M. G. P. Feenstra

Increased activity of surviving locus ceruleus neurons in Alzheimer's disease.

In Alzheimers disease (AD) there is neuronal loss in the locus ceruleus (LC), and the noradrenergic system may be even more affected in depressed AD patients. However, this neuronal loss may go together with an increase in activity of the remaining noradrenergic neurons. We prospectively evaluated 16 AD patients (6 depressed, 5 transiently depressed, and 5 nondepressed) and 10 controls. We determined norepinephrine and its metabolite 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) in various brain areas, and compared these data with previously established neuron numbers in the LC in the same patients. We could not confirm earlier studies reporting lower norepinephrine concentrations in depressed than in nondepressed dementia patients. The mean norepinephrine concentrations in AD patients were significantly lower than those in control patients, whereas the mean concentrations of MHPG were not different. Moreover, we found significant inverse relationships between the number of remaining pigmented LC neurons and the MHPG/norepinephrine ratio in the frontal cortex and LC. These data are the first to provide direct evidence for the hypothesis that remaining LC neurons are activated to compensate for decreased cerebral norepinephrine levels in AD, by demonstrating that the MHPG/norepinephrine ratio is significantly higher in AD, indicating increased metabolism. Ann Neurol 1999;45:82–91

Dopamine and noradrenaline efflux in the rat prefrontal cortex after classical aversive conditioning to an auditory cue.

We used bilateral microdialysis in the medial prefrontal cortex (PFC) of awake, freely moving rats to study aversive conditioning to an auditory cue in the controlled environment of the Skinner box. The presentation of the explicit conditioned stimuli (CS), previously associated with foot shocks, caused increased dopamine (DA) and noradrenaline (NA) efflux. This conditioned response was dependent on the immediate pairing of the two stimuli; in the pseudoconditioned group that received an equal number of both stimuli, but in an unpaired fashion, no conditioned increases in efflux were observed.

Dopamine efflux in nucleus accumbens shell and core in response to appetitive classical conditioning

Dopamine transmission within the nucleus accumbens has been implicated in associative reinforcement learning. We investigated the effect of appetitive classical conditioning on dopamine efflux in the rat nucleus accumbens shell and core, as dopamine may be differentially activated by conditioned and unconditioned stimuli (CS, US) in these subregions. After implantation of microdialysis cannulae, rats were food restricted and trained for three consecutive days with three acquisition sessions per day. A 10‐s noise (CS) was immediately followed by the delivery of two reward pellets (US) for the conditioned group (paired presentation), whereas conditioned stimuli and unconditioned stimuli were presented at random for the control group (unpaired presentation). On the fourth day, all rats were given a further CSu2003+u2003US session and two CS‐alone sessions, and extracellular dopamine concentrations were measured (7.5u2003min/per sample). Behavioural measures (number of nose pokes, latency to nose poke after conditioned stimuli onset, locomotor activity) demonstrated that the paired groups showed a high level of conditioning. CSu2003+u2003US presentation increased dopamine equally in both shell and core of the paired and unpaired groups. CS alone presentation induced a conditioned dopamine release only in the paired groups. No significant difference was found between shell and core. Unlike previous conditioning paradigms involving either a more salient US (foot shock, addictive drug) or a more complex CS, the present paradigm, using normal reward pellets as US and a discrete auditory stimulus as CS, did not lead to differential responses in dopamine efflux in shell and core subregions of the nucleus accumbens.

Central monoamine metabolism in the male brown-Norway rat in relation to aging and testosterone

Concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in brain regions of 5-, 20-, and 32-month-old male Brown-Norway rats using high pressure liquid chromatography. In view of the activating effects of sex steroids on peptide and monoamine transmitter systems and the declining plasma testosterone levels with aging, the effects of testosterone supplementation on age-related changes in central monoamine metabolism were also studied. Age-related decreases in monoamine metabolism were observed in nigrostriatal, mesocortical and coeruleohippocampal systems. Marked reductions in DOPAC (35%) and HVA (50%) occurred in the ventral tegmental area between 20 and 32 months of age. 5-HT and 5-HIAA levels showed reductions and increases depending on the brain region. Testosterone administration resulted in elevations of HVA in the substantia nigra and MHPG in the locus coeruleus and hippocampus, which were most pronounced in young animals. It is concluded that there are marked differences in age-related changes between nigrostriatal, mesocortical and coeruleohippocampal systems and that testosterone exerts a stimulatory influence on some aspects of monoamine metabolism in young but not in aged animals.

Sex differences in passive avoidance depend on the integrity of the central serotonergic system

Effects of the neurotoxin para-chloroamphetamine (PCA) on sex differences in passive avoidance were studied. Seven days prior to passive avoidance training and testing, male and female rats were injected with PCA (5 mg/kg) or physiological saline (SAL). Treatment effects on brain monoamines levels were evaluated in brains collected shortly after the passive avoidance test. Compared to SAL-treated control groups PCA severely reduced both serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA) in the frontal cortex of males and females. Levels of dopamine (DA) and homovanillic acid (HVA) in the frontal cortex were not affected. These data are indicative of a strong and selective depression of the central 5-HT activity. PCA- and SAL-treated male and female rats were trained and tested in a two-compartment step-through passive avoidance apparatus. Sex differences in passive avoidance were clearly observed in the SAL-treated control groups; a higher number of males did not enter either compartment within the maximum test duration. After PCA treatment sex differences in passive avoidance were abolished, mainly resulting from an increase in the number of PCA-males reentering. Irrespective of sex or treatment subjects seldom failed to choose the nonshock compartment when entering during the passive avoidance test, indicating that disturbance of memory or learning cannot explain for the present results. Rather, the data are discussed in terms of a sex-specific role of central 5-HT in punishment-induced behavioral suppression.

Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat

Abstractu2002Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. Objectives: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. Conclusions: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ, suggesting a role for it in anxiety.

Concept of functional neuroteratology and the importance of neurochemistry.

Publisher Summary This chapter focuses on the concept of functional neuroteratology and the importance of neurochemistry. The concept that more subtle behavioral or functional defects might be because of chemicals during pregnancy was put forward for the first time by Werboff and Gottlieb, who introduced the term behavioral teratology in scientific literature. Functional neuroteratology is, consequently quite a new concept in neurosciences. It is the existence of behavioral or other functional defects owing to the effect of chemicals during brain development in the neurosciences with important fundamental and clinical consequences. Neurochemical alterations, in relation to functional teratology, were reported soon after these observations. Alcohol now appears to be only one example of the many compounds that may cause functional teratology. Some chemicals may cause only classic teratology (e.g., limb malformations), while others cause only functional teratological defects but no gross central neural tissues (CNS) malformations. In addition, functional teratology may contribute to multi causal disease entities—for example, schizophrenia, autism, SIDS, hyperactive child syndrome, depression or anxiety.

Activation of mesocortical dopaminergic system in the rat in response to neonatal medial prefrontal cortex lesions. Concurrence with functional sparing

Neonatal lesions of the medial part of the rat prefrontal cortex (mPFC) (performed at the age of 6 days) resulted in a sparing in the performance of spatial delayed alternation (SDA) and an increase in dopaminergic (DA) innervation. The increased DA innervation was primarily observed in the remaining part of the mPFC. The DA fibre density was considerably higher in the non-ablated part of the mPFC, and the fibres were thicker with more large varicosities compared with sham-operated controls. Biochemical measurements showed a 3.5-fold increase in DA concentration in the remaining part of the mPFC of the animals with neonatal lesions when compared with the mPFC of sham-operated animals. In addition the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased. The metabolite/transmitter ratios, indicating DA utilisation, did not significantly differ from controls. The increased DA innervation and the increased concentration of DA and its metabolites in the animals with neonatal lesions further support our hypothesis that the mesocortical DA system is involved in the neural mechanism of sparing of function observed after neonatal mPFC lesions. However, sparing of function in animals with no discernable mPFC forces us to conclude that this DA response cannot be the only factor involved in the mechanism of sparing of function.

Functional deprivation of noradrenaline neurotransmission: effects of clonidine on brain development.

Publisher Summary The purpose of this chapter is to provide foundations for a working hypothesis on drug-induced functional neuroteratology. A class of centrally acting antihypertensive drugs, including clonidine, which are still being prescribed during pregnancy in humans, is used as the model. A hypothesis is put forward in this chapter which proposes that behavioral state-dependent changes in monoaminergic neuronal firing levels and patterns play a key role during early ontogeny in regulating neuron membrane potential, neurotransmitter release and neurotransmitter receptor sensitivity patterns in adulthood. Neurons show spontaneous activity that varies as a function of the behavioral state of the organism. This has been demonstrated for noradrenergic neurons of the locus coeruleus (LC), serotonergic neurons of the dorsal raphe (DR), dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsolateral part of the pons and basal forebrain. Because centrally acting antihypertensives predominantly affect the noradrenaline (NA) system in the brain, the induced modifications of central NA neurotransmission is also emphasized in this chapter.

Monoamine concentrations in rat prefrontal cortex and other mesolimbocortical structures in response to partial neonatal lesions of the medial prefrontal cortex

In an earlier study it was found that partial neonatal lesions of the medial prefrontal cortex (mPFC) resulted in an increased dopaminergic innervation in the remaining part of mPFC along with functional sparing. The present study assessed whether this response is restricted to this part of the cortex or whether also other structures of the mesolimbocortical system are involved. Furthermore, it was investigated whether the other monoaminergic systems were affected by neonatal mPFC lesions. In 6-day-old rats, the mPFC was partially ablated or a sham operation was made. The concentrations of dopamine (DA) and its metabolites increased to 250-350% in the remaining part of the mPFC compared to the sham-operated controls. The response was most prominent in this part of the cortex; no other mesolimbocortical structure showed such major changes of DA and its metabolites. In addition, a small increase in the concentrations of noradrenaline, serotonin and their metabolites was also spotted in the remaining mPFC and some other mesolimbocortical structures of the lesioned animals. The present data support the suggested involvement of DA in the neural mechanism of sparing of function, and this DA response seems to be most prominent in the remaining mPFC. However, the responses of the noradrenergic and serotonergic systems may also be important for sparing of function to occur.