NPY induced similar HR reductions in age-matched rats regardless of rat strain. Furthermore, doses of infused pNPY that elicited significantly greater pressor responses in SHR and WKY (0.32 nmol/kg/min in 12- to 17-week-old rats and 1.0 nmol/kg/min in 6-week-old rats) resulted in essentially identical plasma pNPYir concentrations in the two rat strains. In contrast, hyperresponsiveness to the MAP effects of bolus injections of pNPY in 12- to 17-week-old SHR was manifested as an increase in efficacy rather than potency, was associated with significantly smaller reductions in HR in SHR than in WKY and occurred at plasma pNPYir concentrations that were significantly larger than those required for infusion-associated hyperresponsiveness. These results are consistent with the hypothesis that NPY is an important contributor to the development and maintenance of essential hypertension.

Age-dependent hyperresponsiveness of spontaneously hypertensive rats to the pressor effects of intravenous neuropeptide Y (NPY): role of mode of peptide administration and plasma NPY-like immunoreactivity.

It has been suggested that cocaine acts directly in the brain to enhance central sympathetic outflow. However, some studies suggested that the cardiovascular effects of cocaine are related to a peripheral action. To characterize further the site of cocaine's cardiovascular effect, we compared the hemodynamic effects of cocaine (2 mg/kg, i.v. bolus) with those observed after administration of an equimolar dose (2.62 mg/kg, i.v. bolus) of cocaine methiodide, a quaternary derivative of cocaine that does not penetrate the blood-brain barrier, by using sufentanil-sedated dogs. Cocaine produced significant (p < 0.05) increases in heart rate (+37+/-11 beats/min), mean arterial pressure (+55+/-11 mm Hg), left ventricular end-diastolic pressure (+5.3+/-1.0 mm Hg), and cardiac output (+2.4+/-0.9 L/min). Cocaine methiodide produced increases in heart rate (+57+/-11 beats/min), mean arterial pressure (+45+/-11 mm Hg), left ventricular end-diastolic pressure (+3.4+/-1.0 mm Hg), and cardiac output (1.1+/-0.9 L/min), which were not significantly different from those observed with cocaine. Because opiate sedation potentially might have attenuated central sympathetic outflow, we further confirmed the qualitative similarity of the actions of cocaine and cocaine methiodide on heart rate and blood pressure in unsedated, conscious dogs. Our data suggest that the cardiovascular effects of cocaine result primarily from a peripheral site of action.

Cocaine-induced cardiovascular effects: lack of evidence for a central nervous system site of action based on hemodynamic studies with cocaine methiodide.

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists

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Age-dependent hyperresponsiveness of spontaneously hypertensive rats to the pressor effects of intravenous neuropeptide Y (NPY): role of mode of peptide administration and plasma NPY-like immunoreactivity.

Cocaine-induced cardiovascular effects: lack of evidence for a central nervous system site of action based on hemodynamic studies with cocaine methiodide.

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists