Search PubMed⌕ Search

Biomedical subjects

M G Feenstra

Publications and source records attributed to M G Feenstra.

At least 19 recordsLinked to original sources

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.

Acoustic Stimulation↗

[Increased activity of stress-regulating systems in Alzheimer disease].

Behavioral, i.e. non-cognitive, disturbances, such as anxiety, agitation, sleep disturbances and depression occur in the majority of Alzheimer's disease (AD) patients, but their neurobiological basis is unknown. Disturbance of stress regulating systems, like the locus coeruleus, could play an important role. The locus coeruleus, the main production site of noradrenaline in the central nervous system, is involved in phenomena like attention, arousal and the response to the environment. In Alzheimer's disease, there is a marked reduction of noradrenergic neurons in the locus coeruleus. We studied the activity in the remaining locus coeruleus neurons and found an inverse relationship between the number of remaining neurons and the noradrenergic activity. This could indicate compensatory activity and loss of flexibility of this system. Clinically, the loss of flexibility could result in an impairment to focus attention and to respond to the environment. These results can be related to another stress related system, the hypothalamo-pituitary-adrenal-(HPA)axis. This means that further evaluation of both of these systems is necessary.

Aged↗

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

RATIONALE: 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.

Animals↗

Dopamine and noradrenaline efflux in the prefrontal cortex in the light and dark period: effects of novelty and handling and comparison to the nucleus accumbens.

We used on-line microdialysis measurements of dopamine and noradrenaline extracellular concentrations in the medial prefrontal cortex of awake, freely moving rats during the dark and the light period of the day to study whether (i) basal efflux would be higher in the active, dark period than in the inactive, light period; (ii) the activation induced by environmental stimuli would be dependent on these conditions. When determined one day after cannula placement, noradrenaline and dopamine levels were higher during the dark. Maximal relative increases induced by novelty and handling were 150% and 175-200%, respectively, and were very similar in the light and the dark, but the net increases were higher in the dark. Separate groups were tested one week after cannula placement to ensure recovery of possibly disturbed circadian rhythms. While basal levels in the dark were now approximately twice those in the light, the maximal relative and net increases after both novelty and handling were very similar. Basal levels of dopamine in the nucleus accumbens (one day after cannula placement) were not different in the light or dark, but were increased by novelty and handling to about 130% only in the light period, not in the dark. Thus, in the prefrontal cortex, dopamine strongly resembles noradrenaline, in that basal efflux was state dependent, whereas activation by stimuli was not. In the nucleus accumbens, basal dopamine efflux was not state dependent, but activation by stimuli was. These results suggest that there are differential effects of circadian phase on basal activity and responsiveness of the mesolimbic vs the mesocortical dopamine system.

Animals↗

Comparison of dopamine and noradrenaline release in mouse prefrontal cortex, striatum and hippocampus using microdialysis.

In vivo release of dopamine (DA) and noradrenaline (NA) in mouse medial prefrontal cortex, medial striatum and hippocampus was characterized using in vivo microdialysis. Basal release of NA was similar in these areas, but DA in striatum was 13-30 times higher than in other areas. Unconditioned stimuli (handling, novelty) induced strong increases, except for striatal DA. Striatal NA was more sensitive to handling than NA in other areas.

Animals↗

Dopamine and noradrenaline release in the prefrontal cortex of rats during classical aversive and appetitive conditioning to a contextual stimulus: interference by novelty effects.

Extracellular dopamine and noradrenaline concentrations in the medial prefrontal cortex were determined using online microdialysis in freely moving rats during classical appetitive or aversive conditioning to a contextual conditioned stimulus (CS). As CS we used placement in a Skinner box where either foot shocks or food pellets were delivered as unconditioned stimuli. In the aversive conditioning group we observed a conditioned increase in noradrenaline, but not in dopamine release, upon a final exposure to CS-alone. Other conditioned effects were possibly masked by the continued presence of novelty and handling effects of the transfer to the Skinner box.

Animals↗

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

In Alzheimer's 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.

3,4-Dihydroxyphenylacetic Acid↗

Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway.

In view of mounting evidence that the suprachiasmatic nucleus (SCN) is directly involved in the setting of sensitivity of the adrenal cortex to ACTH, the present study investigated possible anatomical and functional connections between SCN and adrenal. Transneuronal virus tracing from the adrenal revealed first order labelling in neurons in the intermedio-lateral column of the spinal cord that were shown to receive an input from oxytocin fibres and subsequently second-order labelling in neurons of the autonomic division of the paraventricular nucleus. The latter neurons were shown to receive an input from vasopressin or vasoactive intestinal peptide (VIP) containing SCN efferents. The true character of this SCN input to second-order neurons was also demonstrated by the fact that third-order labelling was present within the SCN, vasopressin or VIP neurons. The functional presence of the SCN-adrenal connection was demonstrated by a light-induced fast decrease in plasma corticosterone that could not be attributed to a decrease in ACTH. Using intact and SCN-lesioned animals, the immediate decrease in plasma corticosterone was only observed in intact animals and only at the beginning of the dark period. This fast decrease of corticosterone was accompanied by constant basal levels of blood adrenaline and noradrenaline, and is proposed to be due to a direct inhibition of the neuronal output to the adrenal cortex by light-mediated activation of SCN neurons. As a consequence, it is proposed that the SCN utilizes neuronal pathways to spread its time of the day message, not only to the pineal, but also to other organs, including the adrenal, utilizing the autonomic nervous system.

Adrenal Cortex↗

Disinhibition of the mediodorsal thalamus induces fos-like immunoreactivity in both pyramidal and GABA-containing neurons in the medial prefrontal cortex of rats, but does not affect prefrontal extracellular GABA levels.

Stimulation of the mediodorsal and midline thalamic nuclei excites cortical neurons and induces c-fos expression in the prefrontal cortex. Data in the literature data suggest that pyramidal neurons are the most likely cellular targets. In order to determine whether cortical interneurons are also impacted by activation of mediodorsal/midline thalamic nuclei, we studied the effects of thalamic stimulation on (1) Fos protein expression in gamma-aminobutyric acid (GABA)-immunoreactive neurons and on (2) extracellular GABA levels in the prefrontal cortex of rats. Perfusion of the GABA-A receptor antagonist bicuculline for 20 minutes through a dialysis probe implanted into the mediodorsal thalamus induced Fos-like immunoreactivity (IR) approximately 1 hour later in the thalamus and in the medial prefrontal cortex of freely moving rats. Immunohistochemical double-labeling for Fos-like IR and GABA-like IR showed that about 8% of Fos-like IR nuclei in the prelimbic and infralimbic areas were located in GABA-like IR neurons. Fos-like IR was detected in three major subsets of GABAergic neurons defined by calbindin, parvalbumin, or vasoactive intestinal peptide (VIP)-like IR. Dual probe dialysis showed that the extracellular levels of GABA in the prefrontal cortex did not change in response to thalamic stimulation. These data indicate that activation of thalamocortical neurons indeed affects the activity of GABAergic neurons as shown by the induction of Fos-like IR but that these metabolic changes are not reflected in changes of extracellular GABA levels that are sampled by microdialysis.

Animals↗

Local activation of metabotropic glutamate receptors inhibits the handling-induced increased release of dopamine in the nucleus accumbens but not that of dopamine or noradrenaline in the prefrontal cortex: comparison with inhibition of ionotropic receptors.

On-line in vivo microdialysis was used to determine the effects of a 16-min handling period on release of dopamine (DA) in the nucleus accumbens and of DA and noradrenaline (NA) in the medial prefrontal cortex of awake, freely moving rats. DA and NA were determined in one HPLC run. Handling resulted in an immediate and strong increase of both catecholamines in the prefrontal cortex. Maximal values for DA were 295%, and for NA 225%, of controls. DA in the nucleus accumbens was also increased (to 135% of controls) but only after a short delay. Local inhibition of ionotropic glutamate receptors by continuous reversed dialysis of the drugs 6-cyano-7-nitroquinoxaline, D-2-amino-5-phosphonopentanoic acid, or dizocilpine did not significantly affect handling-induced increases in cortical DA and NA release. Neither did the agonist of metabotropic glutamate receptors, trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), or the GABA-B agonist baclofen. Reversed dialysis of dizocilpine in the nucleus accumbens was equally ineffective, but ACPD inhibited the increase in DA release in this area. Stimulation of metabotropic glutamate receptors in the nucleus accumbens was previously reported to inhibit activation of DA release in that area after stimulation of glutamatergic or dopaminergic afferents. It is concluded that metabotropic receptors in the nucleus accumbens are important for the control of activation of DA release in the accumbens by physiological stimuli but that a similar mechanism is lacking in the prefrontal cortex.

3,4-Dihydroxyphenylacetic Acid↗

Modulatory role of catecholamines in the transsynaptic expression of c-fos in the rat medial prefrontal cortex induced by disinhibition of the mediodorsal thalamus: a study employing microdialysis and immunohistochemistry.

We studied the interaction of catecholaminergic and thalamic afferents of the medial prefrontal cortex (PFC) by analyzing the effects of catecholamine depletion on thalamus-induced c-fos expression in the PFC of freely moving rats. Thalamic projections to the PFC were pharmacologically activated by perfusing the GABA-A receptor antagonist bicuculline (0.03 mM or 0.1 mM) through a dialysis probe implanted into the mediodorsal thalamic nucleus. Bicuculline perfusion induced Fos-like immunoreactivity in the thalamic projection areas, including the PFC, and in the thalamic nuclei surrounding the dialysis probe. 6-Hydroxydopamine lesions of the ventral tegmental area causing a 70-80% depletion of catecholamines in the PFC did not influence the increase in the number of Fos-like immunoreactive nuclei in the prefrontal cortex in response to thalamic stimulation. However, densitometric image analysis revealed that the intensity of Fos-like immunoreactivity in the PFC of lesioned rats perfused with 0.1 mM bicuculline was higher than in correspondingly treated controls. The behavioral activity to bicuculline perfusion, an increase of non-ambulatory activity (0.03 mM) followed by locomotion and rearing (0.1 mM), was not changed in 6-hydroxydopamine-lesioned rats. It is suggested that the thalamically induced c-fos response is directly mediated by excitatory, presumably glutamatergic, transmission and not indirectly by an activation of catecholaminergic afferents of the PFC. The increase in the intensity of Fos-like immunostaining in strongly stimulated, catecholamine-depleted rats suggests that catecholamines modulate the degree to which thalamic activity can activate the PFC of awake animals.

3,4-Dihydroxyphenylacetic Acid↗

Rapid sampling of extracellular dopamine in the rat prefrontal cortex during food consumption, handling and exposure to novelty.

We report the effects of physiological stimuli on extracellular dopamine (DA) in the medial prefrontal cortex (PFC) of the rat determined on-line in dialysates obtained every 5.5 min. The detection limit for DA was 0.03-0.1 pg/5 microl injection using a conventional HPLC set-up. Basal levels in PFC were at the detection limit, therefore 3 microM nomifensine was included in the Ringer perfusion fluid, producing readily detectable DA levels of 0.9 pg/injection. Perfusion with 3 microM TTX for 30 min decreased DA within 11 min to 10% of control. The routine use of rapid sampling of extracellular DA was applied to study cortical DA release in relation to behaviour. Exposure to a novel environment for 5.5 min led to an increase to 135%. Presentation of a food pellet to food-deprived rats resulted in a rapid increase to 150% within 5.5 min, which lasted 30-40 min, which is 10-20 min more than the time spent eating. Handling the rat for 5.5 min increased DA in PFC within 5.5 min to 160% and in 11 min to 190% of control followed by a 25-min period of a 50% increase, probably reflecting increased arousal. The results suggest that emotional arousal is a common denominator of increased cortical DA release and that responses are graded depending on the intensity of the stimulus.

Animals↗

Decreased hypothalamic serotonin levels in adult rats treated neonatally with clomipramine.

Early postnatal treatment with the antidepressant drug clomipramine has repeatedly been shown to lead to behavioural and physiological changes in adult rats. To provide some neurochemical correlates to these studies we have measured a number of monoaminergic parameters in the brains of adult (one year old) rats that were treated twice daily with 15 mg/kg clomipramine from postnatal day 2-14. The most consistent finding was that the hypothalamic levels of serotonin (5-HT) were decreased and those of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) were increased in rats irrespectively whether they went through a range of behavioural and physiological tests or not. The numbers of beta-adrenoceptors in the frontal cortex and of alpha 2-adrenoceptors in the amygdala/piriform cortex were not changed. The decrease in hypothalamic 5-HT concentrations appears to be up to now the most consistent neurochemical alteration in adult rats that were neonatally treated with antidepressant drugs. It is, however, not clear what the relation is with the functional changes in these rats, that are proposed by some authors as an animal model for depression.

Animals↗

Concentration-dependent dual action of locally applied N-methyl-D-aspartate on extracellular dopamine in the rat prefrontal cortex in vivo.

Using microdialysis, the glutamate agonist N-methyl-D-aspartate (NMDA) was perfused for 20 min through the medial prefrontal cortex of freely moving rats, and its effects on extracellular concentrations of dopamine (DA) were determined. NMDA (1 mM) increased DA to 170-1500%, depending on the intensity and duration of the clonic forelimb jerks and convulsions that were induced. NMDA (0.1 mM), however, decreased DA to 61%. Metabolites of DA were decreased after both concentrations of NMDA. The effects of both 0.1 mM and 1 mM NMDA were blocked by 0.5 mM of the competitive NMDA-antagonist D-AP-5. The NMDA-induced decrease in release and metabolism possibly results from an indirect action via an inhibitory local interneuron or polysynaptic circuit.

2-Amino-5-phosphonovalerate↗

Novelty-induced increase in dopamine release in the rat prefrontal cortex in vivo: inhibition by diazepam.

The effects of graded stressful conditions on extracellular concentrations of dopamine (DA) in the medial prefrontal cortex of rats were measured in vivo using microdialysis. Picking up the rat twice with a 20-min interval increased extracellular DA to 120%, exposure to a novel environment by placement in a clean cage for 20 min to 150% and holding the rat in the hands for 20 min to over 200%. Diazepam (5 mg/kg) decreased DA to about 75% and attenuated the novelty- and handling-induced increases. Exposure to novelty or handling are easy and simple methods to obtain graded increases of in vivo cortical DA release.

Animals↗

Development and isoproterenol-induced regulation of adrenoceptor binding in cultured rat neocortical explants is seen only with the beta-1, not with the beta-2 subtype.

The presence and time-course of beta-adrenoceptor density in cultured explants of neocortex obtained from 6-day-old rat pups were investigated using a [125I]ICYP binding assay. A delayed, but more pronounced, increase in the receptor expression was observed as compared to the situation previously described in vivo. These changes only occurred for the beta 1-subtype of the receptor, whereas the beta 2-subtype binding remained constant up to 3 weeks in vitro. The delay of beta 1-adrenoceptor expression may be due to the incomplete presence of the proper maturational input, and the late enhancement of receptor expression to upregulation related to the absence in vitro of noradrenergic input. Decreased beta-adrenoceptor levels could be induced by chronic treatment of the beta-agonist isoproterenol (1 microM) introduced either for 3 or 13 days. Again, changes in density were found only for the beta 1-adrenoceptor binding sites. There is no reduction of receptor density following return to control conditions for 10 days after a 3-day treatment with isoproterenol, demonstrating the ability of this model to attain its final receptor density notwithstanding the developmental insult.

Animals↗