Michel M. M. Verheij

Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility

Creatine kinases are important in maintaining cellular‐energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine‐like compounds. Herein we examine whether ablation of the cytosolic brain‐type creatine kinase (B‐CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B‐CK (B‐CK–/–) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra‐ and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr ⇆ ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B‐CK–/– animals showed diminished open‐field habituation. In the water maze, adult B‐CK–/– mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24‐month‐old, aged B‐CK–/– mice, on top of the age‐related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole‐induced seizures (creating a high‐energy demand) was observed in B‐CK–/– mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho‐creatine shuttle provides compensation for the loss of B‐CK in the brain. Our studies indicate a role for the creatine–phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B‐CK can be compensated for by other systems in the versatile and robust metabolic‐energy network of the brain.

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. This review gives an overview of the studies that have been performed in our institute during the last 20 years to investigate individual differences in accumbal dopamine release. Data are summarised demonstrating that individual differences in accumbal dopamine release are due to individual differences in: the functional reactivity of the noradrenergic system, the accumbal concentration of vesicular monoamine transporters and tyrosine hydroxylase as well as in the quantal size of the presynaptic pools of dopamine. Our data are embedded in the available literature to create a model that illustrates the putative hardware giving rise to the individual-specific release of accumbal dopamine. An important role is contributed to individual differences in the reactivity of the: hypothalamic-pituitary-adrenal axes, the reactivity of second messenger systems as well in the aminergic reactivity of the accumbens shell and core. The consequences of the individual-specific make-up and reactivity of the nucleus accumbens on the regulation of behaviour and the response to drugs of abuse will also be discussed. Apart from agents that interact with dopaminergic receptors, re-uptake or breakdown, noradrenergic agents as well as agents that interact with vesicular monoamine transporters or tyrosine hydroxylase are suggested to have therapeutic effects in subjects that are suffering from diseases in which the dopaminergic system is disturbed.

Distinct kinds of novelty processing differentially increase extracellular dopamine in different brain regions

Behaviourally relevant novel stimuli are known to activate the mesocorticolimbic dopaminergic (DAergic) system. In this study we tested the reactivity of this system in response to distinct kinds of novelty processing. Using the in vivo microdialysis technique, we measured extracellular amounts of dopamine (DA) in different DAergic terminal regions during a social learning task in rats. In the first session (40 min) rats were exposed to two never previously encountered juveniles (i.e. unconditional novelty). Afterwards, the animals were divided into three groups: Control group was not exposed to any other stimulus; Discrimination group was exposed to one familiar and one new juvenile (i.e. novel stimulus discrimination); and Recognition group was re‐exposed to the two familiar juveniles (i.e. familiarity recognition). In both the medial prefrontal cortex and the nucleus accumbens shell DA increased in response to the first presentation of the juveniles, showing that both structures are involved in processing unconditional social novelty. During the novel stimulus discrimination, we found no change in the prefrontal cortex, although DA increased in the accumbal shell in comparison with the group exposed to two familiar juveniles, showing that the shell is also involved in processing novel social stimulus discrimination. None of the stimuli presented affected DA in the accumbal core. This study provided the original evidence that DA in the various terminal regions is differentially coupled to distinct aspects of novelty processing.

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. Total and vesicular levels of accumbal dopamine as well as accumbal vesicular monoamine transporter‐2 levels were established in high (HR) and low responders (LR) to novelty rats. Moreover, the effects of reserpine (RES) on the COC‐induced increase of extracellular accumbal dopamine were investigated. HR displayed higher accumbal levels of total and vesicular dopamine than LR. Moreover, HR displayed more accumbal vesicular monoamine transporters‐2 than LR. COC increased extracellular accumbal dopamine more strongly in HR than in LR. A low dose of RES prevented the COC‐induced increase of accumbal dopamine in LR, but not in HR. A higher dose of RES was required to inhibit the COC‐induced increase of accumbal dopamine in HR. These data demonstrate that HR were marked by a larger accumbal dopaminergic storage pool than LR. It is hypothesized that HR are more sensitive to COC than LR, because COC can release more dopamine from accumbal storage vesicles in HR than in LR.

Chronic Loss of Melanin-Concentrating Hormone Affects Motivational Aspects of Feeding in the Rat

Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding. Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch +/+ or pmch −/− rats. However, acute administration of MCH to the AcbSh of adult pmch −/− rats elevated feeding behavior towards wild type levels. Finally, adult pmch −/− rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system. Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.

Differential contribution of storage pools to the extracellular amount of accumbal dopamine in high and low responders to novelty: effects of reserpine.

The present study examined the effects of reserpine on the extracellular concentration of accumbal dopamine in high responders (HR) and low responders (LR) to novelty rats. Reserpine reduced the baseline concentration of extracellular accumbal dopamine more in HR than in LR, indicating that the dopamine release is more dependent on reserpine‐sensitive storage vesicles in non‐challenged HR than in non‐challenged LR. In addition, reserpine reduced the novelty‐induced increase of the extracellular concentration of accumbal dopamine in LR, but not in HR, indicating that the dopamine release in response to novelty depends on reserpine‐sensitive storage vesicles only in LR, not in HR. Our data clearly demonstrate that HR and LR differ in the characteristics of those monoaminergic storage vesicles that mediate accumbal dopamine release.

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

RationaleThe 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.ObjectivesA 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.MethodsLow responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials.ResultsThe duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented.ConclusionsThese data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.

Stress rapidly dysregulates the glutamatergic synapse in the prefrontal cortex of cocaine‐withdrawn adolescent rats

Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress‐induced response of the glutamatergic synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28–42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma.

The Melanin-Concentrating Hormone (MCH) System Modulates Behaviors Associated with Psychiatric Disorders

Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

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. An ineffective dose of prazosin (6pmol) counteracted the methoxamine (24pmol)-induced decrease of dopamine efflux. The prazosin (6000pmol)-induced increase of noradrenaline efflux, but not the decrease of dopamine efflux, was suppressed by the co-administration of an ineffective dose of methoxamine (0.024pmol). Neither the α(2)-adrenoceptor agonist clonidine (300pmol) and UK 14,304 (300pmol) nor the α(2)-adrenoceptor antagonist RX 821002 (0.6, 3, 600 and 6000pmol) significantly affected the accumbal noradrenaline and dopamine efflux. The doses mentioned are the total amount of drug over the 60-min infusion period. The present results show that (1) accumbal α(1)-adrenoceptors which are presynaptically located on noradrenergic nerve terminals inhibit the accumbal noradrenaline efflux, increasing thereby the accumbal dopamine efflux, (2) accumbal α(1)-adrenoceptors which are postsynaptically located on dopaminergic nerve terminals inhibit the accumbal dopamine efflux, and (3) accumbal α(2)-adrenoceptors play no major role in the regulation of accumbal efflux of noradrenaline and dopamine.