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Biomedical subjects

J M van Ree

Publications and source records attributed to J M van Ree.

At least 55 records · Page 3Linked to original sources
PubMed1996

Altered lipid metabolism in apolipoprotein E-deficient mice does not affect cholesterol balance across the liver.

Adaptation of cholesterol and bile acid synthesis and of biliary cholesterol secretion represent key metabolic responses to maintain cholesterol homeostasis and have been suggested to be influenced by apolipoprotein E (apoE) phenotype in humans. We have investigated hepatic metabolism and secretion of cholesterol into bile in homozygous apoE-deficient (apoE -/-) mice fed normal lab chow. Plasma cholesterol levels were 10 times higher in apoE (-/-) mice than in controls (+/+); triacylglycerol levels were only minimally affected. Hepatic cholesterol (+56%) and triacylglycerol (+232%) contents were significantly increased in apoE (-/-) mice, whereas those of cholesteryl ester and of phospholipids were similar in both groups. Lipid accumulated predominantly in periportal areas of apoE (-/-) livers. Hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) messenger RNA (mRNA) level and activity were reduced by 45% and 50%, respectively, in apoE (-/-) mice. In contrast, plasma lathosterol/cholesterol ratios, indicative for whole-body cholesterol synthesis, were fourfold increased in these mice. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was similar in livers of both groups. Despite the marked changes in hepatic cholesterol metabolism, neither hepatic bile acid synthesis, bile acid pool size and composition, nor hepatic cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase mRNA levels differed between apoE (-/-) and (+/+) mice. In addition, biliary cholesterol secretion was unaffected in the knock-out mice. Our results show that lack of apoE leads to marked changes in hepatic cholesterol metabolism without altering cholesterol balance across the liver. The data are compatible with increased peripheral cholesterol biosynthesis in apoE-deficient mice.

Animals↗
PubMed1996

Modifications in glutamatergic transmission after dopamine depletion of the nucleus accumbens. A combined in vivo/in vitro electrophysiological study in the rat.

The interaction between the glutamatergic and dopaminergic input in the nucleus accumbens was examined by studying the effects of dopamine depletion of the nucleus accumbens on the local field potentials, and the L-glutamate elicited responses of the nucleus accumbens in anaesthetized rats in vivo. A characteristic field potential in the nucleus accumbens is evoked by electrical stimulation of the fornix/fimbria fibres, with a monosynaptic positive peak at 10 ms (P10). Rats were unilaterally injected with 6-hydroxydopamine in the nucleus accumbens. The contralateral accumbens was sham lesioned. The rats were divided into short-term and long-term survival groups of one to two weeks and 24 weeks, respectively. In the short-term group, a striking increase (up to three times) of the amplitude of the P10 components, at the site of the lesion, compared with the sham lesioned contralateral accumbens and untreated rats, was found. The long-term group could still display a slight increase although on average this was not significantly different from controls. In the short-term group, at the centre of the lesion, the paired-pulse facilitation ratio was significantly smaller than at the more ventral, less denervated, border of the accumbens. These differences were no longer visible in the long-term group. Single-unit activity of the accumbens, elicited by the iontophoretical application of L-glutamate showed, in controls, a maximal firing frequency ranging from 5 to 40 Hz (mean 25 Hz), whereas in the short-term group more than 50% of the accumbens neurons fired with higher frequencies, reaching up to 90 Hz (mean 55 Hz). In the long-term group the firing frequency varied from 5 to 60 Hz (mean 41 Hz). No changes in threshold ejection glutamate current were found for both lesioned groups. In control rats the L-glutamate elicited responses of six cells tested could be suppressed by dopamine whereas in lesioned rats three of the six cells tested were unresponsive to dopamine. Intracellular recordings of accumbens cells in slices in 6-hydroxydopamine and sham lesioned rats, showed no significant changes in the intrinsic membrane properties, e.g. resting membrane potential, input resistance, spike threshold, action potential amplitude or duration. We conclude that dopamine denervation leads to an increase of excitability of the principal accumbens neurons. This is reflected by the increase of the firing frequency of these cells and of the amplitude of the evoked field potentials. The former is more likely of postsynaptic origin whereas the latter may also have a presynaptic contribution. These effects cannot be attributed to changes in intrinsic membrane properties of the cells.

Adrenergic Agents↗
PubMed1996

A controlled trial with ORG 2766, an ACTH-(4-9) analog, in 50 relatively able children with autism.

The aim of the present study was to replicate earlier findings of beneficial effects of ORG 2766, an ACTH-(4-9) analog, in autistic children. Fifty children with autism, 7-15 years old and with a Performance IQ of more than 60, participated in a double-blind placebo controlled parallel trial. Active treatment was 40 mg ORG 2766 for 6 weeks. The outcome was assessed on the basis of the Aberrant Behavior Checklist completed by parents and teachers, and by means of a detailed behavioral observation (30 subjects). ORG 2766 failed to improve social and communicative behavior at a group level. The rate of individual response, defined as a reliable change in social withdrawal at home and at school, to ORG 2766 (10 out of 30) and placebo (4 out of 20) was not significant either. The children who responded to ORG 2766, but not those who responded to placebo, manifested significant improvements outside the changes in the defining variables, including a decrease in hyperactivity at school. The responders to ORG 2766 were characterized mainly by a relatively lower PIQ; further by more initial hyperactivity, stereotypies and abnormal speech, and less initial eye contact. The responders to placebo could not be differentiated from the non-responders to placebo. Future studies should examine whether ORG 2766 differentially affects various subtypes of autism.

Adolescent↗
PubMed1996

Prenatal exposure to morphine affects juvenile play behavior and adult social behavior in rats.

The effects of morphine exposure in utero on play behavior and social behavior were investigated in a longitudinal study. Wistar rat dams were SC injected daily with saline (control) or 10 mg/kg morphine from day 8 to day 21 of gestation. Play behavior of the offspring was measured at 3 and 4 weeks of age and social behavior at 3 months of age. Pinning, a measure for play behavior and social grooming of the morphine-treated offspring were significantly elevated compared to saline controls, especially on day 21. The onset-latency of pinning behavior was not changed. Furthermore, prenatal morphine treatment resulted in more social approach and less social avoidance behavior in adulthood, whereas changes in general locomotor activity were not observed. The results are discussed in relation to the effects of in utero exposure of morphine on the development of incentive aspects of play and social behavior.

Animals↗
PubMed1995

Immunoglobulin production in vitro in major depression: a pilot study on the modulating action of endogenous cortisol.

To investigate the possible differential sensitivity of hydrocortisone (HCO) on immunoglobulin (Ig) production in depression in relation to endogenous cortisol levels, blood was obtained at 8 AM and 4 PM from 10 inpatients with major depression according to DSM-III-R criteria and 10 age- and sex-matched healthy subjects. Peripheral blood lymphocytes were cultured in the presence of graded concentrations (10(-9)-10(-5) M) of HCO to study the effect on immunoglobulin (IgG and IgM) synthesis. In addition, peripheral blood lymphocytes were cultured in the presence of pokeweed mitogen (PWM) to study any additional effect of graded concentrations of HCO (10(-9)-10(-5) M) on IgG and IgM synthesis. Mean plasma cortisol levels at both time points were higher in patients compared to controls. HCO--preferentially at concentrations of 10(-8)-10(-6) molar--stimulated IgG and IgM production in controls, except for IgM production in the 8 AM samples, when the cells were cultured in the absence of PWM. Under these culture conditions, HCO stimulated IgG but not IgM synthesis in depressed patients. PWM-driven IgG and IgM synthesis in controls was stimulated by HCO in both the 8 AM and the 4 PM samples. In patients PWM driven IgG synthesis was stimulated by HCO in the 8 AM but not in the 4 PM samples. PWM-stimulated IgM synthesis was not augmented by HCO in depressed patients. We conclude that a differential sensitivity to the effects of HCO exists in in vitro IgG and IgM synthesis between depressed patients and controls. Furthermore, we suggest that immunocompetent cells of depressed patients possess corticosteroid-resistant properties.

Adult↗
PubMed1995

Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats.

Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaine's motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01-1.0 mg/kg-1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg-1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaine's motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.

Animals↗
PubMed1995

Assessment of motivational aspects involved in initiation of cocaine and heroin self-administration in rats.

A behavioral paradigm was explored to assess the motivational aspects involved in drug-taking behavior during initiation of drug self-administration. In separate saline-controlled experiments, naive animals were allowed to self-administer either cocaine or heroin (0.16 and 0.32 mg/kg per infusion) during five consecutive daily 3-h sessions by pressing one of two levers present in the test cage. During 15 min preceding the last four self-administration sessions, the animals had access to the levers but pressing the reinforcement lever did not result in a drug infusion. The animals properly self-administered both doses of cocaine and heroin, because the amount of self-infusions was higher than their saline control groups. Animals self-administering the high dose of cocaine and either dose of heroin performed lever-press behavior during the preceding period in a similar fashion as during the self-administration sessions, suggesting that this behavior during the preceding period was performed in the absence of the primary reinforcer, this behavior likely reflects the motivational state of animals to obtain the drug reinforcer, and thus may serve as a measure of the motivational aspects involved in the initiation of drug self-administration.

Animals↗
PubMed1995

Regulation of masculine sexual behavior: involvement of brain opioids and dopamine.

In recent years much has become known about the substrates in the brain involved in the regulation of masculine sexual behavior and the involvement of specific neurochemicals in these brain areas. In the present paper the experimental data concerning the involvement of a number of brain areas in sexual behavior are reviewed, in relation to an incentive motivational theory of sexual behavior. The review is restricted to the involvement of opioids and dopamine, of which the role in sexual motivation and behavior is best documented. Opioids in the medial preoptic area (mPOA) impair sexual performance, although the endogenous opioids systems may be quiescent in normal, sexually active rats. Dopamine in the mPOA has a facilitative role in the masculine sexual performance. The corticomedial amygdala is involved in processing of sensory information, especially olfactory stimuli, which are subsequently directed towards the mPOA. Local beta-endorphin infusion interferes with this processing. Endogenous opioids in the ventral tegmental area activate the mesoaccumbens dopamine system and stimulate the sexual motivation. Increased dopamine transmission in the nucleus accumbens correlates with increased sexual motivation and vice versa. The basolateral amygdala plays an essential role in the association of environmental stimuli with reward and therefore in the expression of conditioned sexual motivation. Finally, the reviewed data are integrated and a comprehensive view on the relations between various neural substrates is composed.

Animals↗
PubMed1995

The behavioral effects of habituation and challenge with apomorphine after 6-OHDA lesioning of the nucleus accumbens in rats.

In rats the function of the dopamine system in the nucleus accumbens was tested after 6-OHDA lesioning of this brain area and after ORG 2766 induced facilitation of recovery in 6-OHDA lesioned animals. A low dose of systemically administered apomorphine (50 micrograms/kg) decreased motility when sham operated rats were placed in a novel environment. A similar decrease was found in saline treated rats tested for the second time 1 day later. In thus habituated animals, the low dose of apomorphine did not induce hypomotility. Thus habituation and hypomotility after a low dose of apomorphine may be due to a similar mechanism, viz. diminished dopamine release. A higher dose of apomorphine (125 micrograms/kg) increased motility, but only when the rats were habituated to the test environment. Animals with a bilateral 6-OHDA lesion of the nucleus accumbens showed hypomotility when tested for the first time 1 week after the lesion. The low and the higher dose of apomorphine elicited hypermotility in both nonhabituated and habituated lesioned rats. Their activity was higher than in sham operated animals, suggesting supersensitivity of postsynaptically located dopamine receptor systems in lesioned rats. Treatment with the ACTH(4-9) analog ORG 2766 during the first week after induction of the lesion counteracted the hypomotility of the lesioned rats. Furthermore ORG 2766 enhanced the supersensitivity as revealed by challenge with the low dose of apomorphine.

Adrenocorticotropic Hormone↗
PubMed1995

Endocrine and cardiovascular responses to a series of graded physical and psychological stress stimuli in healthy volunteers.

To investigate the endocrine and cardiovascular responses to a series of psychological and physical stress stimuli and to investigate the possibility of a stimulus intensity-response relation of endocrine and cardiovascular reactivity, 18 healthy volunteers were exposed to psychological and physical stimuli of increasing intensity. Each volunteer participated in three experimental sessions on separate days. The sequence of the sessions was such that all volunteers first participated in a session in which they were not exposed to a stress stimulus, i.e. the control session. Then they were randomly assigned to enter two trial sessions in which they were consecutively exposed to a series of psychological stressors and a series of physical stressors. During each session blood pressure (BP) and heart rate (HR) were assessed and blood samples were taken, to determine cortisol and noradrenaline levels. During the physical stress session increments in systolic and diastolic blood pressure and noradrenaline were observed, proportional to the intensity of the stimuli. In contrast, during the psychological stress session pronounced increments in heart rate were observed, with maximum responses at the second and third stimuli. Diastolic blood pressure responses showed a similar pattern, whereas no changes in noradrenaline were observed. Plasma cortisol was not increased by the psychological stressor, whereas it was stimulated by the physical stressor but at the highest stimulus intensity only. Although the size of the study population precludes any firm conclusions, the results suggest that a stimulus intensity approach in human stress research is possible. Furthermore, the results also appear to indicate that the cardiovascular and pituitary-adrenal systems may display stress-specific responses.

Adolescent↗
PubMed1995

Opioids and sexual behavior of male rats: involvement of the medial preoptic area.

Local infusion of beta-endorphin (beta-END) into the medial preoptic area (MPOA) dose-dependently impaired the gating of the copulatory response and the execution of the sexual performance of sexually experienced, intact male rats. Local naloxone treatment prevented the impairment of the sexual response by beta-END, but failed to facilitate unimpaired copulation. Local infusion into the MPOA of equimolar doses of alpha-endorphin, dynorphin-A-(1-17) or met-enkephalin were less effective than beta-END. It is suggested that endogenous opioid systems in the MPOA are normally quiescent, and increased activity may be related to disrupted or inhibited male sexual behavior.

Animals↗
PubMed1994

Endogenous opioids and sexual motivation and performance during the light phase of the diurnal cycle.

The sexual motivation and performance of sexually experienced male rats were tested during the light phase of the diurnal cycle after treatment with saline or 1 mg.kg-1 naloxone in a bilevel testing box. The sexual motivation during the light phase, as assessed by the increase in anticipatory level changes prior to introduction of a receptive female on subsequent weekly sessions, was comparable to that during the dark phase. Opioid blockade reduced the increase of level changes, suggesting that endogenous opioids are involved in sexual motivation. The sexual performance was impaired during the light phase. Naloxone treatment failed to affect the sexual performance, other than that the post ejaculatory refractory period was increased. This increased latency to re-initiate copulation may be an expression of the reduced sexual motivation. It is concluded that endogenous opioids are not involved in the regulation of the impaired sexual performance during the light phase of the diurnal cycle. In contrast, the sexual motivation, which displays no marked diurnal variation, may be stimulated by endogenous opioids.

Animals↗
PubMed1994

Neuropeptides and alcohol addiction in monkeys.

Neuropeptides have been implicated in experimental drug addiction. Desglycinamide (Arg8) vasopressin (DGAVP) attenuates heroin and cocaine intake during initiation of drug self-administration in rats. beta-Endorphin is self-administered in rats and a role of endogenous opioids in cocaine reward has been proposed. The present studies deal with voluntary alcohol consumption in monkeys under free choice conditions. Monkeys initiated alcohol drinking within a few days and after a stable drinking pattern was acquired increased their ethanol consumption during a short period following interruption of the alcohol supply (relapse). The alcohol drinking behavior seems under the control of reinforcement principles. DGAVP reduced the acquisition of alcohol drinking in the majority of treated monkeys. Initiation of alcohol drinking induced modifications in neuroendocrine homeostasis e.g. an increased plasma beta-endorphin. Both the opioid antagonist naltrexone and the opioid agonist morphine dose-dependently decreased alcohol intake during continuous supply and after imposed abstinence. The monkeys were more sensitive to both drugs after imposed abstinence. The effects are interpreted in the context of the endorphin compensation hypothesis of addictive behavior. It is suggested that endorphins may be particularly implicated in craving for addictive drugs and in relapse of addictive behavior.

Alcoholism↗
PubMed1994

Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat.

The involvement of dopamine D1 receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D1 antagonist SCH23390 on the initiation of heroin self-administration in rats. The D1 antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg-1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg-1 was not effective. Local administration of SCH23390 (0.5 and 2.5 micrograms/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D1 receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement-related behavior. The dopamine D1 receptors present in the NAC are probably not involved in opiate reward.

Animals↗
PubMed1994

Subchronic treatment with the neuroleptic-like peptide desenkephalin-gamma-endorphin may decrease dopaminergic neurotransmission in the nucleus accumbens of rats.

In rats, subchronic administration of desenkephalin-gamma-endorphin (DE gamma E) into the nucleus accumbens or subcutaneously for 10 days resulted in hypoactivity. Intra-accumbens administration caused a significant reduction in the nucleus accumbens tissue levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Systemic administration of DE gamma E decreased DOPAC and 5-hydroxyindoleacetic acid (5-HIAA) levels in nucleus accumbens tissue. Subchronic subcutaneous DE gamma E treatment reduced the basal release of [3H]DA from rat nucleus accumbens slices in vitro and the basal release of endogenous DA and DOPAC in vivo as assessed with on-line dialysis in the nucleus accumbens of freely moving rats. The DA agonist N,N-dipropyl-7-hydroxy-2-aminotetralin (DP-7-ATN) was equally effective in inhibiting [3H]DA release elicited by electrical stimulation from slices of subchronically DE gamma E and placebo treated rats. Administration of a small dose of apomorphine caused similar reductions of the in vivo release of DA and DOPAC in both placebo and DE gamma E treated rats. These results indicate that subchronic DE gamma E treatment may decrease dopaminergic neurotransmission in the nucleus accumbens. This effect is probably not due to alterations in the sensitivity of presynaptically located DA autoreceptors mediating DA release in vitro and in vivo.

Animals↗
PubMed1994

Endogenous opioids are differentially involved in appetitive and consummatory aspects of sexual behavior of male rats.

The sexual activity of 40 male Wistar rats was tested weekly in a bilevel test chamber to evaluate the involvement of endogenous opioids in the appetitive and consummatory aspects of sexual behavior. It has been suggested that the increase of the anticipatory level-changing behavior over repeated testing, displayed before the introduction of a receptive female, is sexually motivated. Two doses of the opioid antagonist naloxone, 1 and 10 mg/kg, prevented the increase of the anticipatory level-changing over four repeated tests of sexually experienced rats without prior experience in the bilevel test chamber and decreased the number of level changes of rats displaying a high number of level changes. Analysis of the pattern of inhibition suggested that the lower dose of naloxone may reduce sexual reward and that, in addition, the higher dose may block the expression of motivation. In contrast, naloxone treatment facilitated the efficiency of the sexual performance, with less mounts and intromissions preceding ejaculation and a shorter ejaculation latency, implying an inhibitory role of endogenous opioids in the neural control of some aspects of sexual performance (e.g., ejaculatory threshold). These results suggest that endogenous opioids may increase sexual appetite and diminish sexual performance.

Analysis of Variance↗