Biomedical subjects

R P Heinsbroek

Publications and source records attributed to R P Heinsbroek.

At least 19 recordsLinked to original sources

PubMed2000

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↗

PubMed1997

Spatial delayed alternation of rats in a T-maze: effects of neurotoxic lesions of the medial prefrontal cortex and of T-maze rotations.

The medial prefrontal cortex (mPFC) is usually considered to be a brain area important for working memory processes. In rats this statement is evidenced by their diminished performance in delay-type tasks following mPFC damage, notably in spatial delayed alternation (SDA) in a T-maze. This study has addressed two questions. First, to examine whether the functional deficiency in SDA, observed in rats with (usually large) mPFC damage, can be ascribed to an anatomically defined subarea of mPFC, the dorsal anterior cingulate area (ACd). Small, bilateral, NMDA-induced lesions were made, restricted to the dorsal part of mPFC. The performance of such animals in a T-maze paradigm, using delays of 0 and 15 s, was compared with sham-operated animals. Although these small lesions resulted in an increased number of perseverative errors, this effect was not delay-dependent, and, moreover, by the end of the training group differences had disappeared. The second aim was to study whether or not spatial (extra-maze) cues are important for the performance of this task. This was achieved by subjecting the well-trained sham-operated animals to a series of systematic trial-to-trial variations in the position of the maze in the experimental room. These spatial manipulations severely impaired the performance of the SDA task, indicating that extra-maze information is required to solve this task. In animals with ACd lesions, subjected to the same manipulations, the deficiency was comparable to that of the sham-operated animals.

Animals↗

PubMed1996

Effects of local application of dopaminergic drugs into the medial prefrontal cortex of rats on latent inhibition.

The involvement of the dopamine (DA) innervation of the medial prefrontal cortex (PFC) in attention was studied in a latent inhibition (LI) paradigm in rats. LI becomes evident by a retardation of conditioning to a stimulus after nonreinforced preexposure to that stimulus. LI is thought to reflect an animal's ability not to attend to irrelevant stimuli and is often used as an animal paradigm modeling schizophreniclike attentional deficits. In the present study the effects of bilateral infusions of the DA receptor agonist apomorphine (APO, 9.0 micrograms/side) and the DA receptor antagonist cis-flupenthixol (FLU, 12.0 micrograms/side) into the medial PFC on LI were assessed. Although in comparison with vehicle both APO and FLU infusions attenuated response suppression in nonpreexposed animals, the drugs differentially affected LI in preexposed animals. After infusions of APO animals failed to show conditioned suppression, whereas FLU-treated animals displayed as much suppression of responding as nonpreexposed animals. The abolition of LI induced by FLU infusions into the medial PFC suggests that prefrontal DA is involved in attentional processes in a way opposite to the established role of subcortical DA systems in these processes.

Animals↗

PubMed1996

Spatial learning and memory in calpastatin-deficient rats.

The present experiments were concerned with the examination of the hypothesis that a deficiency in calpastatin, the endogenous inhibitor of calpain, enhances learning and memory performance. In the first experiment we used rats with an altered calpain/calpastatin balance (Milan hypertensive strain, MHS, low calpastatin) to investigate the learning and memory of a spatial task in the Morris water maze in comparison with control rats with a normal calpain/calpastatin balance (Milan normotensive strain, MNS). Since the two strains also differ in blood pressure, a third strain of rats was included to assess the role of hypertension (spontaneously hypertensive rats, SHR). Although the acquisition rate of the spatial task was better in the low-calpastatin MHS rats than in their normal-calpastatin MNS controls, their performance was similar to that of the SHR rats, thus thwarting the conclusion that differences were due to the low level of calpastatin. The availability of another mutant strain, low-calpastatin level and normotensive (MH.NE), allowed a further examination of the hypothesis. In the second experiment rats of the MH.NE strain acquired the spatial task as well as their normotensive controls, but their memory retrieval was clearly less than that of their normal-calpastatin controls. This deficiency was not due to impaired visual function or a slower swimming speed. The conclusion is that an inbalanced calpain/calpastatin ratio, although favoring calpain activity, is disadvantageous for remembering a spatial task. This disadvantage is clearly overruled when this inbalance is accompanied by hypertension.

Animals↗

PubMed1995

The role of the medial prefrontal cortex of rats in short-term memory functioning: further support for involvement of cholinergic, rather than dopaminergic mechanisms.

The putative involvement of the dopaminergic innervation of the medial part of the prefrontal cortex (PFC) in short-term memory functioning was investigated by evaluating the effects of local infusions of dopaminergic drugs into the ventral part of the medial PFC of rats in an operant delayed-matching-to-position (DMTP) task. Two separate groups of rats were tested after bilateral microinfusion of several doses of either the dopamine receptor agonist apomorphine (APO) or the dopamine receptor antagonist cis-flupenthixol (FLU) into the ventromedial PFC. In addition, all animals were tested after infusion of several doses of the muscarinic receptor antagonist scopolamine (SCO) and the dopamine DI receptor antagonist SCH-23390 (SCH). The drugs tested affected DMTP performance differentially. APO had no effect on response accuracy, although it dose-dependently affected nose poke activity and response latencies. FLU and SCH both induced a dose-dependent, but delay-independent deterioration of response accuracy that was paralleled by increases in response latencies and decreases in nose poke frequencies, causing some animals to stop responding after infusion of the highest doses of both drugs. In contrast, SCO infusions into the ventromedial PFC induced a dose- and delay-dependent deterioration of response accuracy, that was accompanied by an increase in response latencies only. Taken together, these results provide additional support for the involvement of cholinergic, rather than dopaminergic mechanisms in short-term memory supported by the medial PFC of the rat, and they are not in favor of a functional dissociation between the dorsomedial PFC and the ventromedial PFC in the role.

Animals↗

PubMed1995

C-Fos expression in the rat brain after pharmacological stimulation of the rat "mediodorsal" thalamus by means of microdialysis.

In order to visualize target cells of thalamic projections in the rat brain we examined the induction of c-fos messenger RNA and Fos-like immunoreactivity following stimulation of the "mediodorsal" thalamus (midline, mediodorsal and intralaminar nuclei) in freely moving rats. The thalamic neurons were activated through disinhibition by perfusion of the GABAA antagonist bicuculline-methyl chloride via a microdialysis cannula placed in the mediodorsal nucleus of the thalamus. The rats were allowed a recovery period of at least 20 h after surgery before being coupled to the perfusion pump. Cannula implantation with or without 4 h of Ringer perfusion caused hardly any detectable c-fos expression in the brain, but 20 min of bicuculline (0.1 mM) perfusion induced high levels of c-fos messenger RNA and Fos protein expression in the area adjacent to the dialysis membrane, indicating activated thalamic neurons. In situ hybridization as well as immunohistochemical analysis of the frontal cortical areas and limbic structures showed a rapid, specific and transient c-fos expression in the medial and lateral prefrontal cortex, nucleus accumbens, mediodorsal striatum, claustrum, nucleus reticularis of the thalamus and amygdala. The overall spatial distribution of the c-fos response was comparable to the innervation patterns of thalamic efferents known from anatomical tracing experiments. The rats were perfused with Ringer while asleep, but they woke up during treatment with bicuculline and displayed an increase in general behavioural activity, which could be correlated to the amount of bicuculline measurable in the dialysate. Pathological behaviours, such as epilepsy, were not noticeable during bicuculline treatment. These results show that it is possible to selectively activate defined anatomical pathways by pharmacological application of drugs using microdialysis in unanesthetized unrestrained animals and to visualize the transsynaptically activated target neurons of these projections. We conclude that this novel experimental approach is indeed suitable for studying functional anatomical pathways.

Animals↗

PubMed1994

A behavioural analysis of rats with damage to the medial prefrontal cortex using the Morris water maze: evidence for behavioural flexibility, but not for impaired spatial navigation.

In this study, the functional properties of the medial prefrontal cortex (mPFC) of the rat were examined in a task for spatial navigation. The dorsomedial (dmPFC) and ventromedial (vmPFC) parts of the PFC differ in their connectivity with the hippocampus, vmPFC being the main recipient of hippocampal input. Therefore, it is hypothesized that in a spatial task known to be particularly sensitive to hippocampal, but also to prefrontal cortical damage, especially vmPFC is committed to proper spatial learning and memory. Using the Morris water maze task, with an invisible platform, male rats with either partial (dmPFC or vmPFC) or whole (mPFC) bilateral lesions were subjected to various procedures reflecting spatial learning and memory, including a spatial reversal. Animals with dmPFC, vmPFC and mPFC lesions learned and remembered the spatial task equally well as their controls, regardless of the size or site of the bilateral lesion. However, when presented with a spatial reversal, animals with whole mPFC lesions were initially slower in locating the invisible platform than controls and animals with partial mPFC damage, but this effect was only short-lasting. When subsequently presented with a visible platform, all animals with partial (dmPFC or vmPFC) or whole mPFC damage needed significantly more time to locate the platform than the controls. This effect was transient and lasted longer in the animals with whole mPFC damage than in animals with partial damage. On the basis of these findings we conclude that an intact mPFC is not necessary for proper spatial learning and memory. The impairments in the reversal task and especially in the visually-cued task can best be explained as a diminished behavioural flexibility when a shift in task demands occurs. Since the degree of this impairment was related to the size of these lesions, but not to their sites, these differences are ascribed to a 'mass action' of medial prefrontal cortex lesions.

Animals↗

PubMed1994

Effects of local application of dopaminergic drugs into the dorsal part of the medial prefrontal cortex of rats in a delayed matching to position task: comparison with local cholinergic blockade.

Lesions of the medial prefrontal cortex (mPFC) disrupt performance in a variety of delay tasks, which suggests that the mPFC supports short-term memory processes. The putative involvement of the dopaminergic innervation of the mPFC in these mnemonic processes was investigated by evaluating the effects of local infusions of dopaminergic drugs into the mPFC of rats in an operant delayed-matching-to-position (DMTP) task. Trained animals were provided with bilateral guide cannulae aimed at the dorsal part of the mPFC. Two separate groups of rats were tested after microinfusion of several doses of either the dopamine agonist apomorphine (APO) or the dopamine antagonist cis-flupenthixol (FLU). In addition, all animals were tested after infusion of several doses of the muscarinic antagonist scopolamine (SCO). Animals were tested 0 and 135 min after each infusion. At the 0 min interval, neither APO nor FLU affected accuracy of DMTP performance, while both drugs dose-dependently increased response latencies and decreased nosepoke frequencies. At the 135 min interval, APO had almost no effect, whereas the effects of FLU were very prominent. A number of animals no longer responded after infusion of the highest doses of FLU and those that did showed a delay-independent decrease in response accuracy. In contrast, SCO infusions into the mPFC induced a dose- and delay-dependent deterioration of DMTP performance. Taken together, these results support a direct involvement of the rat mPFC in short-term memory processes, although they implicate cholinergic rather than dopaminergic mechanisms in this function.

Animals↗

PubMed1994

Mild sustained effects of neonatal vasopressin and oxytocin treatment on brain growth and behavior of the rat.

The lasting effects of a 9-day neonatal exposure to vasopressin and oxytocin were examined in the rat to discover if peptide administration results in organizational effects. When tested in young adulthood, brain growth, not body growth, appeared to be impaired. Basal and challenge tests of urine production, carried out to see the development of the hormonal antidiuretic function of vasopressin, revealed no lasting changes, and therefore did not confirm earlier findings of an induced mild polyurea. Behavioral testing of learning by making use of a one-trail step-through paradigm with a 24-h retention trial--a test that is sensitive to vasopressin--did not show impairments. Open field tests, however, showed enhanced emotionality in the vasopressin-treated females, as well as an initially increased ambulation in the males, and increased grooming in both sexes, the latter also having been reported to be induced by vasopressin administration in the septal areas. Oxytocin treatment did not produce lasting changes. Our conclusion, therefore, is that peripherally circulating vasopressin can affect the organizational development of the rat brain. It remains to be established whether this is an effect obtained through changes in the general peripheral physiology or a reflection of plasticity phenomena at the level of central vasopressin neurotransmission.

Animals↗

PubMed1993

In vivo microdialysis of noradrenaline overflow: effects of alpha-adrenoceptor agonists and antagonists measured by cumulative concentration-response curves.

1. The purpose of the present study was to compare the effects of several alpha-adrenoceptor agonists and antagonists on cerebral cortical overflow of endogenous noradrenaline (NA) in freely moving rats. One or two days after the implantation of transcerebral dialysis tubes in the frontoparietal cortex, extracellular NA levels were monitored on-line with high performance liquid chromatography and electrochemical detection. The drugs were applied locally via the dialysis membrane, and effects on NA overflow were determined in cumulative concentration-response curves. 2. The average basal cortical NA overflow of all experiments was 0.25 pg min-1. The alpha 2-adrenoceptor agonists caused a concentration-dependent decrease in NA levels. UK-14,304 was the most potent and B-HT 933 the least potent agonist. The maximal decrease in NA overflow was to 10-15% of control levels after UK-14,304 or moxonidine, to 30% after clonidine and to 50% after B-HT 933 administration. Continuous activation of the presynaptic alpha 2-adrenoceptor with 10(-6) M UK-14,304 caused a decrease in NA levels to 40-50% of basal levels. This decrease was reached within 1 h and remained stable for the entire 3 h measurement period. The alpha 1-adrenoceptor agonists, phenylephrine and methoxamine, induced an increase in NA levels to 225% and 300%, respectively, at a concentration of 10(-3) M. 3. Local application of alpha 2-adrenoceptor antagonists caused an increase in NA levels, with idazoxan being more potent than piperoxan. Yohimbine did not cause any significant change. 4. All drugs used in these in vivo experiments had in vitro recoveries across the dialysis membrane between 10 and 20%. 5. We conclude that microdialysis with local drug application is suitable for the comparison of the pharmacological effects of drugs with affinity for alpha-adrenoceptors on cortical NA overflow in vivo,provided that the passage across the membrane is equal for the different drugs.

Adrenergic alpha-Agonists↗

PubMed1992

Intracerebroventricular LHRH may serve as a discriminative stimulus in male rats.

Male Wistar rats (N = 16) were trained to discriminate 5 micrograms/kg LHRH, injected intraperitoneally, from saline in a two-lever, food-reinforced drug discrimination procedure, with an injection-session interval of 45 min. Reliable discrimination of LHRH was acquired within 60 training sessions. Subsequent generalization tests in brain-cannulated animals showed dose-dependent and time-related partial substitution of intracerebroventricular LHRH for intraperitoneal LHRH (ventricle doses ranged from 25-400 ng, and the injection-session intervals ranged from 10-40 min). These results indicate that centrally administered LHRH may serve as a dose- and time-dependent discriminative stimulus in male rats.

Animals↗

PubMed1992

Dose-dependent and time-related stimulus properties of LHRH in male but not in female rats.

Male and female rats (N = 32) were trained to discriminate 5 micrograms/kg LHRH from saline in a two-lever, food-reinforced drug discrimination procedure with injection-session intervals of 15 min or 45 min. When the interval was 15 min, neither males nor females were able to discriminate the stimulus conditions. With an interval of 45 min, LHRH showed sex-dependent stimulus properties. Male, but not female, rats reliably discriminated LHRH from saline within 50 training sessions. In males, generalization tests showed dose-dependent and time-related stimulus effects of LHRH (doses ranged from 62.5 ng/kg to 8 micrograms/kg, and intervals ranged from -15 min to -120 min). The results indicate that LHRH may be an essential part of the stimulus complex in male rats but could not gain control over operant behavior in female rats.

Animals↗

PubMed1991

Controllable and uncontrollable footshock and monoaminergic activity in the frontal cortex of male and female rats.

Effects of controllable and uncontrollable footshock on monoaminergic activity in the frontal cortex and plasma corticosterone levels were studied in male and female rats. Subjects were exposed to a shuttle-box procedure for a period of either 30 min (60 shocks) or 90 min (180 shocks). A shuttle response ended shock presentation for escape subjects, whereas their yoked, same-sex, counterparts were unable to escape from shock presentation. A third group was exposed to the experimental environment, but did not receive any shocks. Concentrations of noradrenaline, serotonin and dopamine and their major metabolites were measured in the frontal cortex by high performance liquid chromatography with electrochemical detection. Plasma corticosterone was measured by radioimmunoassay. Results of this experiment show that: (1) exposure to the experimental environment without shock already increased the activity of all 3 transmitter systems. In particular, serotonin was very responsive to mere confinement to the shuttle-box. Changes induced by exposure to the experimental environment were similar for males and females. (2) Presentation of footshocks further increased transmitter activity. The activation of noradrenaline and dopamine was larger after uncontrollable shock than after controllable shock. Moreover, uncontrollable shock resulted in higher serotonin levels than controllable shock. (3) Sex-dependent effects of controllability were found for noradrenaline and dopamine, but not for serotonin. Differences in catecholaminergic activity between controllable and uncontrollable shock were larger in females than in males. (4) In both males and females, corticosterone levels in plasma were increased by exposure to the experimental environment. A further elevation was found in response to footshock presentation, which was independent of the controllability of shock.

Animals↗

PubMed1991

Sex-dependent effects of aversive stimulation on holeboard and elevated plus-maze behavior.

The behavioral effects of exposure to inescapable shocks (IS) were studied in both the holeboard and the elevated plus-maze, 24 and 72 h after IS in male and female Wistar rats. The following effects were observed at the 24-h interval. In both sexes, head-dipping in the holeboard was reduced by IS, whereas general activity (ambulation and rearing) was reduced in males and not in females. Furthermore, the results of a correlation analysis indicate that previous exposure to IS disrupts the dissociation observed in control groups between exploratory activity directed at the holes (head-dipping) and general activity in the holeboard (ambulation and rearing). Effects of IS on plus-maze behavior could be observed in a clear suppression of rearing in males and not in females. IS did not affect time spent on the open arms. At the 72-h interval, IS affected head-dipping in the holeboard only in males and not in females. The present findings show that the effect of IS on specified behavioral elements is sex-dependent, with stronger and longer-lasting effects in males than in females.

Animals↗

PubMed1991

Sex- and time-dependent changes in neurochemical and hormonal variables induced by predictable and unpredictable footshock.

Previous experiments have revealed sex-dependent effects of inescapable shock in rats. Behavior of male rats was more severely disrupted by inescapable shock than behavior of female rats. These sex differences were found after 1- and 24-hour intervals but not after a 72-hour interval. The present experiment was designed to study various physiological parameters at 1-, 4- and 24-hour intervals after inescapable footshock. The predictability of shock was manipulated by adding a compound light and tone stimulus that preceded shock presentation for one group but was not correlated with shock presentation for another group of subjects. Noradrenaline, dopamine, serotonin, and metabolites of these 3 transmitters were measured in the frontal cortex. Transient shock-induced increments in dopamine and metabolites of dopamine and serotonin were found, but the sex of the animal did not differentially affect this neurotransmitter response. In addition to neurotransmitter concentrations in the frontal cortex, levels of corticosterone were measured in plasma. The pituitary-adrenal axis was activated for a longer period in females than males after shock. The present data do not provide evidence that behavioral sex differences induced by inescapable shock are paralleled by sex differences in neurotransmitter activity. In addition, sex-dependent effects of predictability of shock on neurotransmitter activity were not detected. The relevance of the observed sex-dependent responses in the pituitary-adrenal system is discussed.

Animals↗

PubMed1991

Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock.

In two experiments, the effects of inescapable shock on subsequent shuttle-box escape performance were studied in male and female rats. Effects of treatment with short-duration shocks (2 s) were studied after 1- and 24-hour intervals (Experiment 1), and effects of long-duration shocks (6 s) were studied after 24- and 72-hour intervals (Experiment 2). Experience with inescapable shock resulted in a serious disruption of escape performance in both males and females. A large increment in escape latencies was found both during fixed ratio 1 and fixed ratio 2 escape training; however, effects of inescapable shock were more pronounced in males than in females. In Experiment 1, sex differences were most obvious after the short 1-hour interval whereas, in Experiment 2, sex differences were only present after 24 hours and not after 72 hours. Shuttle activity during 2-min adaptation prior to shock-escape training was reduced in both males and females treated with IS, and this effect was somewhat stronger in males than in females. The data of these experiments show that male rats are more sensitive to the consequences of exposure to inescapable aversive stimulation than female rats. It is proposed that the time-dependency of the sex differences in behavioral consequences of treatment with inescapable shock may be related to sex differences in transient neurochemical or hormonal changes induced by inescapable shock.

Animals↗

PubMed1991

Pituitary and brain beta-endorphin in male and female rats: effects of shock and cues associated with shock.

The present experiment was designed to study whether or not prior exposure to inescapable shock is accompanied by sex-dependent changes in pituitary and central levels of immunoreactive beta-endorphin, which is proposed to play an important role in opioid analgesia induced by aversive stimulation. Further, the effects of brief reexposure (5 min) to the chamber where inescapable shock was experienced earlier, were established in both sexes. Elevated levels of beta-endorphin were found 24 hours after inescapable shock, in the anterior pituitary of males and in the midbrain periaqueductal gray of both males and females. Reexposure to the experimental chamber only affected beta-endorphin levels if shock had been experienced in this chamber. Reexposure after inescapable shock reduced beta-endorphin content of the arcuate nucleus of males and beta-endorphin content of the periaqueductal gray of males and females. The present results are related to previous findings of sensitization and conditioning of analgesic reactions. The sex differences found in the present experiment are discussed with respect to sex-dependent behavioral consequences of inescapable shock.

Animals↗

PubMed1990

Sex-dependent effects of inescapable shock administration on shuttlebox-escape performance and elevated plus-maze behavior.

The present experiment investigated the effects of exposure to inescapable shocks (IS) on subsequent behavior in an elevated plus-maze and on shuttlebox-escape performance in male and female rats. In the elevated plus-maze, exposure to IS resulted in suppression of "total number of arm entries" and "rearings" in males but not in females. In addition "time on open arms" was reduced in both sexes after exposure to IS, but this effect seemed stronger in males than in females. Exposure to IS disrupted shuttlebox-escape performance of males, whereas escape performance of females was unaffected. Affected escape performance in males was transient and limited to the initial phase of escape training. A sex difference in emotional reaction to stress might contribute to the observed sex difference in the acquisition of an escape response. The strong passive avoidance tendency observed in males, which may be strengthened by IS, strongly interferes with the acquisition of the escape response by this sex, resulting in sex differences in susceptibility to behavioral disturbances induced by IS.

Adaptation, Psychological↗