Biomedical subjects

Alexander R Cools

Publications and source records attributed to Alexander R Cools.

At least 19 recordsLinked to original sources

PubMed2006

Writer's cramp: restoration of striatal D2-binding after successful biofeedback-based sensorimotor training.

INTRODUCTION: Previous studies of writer's cramp have detected cerebral sensorimotor abnormalities in this disorder and, more specifically, a reduced striatal D2-binding as assessed by [(123)I]IBZM SPECT. However, empirical data were lacking about the influence of effective biofeedback-based sensorimotor training on D2 receptor binding. METHODS: To determine whether there is a restoration of D2-binding after successful sensorimotor treatment, pre- and posttreatment SPECTs were compared in five patients with writer's cramp and correlated with improvement in handwriting. RESULTS: After treatment, the clinical and electromyographic picture appeared substantially improved connected with a significant increase in D2-binding to nearly normal levels similar to normative data in age/sex-matched healthy subjects. CONCLUSION: The current study supported the view that writer's cramp results from a plastic adaptation of a rectifiable nigrostriatal dopaminergic system and that effective sensorimotor training leads to increased efficacy of striatal dopaminergic transmission.

Adult↗

PubMed2006

Cocaine strongly reduces prepulse inhibition in apomorphine-susceptible rats, but not in apomorphine-unsusceptible rats: regulation by dopamine D2 receptors.

Dopaminergic agonists, such as apomorphine and amphetamine, have been shown to drastically reduce prepulse inhibition of the acoustic startle reflex. The effects of the indirect dopamine agonist cocaine on prepulse inhibition have only been described in a few reports and have yielded conflicting results, possibly due to individual differences within and between rat strains. In this study we therefore used apomorphine-susceptible and apomorphine-unsusceptible rats, as an animal model for individual differences, to study the effects of cocaine (20, 30 mg/kg i.p.) on prepulse inhibition. In addition we tested whether the cocaine-induced deficit in prepulse inhibition could be reversed by the D2-antagonist remoxipride (5 mg/kg i.p.), the alpha-1 adrenoceptor antagonist prazosin (2.5 mg/kg i.p.) and the 5-HT2-antagonist ketanserin (2.0 mg/kg i.p.). Cocaine strongly reduced prepulse inhibition in apomorphine-susceptible rats, but had no effect at all on apomorphine-unsusceptible rats. Remoxipride had no effect on prepulse inhibition, but prazosin and ketanserin increased prepulse inhibition. Both remoxipride and prazosin reversed the cocaine-induced deficit in prepulse inhibition, whereas ketanserin did not. We conclude that apomorphine-susceptible rats are extremely sensitive to the effects of cocaine on prepulse inhibition, while apomorphine-unsusceptible rats are not. The effects of cocaine on prepulse inhibition in apomorphine-susceptible rats were mediated by D2-receptors, but not by 5-HT2-receptors or alpha-1 adrenoceptors.

Acoustic Stimulation↗

PubMed2006

Adrenergic receptors in the nucleus accumbens shell differentially modulate dopamine and acetylcholine receptor-mediated turning behaviour.

The role of alpha- and beta-adrenoceptors in the nucleus accumbens shell in turning behaviour of rats was investigated. Unilateral injections of the alpha-adrenoceptor agonist (phenylephrine; 10 microg) and antagonist (phentolamine; 10 microg) as well as the beta-adrenoceptor agonist (isoprenaline; 1 microg) and antagonist (propranolol; 5 microg) into the nucleus accumbens shell did not produce turning behaviour more than that of control vehicle injection. Unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol, SKF 38393; 5 microg) and D(2) (quinpirole; 10 microg) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting. Such pivoting was dose-dependently inhibited by phenylephrine (5, 10 microg), injected into the nucleus accumbens shell, and the inhibitory effect of phenylephrine (10 microg) was antagonised by phentolamine (10 microg) that per se had no effect on this pivoting. Isoprenaline (0.5, 1 microg) dose-dependently increased the contraversive pivoting induced by the mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell. The effect of isoprenaline (1 microg) was antagonised by propranolol (5 microg) that per se had no effect on this pivoting. It is concluded that stimulation of accumbal alpha-adrenoceptors inhibits the dopamine-dependent pivoting in contrast to stimulation of accumbal beta-adrenoceptors that facilitates this dopamine-dependent pivoting. Unilateral injection of the acetylcholine receptor agonist carbachol (5 microg) into the nucleus accumbens shell has been found to elicit contraversive circling. Such circling was significantly reduced by accumbal administration of either phenylephrine (10, 20 microg) or phentolamine (5, 10 microg) in a dose-independent manner; moreover, both drugs potentiated, but did not counteract, each other's effects. Carbachol-induced circling was also reduced by propranolol (2.5, 5 microg), but again in an aspecific manner. It is concluded that alpha- and beta-adrenergic agents have an effect on accumbal acetylcholine receptor-mediated circling through a non-adrenergic mechanism. The impact of the present study for putative new treatments of various neuropsychiatric and neurological disorders is discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2006

Differences in the cellular mechanism underlying the effects of amphetamine on prepulse inhibition in apomorphine-susceptible and apomorphine-unsusceptible rats.

BACKGROUND: Amphetamine is often used to mimic certain aspects of schizophrenia in laboratory animals, such as a decreased prepulse inhibition. MATERIALS AND METHODS: Apomorphine-susceptible and apomorphine-unsusceptible rats represent a well-characterized animal model for individual differences in the sensitivity to dopaminergic drugs. Moreover, apomorphine-susceptible rats show a wide variety of schizophrenia-like abnormalities. The differential response to administration of amphetamine (1-4 mg/kg, i.p.) was investigated in these two rat lines using the prepulse inhibition paradigm. Because amphetamine promotes dopamine release, the cellular mechanism underlying the line-specific effects of amphetamine was investigated by administration of alpha-methyl-para-tyrosine (aMpT) and reserpine, substances that are known to deplete the cytosolic dopamine pool and the vesicular dopamine pool, respectively, the former being primarily implicated in mediating the effects of amphetamine. RESULTS: All doses of amphetamine decreased prepulse inhibition in apomorphine-susceptible rats, whereas only the highest doses (2 and 4 mg/kg, i.p.) of amphetamine decreased prepulse inhibition in apomorphine-unsusceptible rats. Alpha-methyl-para-tyrosine, but not reserpine, blocked the amphetamine-induced disruption in prepulse inhibition in apomorphine-unsusceptible rats, whereas both substances alone had no effect in apomorphine-susceptible rats. However, the combination of alpha-methyl-para-tyrosine and reserpine did block the amphetamine-induced effects in the latter rat line. DISCUSSION: The present study suggests that apomorphine-susceptible rats are more sensitive to systemic administration of amphetamine than apomorphine-unsusceptible rats. In addition, the data show that the cellular mechanism underlying the effects of amphetamine differs between apomorphine-susceptible and apomorphine-unsusceptible rats. Whereas the effects of amphetamine on prepulse inhibition in apomorphine-unsusceptible rats just require the alpha-methyl-para-tyrosine sensitive dopamine pool, the effects in apomorphine-susceptible rats require both the alpha-methyl-para-tyrosine sensitive and the reserpine sensitive dopamine pool. Because apomorphine-susceptible rats share many features with schizophrenic patients, these data open the perspective that in these patients amphetamine may induce dopamine release from both types of dopamine pool. This might provide an explanation for the increased dopamine release after this psychostimulant drug in patients vs controls.

Amphetamine↗

PubMed2006

Topographical resolution of jaw movements mediated by cyclase- vs. non-cyclase-coupled dopamine D(1)-like receptors: studies with SK&F 83822.

This study examined the effects on orofacial movement topography of SK&F 83822 ([R/S]-6-chloro-7,8-dihydroxy-3-allyl-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), which stimulates dopamine D(1)-like receptors coupled to stimulation of adenylyl cyclase (AC) but not phosphoinositide (PI) hydrolysis, in comparison with SK&F 83959 ([R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), which stimulates PI hydrolysis but not AC. SK&F 83822 alone induced chattering, while SK&F 83959 alone exerted little effect. SK&F 83822 and SK&F 83959 each in combination with the dopamine D(2)-like agonist quinpirole resulted in synergistic induction of non-chattering movements with tongue protrusions. These effects were blocked by the dopamine D(1)-like receptor antagonist SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). However, the dopamine D(2)-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide) exerted a biphasic effect on synergism with SK&F 83822: chattering was initially released but antagonised thereafter. Only antagonism was seen for synergism with SK&F 83959. While both AC- and PI-coupled dopamine D(1)-like receptors participate in synergistic dopamine D(1)-like:D(2)-like receptor interactions, topographically specific synergistic and oppositional dopamine D(1)-like:D(2)-like interactions evident with SK&F 83822 reflect the involvement primarily of D(1)-like receptors coupled to AC rather than PI.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2006

Serotonin and the neurobiology of the ejaculatory threshold.

Disorders of the ejaculatory threshold, such as lifelong premature ejaculation, are fairly common in humans and can have a great impact on the quality of life. Research in humans and rats have indicated that increased serotonin levels in the central nervous system elevate the ejaculatory threshold, probably via 5-HT(1B) and 5-HT(2C) receptors, whereas depletion of serotonin decreases the ejaculatory threshold. 5-HT(1A) receptor activation strongly lowers the ejaculatory threshold, probably mediated by both the reduction of serotonin levels via presynaptic 5-HT(1A) receptors and yet unknown effects of postsynaptic 5-HT(1A) receptors. The present review attempts to integrate psychopharmacological data on serotonergic control over ejaculation with the knowledge of the neuroanatomical substrate of ejaculation, indicating the importance of the lumbosacral spinal cord, the nucleus paragigantocellularis, the lateral hypothalamic area and several other supraspinal areas. In addition, the gaps in our understanding of the role of serotonin in the ejaculatory threshold are discussed. Filling in those gaps might help to design specific drugs that alter the ejaculatory threshold, thereby alleviating ejaculatory disorders.

Animals↗

PubMed2006

Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively.

Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2); EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2); EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of EM-2 and EM-1 to alter the accumbal extracellular dopamine level has not yet been studied in freely moving rats, the present study was performed, using a microdialysis technique that allows on-line monitoring of the extracellular dopamine with a temporal resolution of 5 min. A 25 min infusion of either EM-2 or EM-1 into the NAc (5, 25, and 50 nmol) produced a dose-dependent increase of the accumbal dopamine level. The EM-2 (50 nmol)- and EM-1 (25 and 50 nmol)-induced dopamine efflux were abolished by intra-accumbal perfusion of tetrodotoxin (2 muM). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH(2); 3 nmol) failed to affect the EM-2 (50 nmol)-induced dopamine release, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine release. The EM-1 (50 nmol)-induced accumbal dopamine efflux was significantly reduced by the systemic administration of the putative mu1-opioid receptor antagonist naloxonazine (15 mg/kg, intraperitoneally (i.p.), given 24 h before starting the perfusion). Systemic administration of the aspecific opioid receptor antagonist naloxone (1 mg/kg, i.p., given 10 or 20 min before starting the perfusion) also failed to affect the EM-2 (50 nmol)-induced dopamine efflux, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine efflux. The present study shows that the intra-accumbal infusion of EM-2 and EM-1 increases accumbal dopamine efflux by mechanisms that fully differ. It is concluded that the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors in the NAc.

Analgesics, Opioid↗

PubMed2006

Expression of cocaine-induced conditioned place preference in apomorphine susceptible and unsusceptible rats.

Differences in cocaine self-administration can be attributed to differences in the rewarding value that cocaine has for the individual. An ongoing debate, however, exists whether a high rewarding or a low rewarding value leads to an increase in self-administration. To investigate which of these two alternatives is correct, we investigated the occurrence of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats. We have recently shown that under specific environmental conditions (challenged-not habituated to the environment-as measured by distance travelled) apomorphine susceptible rats consistently self-administer more cocaine than apomorphine unsusceptible rats do. As conditioned place preference allows the assessment of the rewarding value of cocaine, we investigated the expression of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats under the same conditions as the self-administration experiments in order to establish whether the rewarding value of cocaine is greater or smaller in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats. The data clearly showed that challenged apomorphine susceptible rats had a preference for the cocaine-paired compartment with lower doses of cocaine (10 mg/kg) than challenged apomorphine unsusceptible rats. Apomorphine unsusceptible rats expressed conditioned place preference only with the highest dose tested (20 mg/kg). On the basis of these data, we concluded that the rewarding value that cocaine has in challenged apomorphine susceptible rats is greater than that in challenged apomorphine unsusceptible rats. It is suggested that challenged apomorphine susceptible rats self-administer more of a lower dose of cocaine than challenged apomorphine unsusceptible rats do, because the rewarding value of cocaine is greater in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats.

Animals↗

PubMed2006

Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis.

OBJECTIVE: The rat is one of the most important model organisms for biomedical and pharmacological research. However, the generation of novel models for studying specific aspects of human diseases largely depends on selection for specific traits using existing rat strains, thereby solely depending on naturally occurring variation. This study aims to provide the tools to manipulate the rat genome in a more directed way. METHODS: We developed robust, automated, and scaleable reverse genetic methodology based on ENU (N-ethyl-N-nitrosourea)-driven target-selected mutagenesis. Optimal mutagenesis conditions have been determined in three different rat strains and a universal, rapid, and cost-effective dideoxy resequencing-based screening setup was established for mutation discovery. The effectiveness of the approach is illustrated by the identification of 120 induced mutations in a set of genes of interest, including six that result in unique rat knockout models due to the introduction of premature stop codons. In addition, 56 mutations were found that change amino acids, including critical residues in transmembrane domains of receptors and channels. CONCLUSIONS: The approach described here allows for the systematic generation of knockout and protein function altering alleles in the rat. The resulting induced rat models will be powerful tools for studying many aspects of a wide variety of human diseases.

Alkylating Agents↗

PubMed2005

Individual differences in drug dependence in rats: the role of genetic factors and life events.

Drug dependence and addiction is a chronic mental illness that has far reaching consequences for society in terms of economic loss, health costs and judicial problems. A crucial question in drug addiction, is what factors are involved in its aetiology, and especially what mediates the shit from use to abuse. As in most other mental illnesses, addiction can best be described using the so-called three hit model, which states that a disease results from an interaction between genetic factors, early lie events and late environmental factors. However, the precise nature of these factors still remains to be elucidated. This present review discusses the results from an animal model in which these three different hit are currently being investigated. The apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) rats, originally selected on the basis of their behavioural response to the dopaminergic agonist apomorphine, were recently found to be genetically different in the number of gene copies of a component of the gamma-secretase complex called Aph-1b. Whereas APO-UNSUS rats have three copies of the gene, APO-SUS rats have either 1 or 2 copies. In addition we have shown that these rats show differences in cocaine and alcohol self-administration, and that both early life events and late environmental factors can alter this self-administration behaviour. Thus, the data so far support the hypothesis that the APO-SUS and APO-UNSUS rats offer an interesting animal model for drug dependence in which genes and environment interact. We finally propose a theoretical model which can explain this gene-environment interaction.

Amyloid Precursor Protein Secretases↗

PubMed2005

Reduced Aph-1b expression causes tissue- and substrate-specific changes in gamma-secretase activity in rats with a complex phenotype.

The gamma-secretase enzyme complex displays intramembrane catalytic activity toward many type I transmembrane proteins, including the Alzheimer-linked amyloid-beta-protein precursor (APP) and the neuregulin receptor ErbB4. Active gamma-secretase is a tetrameric protein complex consisting of presenilin-1 (or -2), nicastrin, PEN-2, and Aph-1a (or -1b). We have recently discovered that pharmacogenetically bred apomorphine-susceptible Wistar rats (APO-SUS) have only one or two copies of the Aph-1b gene (termed I/I and II/II rats, respectively), whereas their phenotypic counterparts (APO-UNSUS) have three copies (III/III). As a result, APO-SUS rats display reduced Aph-1b expression and a complex phenotype reminiscent of neurodevelopmental disorders. Here we determined in the I/I and III/III rats the gamma-secretase cleavage activity toward the three APP superfamily members, p75 neurotrophin receptor, ErbB4, and neuregulin-2, and found that the cleavage of only a subset of the substrates was changed. Furthermore, the observed differences were restricted to tissues that normally express relatively high Aph-1b compared with Aph-1a levels. Thus, we provide in vivo evidence that subtle alterations in gamma-secretase subunit composition may lead to a variety of affected (neuro)developmental signaling pathways and, consequently, a complex phenotype.

Amyloid Precursor Protein Secretases↗

PubMed2005

Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats.

Selective Serotonin Reuptake Inhibitors (SSRIs) are designed to treat adults, but are increasingly prescribed for adolescents. SSRIs might cause permanent changes in serotonin-related behavior in adolescents, since their serotonergic system is still developing. Male Wistar rats were treated with paroxetine (15 mg/kg p.o.) or fluvoxamine (30 mg/kg p.o.) throughout adolescence. After a washout period their behavior in the elevated plus-maze, prepulse inhibition test, Forced swimming test and elevated T-maze were studied. In addition, the effects of the 5-HT(1A) receptor agonist 8-OH-DPAT on sexual behavior and lower lip retraction were measured. Paroxetine mildly inhibited weight gain during treatment. Both SSRIs caused a reduction in ejaculation frequency and in time spent on the open arm of the elevated plus-maze in adult rats. Fluvoxamine slightly increased avoidance latency in the elevated T-maze compared to paroxetine. No differences between the groups were found in the other tests. Apparently, chronic treatment with SSRIs during adolescence may cause mild changes in adult behavior.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2005

Role of GABA(A) receptors in the retrorubral field and ventral pallidum in rat jaw movements elicited by dopaminergic stimulation of the nucleus accumbens shell.

The role of gamma-aminobutyric acid (GABA)(A) receptors in the retrorubral field in the production of rat repetitive jaw movements was examined, as this nucleus receives a GABAergic, inhibitory input from the nucleus accumbens and is connected with the parvicellular reticular formation, a region that is directly connected with the orofacial motor nuclei. The GABA(A) receptor antagonist bicuculline (150 ng/0.2 microl per side) significantly produced repetitive jaw movements when injected bilaterally into the retrorubral field, but not the ventral pallidum. The effects of bicuculline were GABA(A) receptor specific, because the effects were abolished by muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline-induced jaw movements differed qualitatively from those elicited by injection of a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), agonist at dopamine D1 and D2 receptors respectively, into the nucleus accumbens shell. Nevertheless, bilateral injections of muscimol (10 ng, 25 ng and 50 ng/0.2 microl per side) into the retrorubral field significantly inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation in the nucleus accumbens shell. Bilateral injections of bicuculline (50 ng and 150 ng/0.2 microl per side) also reduced the dopamine D1/D2 receptor-mediated jaw movements. Essentially similar effects were obtained when muscimol and bicuculline were given into the ventral pallidum, a region that is also known to receive GABAergic inhibitory inputs from the nucleus accumbens. In conclusion, GABA(A) receptor blockade in the retrorubral field elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region as well as in the ventral pallidum modulate the accumbens-specific, dopamine D1/D2 receptor-mediated jaw movements.

Animals↗

PubMed2005

Effects of chronic selective serotonin reuptake inhibitors on 8-OH-DPAT-induced facilitation of ejaculation in rats: comparison of fluvoxamine and paroxetine.

RATIONALE: Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) can delay ejaculation in humans, but the extent of this effect differs between SSRIs. The involvement of 5-HT1A receptors is likely, since 5-HT1A receptor agonists accelerate ejaculation and chronic SSRI treatment is thought to desensitize 5-HT1A receptors. OBJECTIVES: This study was conducted to examine the effects of chronic pretreatment with the SSRIs fluvoxamine and paroxetine on the facilitation of ejaculation induced by the 5-HT1A receptor agonist 8-OH-DPAT. METHODS: Sexually experienced Wistar rats with normal ejaculatory behavior were treated for 22 days with vehicle, fluvoxamine (30 mg/kg/day), or paroxetine (10 or 20 mg/kg/day, p.o.). On day 22, rats received a challenge with saline or 8-OH-DPAT (0.4 mg/kg, s.c.). Sexual behavior was tested on days 1, 8, 15, and 22 of the SSRI-treatment. RESULTS: Treatment with both doses of paroxetine, but not fluvoxamine, delayed ejaculation. 8-OH-DPAT strongly accelerated ejaculation under vehicle conditions. Pretreatment with paroxetine reduced the effects of 8-OH-DPAT on ejaculation in a dose-dependent manner and more strongly than fluvoxamine. CONCLUSIONS: SSRIs affect 5-HT1A receptors involved in ejaculation. The degree to which this occurs, with paroxetine exerting a stronger effect than fluvoxamine, might determine the extent of SSRI-induced delayed ejaculation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2005

Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders.

A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a reduced expression of Aph-1b, a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. The reduced expression is due to a duplicon-based genomic rearrangement event resulting in an Aph-1b dosage imbalance. The expression levels of the other gamma-secretase components were not affected. However, gamma-secretase cleavage activity was significantly changed, and the APO-SUS/-UNSUS Aph-1b genotypes segregated with a number of behavioral phenotypes. Thus, a subtle imbalance in the expression of a single, developmentally important protein may be sufficient to cause a complex phenotype.

Amyloid Precursor Protein Secretases↗

PubMed2005

Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity.

The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.

Administration, Oral↗

PubMed2005

Gene - environment interactions determine the individual variability in cocaine self-administration.

Research into factors that determine the propensity to self-administer cocaine has shown that stressors can determine the amount of cocaine self-administered as well as the rate of acquisition. However, the interaction between the genetic make-up of the animal and stress is unknown. This study investigated this interaction by using the genetic animal model consisting of apomorphine susceptible (APO-SUS) and unsusceptible (APO-UNSUS) rats. Animals were allowed to self-administer 0.25 mg/kg cocaine under stressful and habituated conditions. This study revealed that the amount of cocaine consumed was highly dependent on the genetic make-up of the animal as well as the amount of stress during self-administration. Under habituated circumstances the APO-UNSUS rats took far more cocaine than the APO-SUS rats. Under stressful circumstances, however, the APO-SUS rats took far more cocaine than the APO-UNSUS rats. This difference in the amount consumed by APO-SUS and APO-UNSUS rats is likely to be due to the specific neurobiological features of their dopaminergic and, possibly, noradrenergic system as well as the reactivity of their HPA-axis. It is suggested that the amount of a drug consumed and, accordingly, its addictive potential and 'drug-vulnerability' are determined by the interaction between the genetic make-up of the animals and stress, and not by either component alone.

Analysis of Variance↗

PubMed2005

Acetylcholine receptor effects on accumbal shell dopamine-mediated turning behaviour in rats.

The nature of acetylcholine receptor effects on dopaminergic functions within the nucleus accumbens shell was studied in rats, using turning behaviour as read-out parameter. Unilateral injections of the acetylcholine receptor agonist, carbachol (1.0-5.0 microg), into the nucleus accumbens shell dose-dependently elicited contraversive circling. Unilateral injections of the combination of a fixed dose of the dopamine D(2) receptor agonist, quinpirole (10.0 microg), with increasing doses of the dopamine D(1) receptor agonist, SKF 38393 (1.0-5.0 microg), into the nucleus accumbens shell dose-dependently elicited contraversive pivoting. The same held for the combination of a fixed dose of SKF 38393 (5.0 microg) with increasing doses of quinpirole (5.0 and 10.0 microg), which was injected into the nucleus accumbens shell. The nicotinic acetylcholine receptor antagonist, mecamylamine (5.0 and 10.0 microg), injected into the nucleus accumbens shell, which alone did not elicit any turning behaviour, significantly suppressed both the contraversive circling induced by carbachol (5.0 microg) and the contraversive pivoting induced by the mixture of SKF 38393 (5.0 microg) and quinpirole (10.0 microg). The muscarinic acetylcholine receptor antagonist, methylscopolamine (1.0 and 2.5 microg), injected into the nucleus accumbens shell, which alone did not elicit any turning behaviour, significantly suppressed the contraversive circling induced by carbachol (5.0 microg), whereas it significantly increased the contraversive pivoting induced by both the mixture of SKF 38393 (1.0 microg) and quinpirole (10.0 microg) and the mixture of SKF 38393 (5.0 microg) and quinpirole (5.0 microg). Neither SKF 38393 (5.0 microg) nor quinpirole (10.0 microg) injected into the nucleus accumbens shell affected the contraversive circling induced by carbachol (5.0 microg). Carbachol (1.0 microg) injected into the nucleus accumbens shell caused a slight initial potentiation followed by an inhibition of the contraversive pivoting induced by the mixture of SKF 38393 (5.0 microg) and quinpirole (10.0 microg). These results confirm that stimulation of both nicotinic and muscarinic acetylcholine receptors in the nucleus accumbens shell is required for the accumbens-dependent, acetylcholine-mediated circling. The study provides the original evidence that stimulation of nicotinic acetylcholine receptors in the nucleus accumbens shell is required for the accumbens-dependent, dopamine-mediated pivoting. Finally, the present study shows that muscarinic acetylcholine receptors in the nucleus accumbens shell play an inhibitory role in the production of the accumbens-dependent, dopamine-mediated pivoting.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗