The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model.

Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1).

Simultaneous activation of the α1A-, α1B- and α1D-adrenoceptor subtypes in the nucleus accumbens reduces accumbal dopamine efflux in freely moving rats.

Intra-accumbal infusion of the α1-adrenergic agonist methoxamine, which has comparable affinity for α1A-, α1B- and α1D-adrenoceptor subtypes, fails to alter noradrenaline efflux but reduces dopamine efflux in the nucleus accumbens of rats. In-vivo microdialysis experiments were carried out to analyse the putative contribution of α1A-, α1B- and α1D-adrenoceptor subtypes to the methoxamine-induced decrease in accumbal dopamine efflux in freely moving rats. The drugs used were dissolved in the infusion medium and administered locally through a dialysis membrane.

Accumbal α-adrenoceptors, but not β-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage vesicles.

It has previously been demonstrated that mesolimbic α-adrenoceptors, but not β-adrenoceptors, control the release of dopamine that is derived from reserpine-sensitive storage vesicles. The aim of the present study was to investigate whether these storage vesicles also regulate α-adrenoceptor-mediated or β-adrenoceptor-mediated changes in behaviour. Accordingly, rats were pretreated with reserpine before the α-adrenoceptor antagonist phentolamine or the β-adrenoceptor agonist isoproterenol was locally applied to the nucleus accumbens.

Noradrenaline-induced release of newly-synthesized accumbal dopamine: differential role of alpha- and beta-adrenoceptors.

Previous studies have shown that intra-accumbens infusion of isoproterenol (ISO), a beta-adrenoceptor-agonist, and phenylephrine (PE), an alpha-adrenoceptor-agonist, increase the release of accumbal dopamine (DA). In the present study we analyzed whether the ISO-induced release of DA is sensitive to pretreatment with the DA synthesis inhibitor alpha-methyl-para-tyrosine (AMPT). Earlier studies have shown that the PE-induced release of DA is derived from DA pools that are resistant to AMPT.

Reduced cocaine-induced serotonin, but not dopamine and noradrenaline, release in rats with a genetic deletion of serotonin transporters.

It has recently been proposed that the increased reinforcing properties of cocaine and ecstasy observed in rats with a genetic deletion of serotonin transporters are the result of a reduction in the psychostimulant-induced release of serotonin. Here we provide the neurochemical evidence in favor of this hypothesis and show that changes in synaptic levels of dopamine or noradrenaline are not very likely to play an important role in the previously reported enhanced psychostimulant intake of these serotonin transporter knockout rats. The results may very well explain why human subjects displaying a reduced expression of serotonin transporters have an increased risk to develop addiction.

Maternal care affects the phenotype of a rat model for schizophrenia.

Schizophrenia is a complex mental disorder caused by an interplay between genetic and environmental factors, including early postnatal stressors. To explore this issue, we use two rat lines, apomorphine-susceptible (APO-SUS) rats that display schizophrenia-relevant features and their phenotypic counterpart, apomorphine-unsusceptible (APO-UNSUS) rats. These rat lines differ not only in their gnawing response to apomorphine, but also in their behavioral response to novelty (APO-SUS: high, APO-UNSUS: low).

Synergistic, but not separate, stimulation of accumbal β1- and β2-adrenoceptors alters the accumbal dopamine efflux in freely moving rats.

The effects of intra-accumbal infusion of selective agonists for the β-adrenoceptor subtypes on the noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats were investigated, using in vivo microdialysis. Neither β1-(dobutamine: 0.06 and 0.

Nucleus accumbens and dopamine-mediated turning behavior of the rat: role of accumbal non-dopaminergic receptors.

Accumbal dopamine plays an important role in physiological responses and diseases such as schizophrenia, Parkinson's disease, and depression. Since the nucleus accumbens contains different neurotransmitters, it is important to know how they interact with dopaminergic function: this is because modifying accumbal dopamine has far-reaching consequences for the treatment of diseases in which accumbal dopamine is involved. This review provides a summary of these interactions, and our current knowledge about them are as follows: A) AMPA receptors are required for dopamine-dependent behavior and vice versa; NMDA receptors modulate the activity at the level of AMPA and/or dopamine D₁ receptors.

The α₁-, but not α₂-, adrenoceptor in the nucleus accumbens plays an inhibitory role upon the accumbal noradrenaline and dopamine efflux of freely moving rats.

In vivo microdialysis was used to analyse the role of the α(1)- and α(2)-adrenoceptor subtypes in the regulation of noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. Intra-accumbal infusion of α(1)-adrenoceptor agonist methoxamine (24pmol) failed to alter the noradrenaline efflux, but decreased the dopamine efflux. The intra-accumbal infusion of α(1)-adrenoceptor antagonist prazosin (6, 600 and 6000pmol) produced a dose-related increase and decrease of the noradrenaline and dopamine efflux, respectively.

COMT Val158Met modulates the effect of childhood adverse experiences on the risk of alcohol dependence.

Genetic factors and childhood adverse experiences contribute to the vulnerability to alcohol dependence. However, empirical data on the interplay between specific genes and adverse experiences are few. The COMT Val158Met and DRD2/ANKK1 Taq1A genotypes have been suggested to affect both stress sensitivity and the risk for alcohol dependence.

Reduced dopamine receptor sensitivity as an intermediate phenotype in alcohol dependence and the role of the COMT Val158Met and DRD2 Taq1A genotypes.

Context: Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies.

Early-onset alcohol dependence increases the acoustic startle reflex.

Background: Hyperreactivity and impaired sensory gating of the acoustic startle response in alcohol dependence has been suggested to reflect a residual effect of previous detoxifications, increasing the severity of subsequent withdrawal episodes. Previous studies on the acoustic startle only included early-onset alcohol-dependent patients. The observed abnormalities may therefore also be specific for this subtype of alcohol dependence.

In vivo neurochemical evidence that newly synthesised GABA activates GABA(B), but not GABA(A), receptors on dopaminergic nerve endings in the nucleus accumbens of freely moving rats.

GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of GABA released from the neuron. Therefore, we hypothesised that glutamic acid decarboxylase (GAD) which generates GABA in accumbal GABAergic neurons, at least partly determines the GABA receptor subtype-mediated GABAergic tonus.

Reserpine differentially affects cocaine-induced behavior in low and high responders to novelty.

Individuals are known to differ in their sensitivity to cocaine. Cocaine is known to inhibit the re-uptake of monoamines. The response to cocaine has also been found to depend on monoamines inside reserpine-sensitive storage vesicles.

Dopamine D₁-like receptors play only a minor role in the increase of striatal dopamine induced by striatally applied SKF38393.

We studied the effects of the intra-striatal infusion of Ca(2+)-free medium on the intra-striatal injection of 0.5 μg SKF38393-induced striatal dopamine efflux. It is discussed that the amount of extracellular, striatal dopamine seen after striatally applied SKF38393, is the overall result of the (a) release of dopamine from the alpha-methyl-para-tyrosine-sensitive and Ca(2+)-insensitive pool of newly synthesised dopamine, (b) release of dopamine from the reserpine-sensitive and Ca(2+)-sensitive storage pool, (c) inhibition of uptake of dopamine into nerve terminals and glial cells, and (d) facilitation respectively of the inhibition of uptake into blood vessels: dopamine D₁-like receptors play only a very limited role in these processes.

Blockade of dopamine, but not noradrenaline, transporters produces hyperthermia in rats that lack serotonin transporters.

To investigate whether life-long disturbed serotonin neurotransmission may result in adaptive changes of dopaminergic and noradrenergic systems, effects of drugs on stress-induced hyperthermia were studied in serotonin transporter knockout rats. The noradrenalin transporter blocker atomoxetine was more effective in reducing stress-induced hyperthermia, induced by an injection, in serotonin transporter (SERT) knockout (SERT(-/-)) rats compared to SERT(+/+) rats. The dopamine transporter blocker GBR12909 increased the core body temperature in SERT(-/-) rats, and had no effect on the SERT(+/+) rats.

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular dopamine pool and the alpha-methyl-para-tyrosine-sensitive cytosolic dopamine pool. Given the similarities between dexamphetamine and SKF38393, we hypothesized that both types of pool also contribute to the striatally applied SKF38393-induced dopamine efflux.

Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty.

Rationale: The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences.

Objectives: A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment.

The reboxetine-induced increase of accumbal dopamine efflux is inhibited by l-propranolol: a microdialysis study with freely moving rats.

In vivo microdialysis was used to study the effects of the locally applied selective noradrenaline uptake inhibitor reboxetine on the baseline noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. The effects of intra-accumbal infusion of the beta-adrenoceptor antagonist l-propranolol on the reboxetine-elicited noradrenaline and dopamine efflux in the nucleus accumbens were also analysed. The intra-accumbal infusion of reboxetine (1.

Stress-induced hyperthermia and basal body temperature are mediated by different 5-HT(1A) receptor populations: a study in SERT knockout rats.

Disturbances in the serotonergic system are implicated in many central nervous system disorders. The serotonin transporter (SERT) regulates the serotonin homeostasis in the synapse. We recently developed a rat which lacks the serotonin transporter (SERT(-/-)).

Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats.

Rationale: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood.

Objectives: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT-/-) rat and the involvement of compensatory changes in 5-HT1A receptor function are the objectives of the study.

Materials And Methods: The SERT-/- rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine self-administration.

Twenty years of dopamine research: individual differences in the response of accumbal dopamine to environmental and pharmacological challenges.

Individual differences in the dopaminergic system of the nucleus accumbens of rats have extensively been reported. These individual differences have frequently been used to explain individual differences in response to environmental and pharmacological challenges. Remarkably, only little attention is paid to the factors that underlie these individual differences.

Behavioural characterisation of rats exposed neonatally to bisphenol-A: responses to a novel environment and to methylphenidate challenge in a putative model of attention-deficit hyperactivity disorder.

Neonatal exposure of rats to bisphenol-A, an endocrine disruptor, has recently been proposed as a possible animal model of attention-deficit hyperactivity disorder (ADHD), because such rats exhibit motor hyperactivity. To strengthen the face validity of this animal model, the present study replicated the original experiments and additionally analysed both changes in habituation to a novel environment and behavioural responses to methylphenidate, the two phenomena known to be altered in ADHD. Single intracisternal administration of bisphenol-A (20 and 40 microg) into 5-day-old male Wistar rats impaired habituation to a novel environment in the light, but not the dark, phase at 4 weeks of age.

Rats that differentially respond to cocaine differ in their dopaminergic storage capacity of the nucleus accumbens.

Cocaine (COC) inhibits the re-uptake of dopamine. However, the dopamine response to COC also depends on dopamine inside storage vesicles. The aim of this study was to investigate whether rats that differentially respond to COC differ in their dopaminergic storage capacity of the nucleus accumbens.