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Biomedical subjects

G Wolterink

Publications and source records attributed to G Wolterink.

At least 37 records · Page 2Linked to original sources

Short duration of retroactive facilitation of social recognition in rats.

Adult rats spent less time investigating the same juvenile during a second dyadic encounter session. This decrease served as an index for social recognition. Social recognition was not influenced by isolating the juveniles for 7 days prior to experimentation. Retroactive facilitation of social recognition was observed when the two rats were confronted for a longer period of time on a given day by multiple testing. However, this facilitation was not observed after a 24-h interexposure interval between encounter sessions, even when different housing conditions during that time were taken into account, and animals were tested during 5 consecutive days. It is suggested that social recognition may be a form of short-term memory.

Aging↗

The ACTH-(4-9) analogue ORG 2766 facilitates denervation supersensitivity after a unilateral 6-OHDA lesion of the corpus striatum in rats.

UNLABELLED: Direct bilateral 6-OHDA lesioning of the nucleus accumbens causes a temporary reduction in motility, followed by a spontaneous recovery in 3-4 weeks. The ACTH-(4-9) analogue ORG 2766 shortens this period to 1 week. The functional and the peptide-induced facilitation of recovery are accompanied by enhanced motility upon administration of the dopamine agonist apomorphine which may be related to denervation supersensitivity. The present experiments were performed to investigate the interaction between ORG 2766 and denervation supersensitivity in another dopaminergic terminal area i.e. the corpus striatum. After a unilateral 6-OHDA lesion of the right corpus striatum, contralateral rotation was observed upon administration of a high dose of apomorphine 2, 3 and 4 weeks after the lesion, indicating supersensitivity of postsynaptic dopaminergic receptor systems. Contralateral rotation upon administration of this dose of apomorphine was observed in ORG 2766 treated animals, already at 1 week after the lesion. Peptide treatment resulted in an enhanced sensitivity for apomorphine, since contralateral rotation was observed in peptide but not in placebo treated, 6-OHDA lesioned animals after a low dose of apomorphine. IN CONCLUSION: treatment with ORG 2766 facilitates the development of denervation supersensitivity and enhances sensitivity for apomorphine probably through an increased affinity of dopaminergic receptors for dopamine agonists.

Adrenocorticotropic Hormone↗

Analysis of the influence of vasopressin neuropeptides on social recognition of rats.

The facilitatory effect of vasopressin neuropeptides on social recognition of adult male rats was analyzed. The decrease of social investigation behaviors during a second encounter with the same juvenile rat served as index for social recognition. Treatment with desglycinamide-(Arg8)-vasopressin (6 mg.kg-1, s.c.) extended the time that adults recognize the same juvenile from 30 min to 24 h. Structure-activity studies revealed that the effect of vasopressin neuropeptides on social recognition resides in the 5-8 part of the AVP molecule. The peptide (pGlu4,Cyt6) AVP-(4-8) was more potent than DGAVP in this behavioral paradigm. These effects bear similarities with the memory enhancing effects of vasopressin neuropeptides as found in other test procedures.

Animals↗

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. I. Behavioral and biochemical studies.

Bilateral 6-hydroxydopamine (6-OHDA) lesions in the nucleus accumbens of rats induced motor hypoactivity 7 days after the lesion. Spontaneous functional recovery of this impaired behavior occurred in 3-4 weeks. Behavioral and biochemical studies suggest that the hypoactivity is due to damage of the dopamine systems in the nucleus accumbens. The 6-OHDA lesions induced a decrease in the nucleus accumbens levels of dopamine and its metabolites of about 30% both 7 and 20 days after the lesion. The in vitro uptake of [3H]dopamine in nucleus accumbens tissue of the 6-OHDA-lesioned rats was decreased to the same extent at 7, 14 and 28 days after the lesion. Scatchard analysis of [3H]haloperidol binding studies in nucleus accumbens tissue revealed a shift from one type of binding site in tissue of sham-lesioned rats to two types of binding sites in tissue of 6-OHDA-lesioned rats 29 days after the lesion. This shift was not present in nucleus accumbens tissue 8 days after a 6-OHDA lesion. The spontaneously recovered rats showed an enhanced behavioral response upon administration of the dopamine agonist apomorphine. The present data suggest that the spontaneous functional recovery of impaired motor activity is caused by the development of supersensitivity of the dopamine receptor systems in the nucleus accumbens. This supersensitivity may be the result of increased affinity of one type of binding site or an increased number of functional binding sites.

Animals↗

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. II. Facilitation by the ACTH-(4-9) analog ORG 2766.

Functional recovery from motor hypoactivity of rats with 6-OHDA lesions in the nucleus accumbens is accelerated by intra-accumbal or subcutaneous treatment with the ACTH-(4-9) analog ORG 2766. The spontaneous recovery period of 3 weeks is shortened to 7 days by daily treatment with this peptide during the first 6 days after the lesion. The 6-OHDA lesion induced a decrease of about 30-40% in the levels of dopamine, HVA and DOPAC as well as in the uptake of [3H]dopamine in nucleus accumbens tissue in vitro. Treatment with ORG 2766 during the first 6 days following the lesion did not affect the lesion-induced changes in these biochemical parameters. Binding studies with [3H]haloperidol in nucleus accumbens tissue of placebo or ORG 2766-treated sham-lesioned rats revealed a linear Scatchard plot 7 days after the sham lesion. In tissue of placebo-treated 6-OHDA lesioned animals a similar linear Scatchard plot was found but in tissue of ORG 2766-treated 6-OHDA-lesioned rats the Scatchard plot was curvilinear in shape indicating two types of binding sites. In the 6-OHDA-lesioned rats treated with ORG 2766 the behavioral response upon apomorphine challenge was enhanced suggesting the existence of functional supersensitivity of the DA system. Similar changes in Scatchard plots and apomorphine-induced behavioral changes have been previously reported after spontaneous recovery. The present study indicates that ORG 2766 accelerates the process of functional recovery from impaired motor behavior of rats with 6-OHDA lesions in the nucleus accumbens, which may be due to development of denervation supersensitivity.

Adrenocorticotropic Hormone↗

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. III. Further analysis of the facilitating effect of the ACTH-(4-9) analog ORG 2766.

The functional recovery from impaired motor activity caused by 6-OHDA lesions in the nucleus accumbens is accelerated by the ACTH-related peptides ACTH-(4-10), alpha-MSH (ac-Ser1-ACTH-(1-13)NH2), ACTH-(7-10) and the ACTH-(4-9) analog ORG 2766. The peptides ACTH-(4-7) and Phe-D-Lys-Phe were not effective in this respect. This indicates that this effect of ACTH-derived peptides is located in the 7-10 part of the molecule whereas for the effect of ORG 2766 a bigger part of the molecule may be required. ORG 2766 was effective after intra-accumbal, subcutaneous and oral administration. The differences in potencies between the 3 routes of administration (ED50 0.76 ng/kg, 28.5 ng/kg and 80.6 micrograms/kg, respectively) suggest that the peptide exerts its effect by facilitating recovery processes at the lesion site. Studies with ORG 2766 showed that treatment during the first days following the induction of the lesion is essential for the facilitating action of the peptide on spontaneous recovery from brain damage.

Adrenocorticotropic Hormone↗

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. IV. Delay by intra-accumbal treatment with ORG 2766- or alpha-MSH antiserum.

Rats with 6-OHDA lesions in the nucleus accumbens which were treated intra-accumbally with control serum during the first week following the lesion showed a similar level of motor activity 3 weeks after the lesion as sham-lesioned rats treated with control serum. In 6-OHDA-lesioned rats that were identically treated with antiserum against alpha-MSH or the ACTH-(4-9) analog ORG 2766 motor activity was decreased 3 weeks after the lesion. Intra-accumbal treatment with the antisera did not affect motor activity of sham-lesioned rats. The increased motor activity after apomorphine injection into the nucleus accumbens of control serum-treated 6-OHDA-lesioned rats was not observed in 6-OHDA-lesioned rats treated with the antisera. Furthermore, [3H]haloperidol binding studies showed that the changes in the DA receptor systems in the nucleus accumbens of 6-OHDA-lesioned rats treated with control serum, which may reflect denervation supersensitivity, were not observed in 6-OHDA-lesioned rats treated with the antisera. The present data indicate that the functional recovery and the concurrent development of supersensitive DA receptor systems in the nucleus accumbens of 6-OHDA-lesioned rats are delayed by intra-accumbal treatment with ORG 2766 or alpha-MSH antiserum. This suggests that endogenous ACTH/MSH-like factors may be mediating the recovery processes.

Adrenocorticotropic Hormone↗

A single injection of a biodegradable microsphere formulation of the ACTH-(4-9) analogue ORG 2766 accelerates functional recovery after brain damage.

The functional recovery from impaired motor activity induced by 6-hydroxydopamine lesions in rat nucleus accumbens was accelerated by subcutaneous treatment with the ACTH-(4-9) analogue Met/O2/-Glu-His-Phe-D-Lys-Phe (ORG 2766). Treatment was effective after daily injections of ORG 2766 dissolved in saline during the first 6 days following the lesion (ED50: 28.5 ng kg-1 day-1) or after a single injection of the peptide in a biodegradable microsphere formulation administered after the lesion (ED50: 8.9 ng kg-1 day-1). This study shows that a single injection of a microsphere preparation can replace multiple injections with ORG 2766 in order to facilitate functional recovery after brain damage.

Adrenocorticotropic Hormone↗

Antipsychotic substances and dopamine in the rat brain; behavioral studies reveal distinct dopamine receptor systems.

Graded doses of apomorphine were injected into terminal areas of the nigrostriatal, mesolimbic and mesocortical dopamine (DA) systems of the rat brain. Injection of high doses of apomorphine into the nucleus caudatus elicited stereotyped sniffing, but did not affect the motility of the rat. Low and high doses of apomorphine injected into the nucleus accumbens decreased and increased motility, respectively, without changing sniffing behavior. Injection of both low and high doses of apomorphine into the pyriform cortex increased sniffing behavior, but did not affect motility. All these apomorphine-induced behavioral responses were antagonized by local pretreatment with the typical neuroleptic, haloperidol, and the atypical neuroleptic, sulpiride, albeit with different potencies as revealed from the calculated ED50 values (ranging from 0.18-20,462 fmol). Local pretreatment with the antipsychotic peptide, des-enkephalin-gamma-endorphin (DE gamma E), antagonized the behavioral changes induced by injecting low and high doses of apomorphine into the pyriform cortex and low doses into the nucleus accumbens (ED50: 0.22-20.6 fmol), but did not affect the behavioral effects elicited by injecting high doses of apomorphine into the nucleus caudatus or the nucleus accumbens. It is proposed that two distinct types of DA receptor systems are present in the rat brain. These are characterized by the slope of the dose-response curve for the substances to antagonize the apomorphine-induced behavioral effects and by the effectiveness of DE gamma E in this respect. The antipsychotic effects of these compounds may be mediated by DA systems in the nucleus accumbens or in the pyriform cortex; this last system is especially sensitive to the three antipsychotic substances and is equally affected by them (ED50 value for the antagonism of the apomorphine-induced effects: 0.18-0.71 fmol).

Animals↗

Behavioral and neurotrophic activity of ACTH-(7-16)NH2.

The behavioral and neurotrophic effects of ACTH-(7-16)NH2 were assessed in a number of tests in which other ACTH fragments are active. Subcutaneous injection of ACTH-(7-16)NH2 increased motor activity of group-housed rats tested under low light intensity and induced hypokinesia in rats subjected to the mild stress of a nonfunctional "hot" plate. In rats with 6-OHDA lesions in the nucleus accumbens daily subcutaneous treatment with ACTH-(7-16)NH2 during the first week following the lesions reversed the lesion-induced motor hypoactivity. The ED50's for the effects of ACTH-(7-16)NH2 on the environmentally induced changes in motor activity, the stress-induced hypokinesia and the impaired motor activity of 6-OHDA lesioned rats were approximately 8 micrograms/kg. 6.3 micrograms/kg and 0.45 micrograms/kg respectively. It is concluded that ACTH-(7-16)NH2 may mimic the effect of an ACTH-like peptide in the brain involved in brain processes triggered by changes in the environment and by brain damage.

Adrenocorticotropic Hormone↗

The response of apomorphine administered into the accumbens in rats with bilateral lesions of the nucleus accumbens, induced with 6-hydroxydopamine.

Bilateral lesions of the nucleus accumbens, induced with 6-hydroxydopamine, reduced motor activity and produced a 20-35% depletion of the concentrations of dopamine (DA) and its main metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Small doses of apomorphine (1-10 ng), injected into the nucleus accumbens of sham-lesioned rats, decreased motor activity, while larger doses (1-10 micrograms) produced hyperactivity. In rats lesioned with 6-hydroxydopamine, apomorphine caused hyperactivity only, and this apomorphine-induced response was more pronounced than in sham-lesioned rats. Large doses of apomorphine decreased, only in sham-lesioned animals, the levels of DOPAC and HVA. These data suggest that the apomorphine-induced hypomotility is mediated by presynaptically located DA receptor systems in the nucleus accumbens, whereas the apomorphine-induced hypermotility is likely to be mediated by postsynaptically located DA receptor systems.

3,4-Dihydroxyphenylacetic Acid↗

The ACTH4-9 analog ORG 2766 'normalizes' the changes in motor activities of rats elicited by housing and test conditions.

Motor activities of rats were decreased by short-term (7 days) social isolation as well as by intense light test conditions. The ACTH4-9 analog ORG 2766, s.c. administered 50 min before testing, dose-dependently decreased the high motor activities of group-housed rats tested under low light conditions and increased the low motor activities of short-term isolated rats tested under intense light conditions (ED50: 0.01-0.03 microgram/kg). Structure-activity studies suggest that the essential structure for these effects may be located in the C-terminal tripeptide Phe-D-Lys-Phe. Treatment with ACTH4-10 (100 micrograms/kg) tended to enhance some of the effects of the environmental conditions. Pretreatment of rats with the opioid antagonist naltrexone (450 micrograms/kg, s.c.) completely blocked the 'normalizing' effects of ORG 2766, implicating endogenous opioids in this action of ORG 2766. Since social behaviors of rats are similarly affected by ORG 2766 as motor activities, it is suggested that this peptide affects the integration of sensoric stimuli rather than the specific motor output systems of these behaviors.

Adrenocorticotropic Hormone↗

Effects of endotoxin-treatment on inflammatory cell infiltrates in murine Meth A sarcoma.

The effect of intravenously injected endotoxin on inflammatory cells within solid Meth A tumours was studied and central hyperaemia, necrosis and early collapse were observed macroscopically at 4, 24 and 48 h, respectively. The effects were studied in semithin sections and cytocentrifuge preparations of the tumours. The inflammatory cell reaction evoked by the tumours in untreated animals was relatively slight. It was located predominantly around the lateral margins of the tumours and only a few inflammatory cells were found inside the tumour. Prominent effects of endotoxin included a transient increase of mononuclear inflammatory cells in the centre of the tumour by 4 h and a reduction of the influx of lymphocytes, observed in and around the margin of control tumours, by 48 h. Mast cells formed an important part of the inflammatory cell infiltrate, but no distinct changes in number and appearance were observed with time or following treatment. Total host cell numbers within tumours did not increase significantly upon endotoxin-treatment. Results suggest that a direct cytotoxic action of host cells cannot account for the extensive tumour damage observed. Rather, endotoxin-induced regression seems to be related to decreased lymphocyte numbers.

Animals↗

In vivo interaction of gamma-type endorphins with dopaminergic ligands in rat brain.

The beta-endorphin (beta E) fragment des-Tyr1-gamma-endorphin (DT gamma E, beta E-(2-17)) has been reported to interact with neuroleptic binding in vivo but not in vitro. We have attempted to replicate the in vivo experiments and extended the work to include conditions in which des-enkephalin-gamma-endorphin (DE gamma E, beta E-(6-17)) exhibited behavioral activity. Systemically administered haloperidol significantly elevated plasma and decreased striatal [3H]spiperone. DE gamma E significantly elevated plasma [3H]apomorphine when both substances were injected directly into the nucleus accumbens. gamma-type endorphins consistently but non significantly decreased brain spiperone or apomorphine binding. It is concluded that the interaction between gamma-type endorphins and dopaminergic binding sites may be either indirect or limited to a subset of these sites.

Animals↗

Non-opiate beta-endorphin fragments and dopamine--III. gamma-Type endorphins and various neuroleptics counteract the hypoactivity elicited by injection of apomorphine into the nucleus accumbens.

The hypoactivity in rats induced by small doses of apomorphine, injected bilaterally into the nucleus accumbens area of the brain, could be antagonized by pretreatment with the neuroleptic-like neuropeptide des-enkephalin-gamma-endorphin (DE gamma E, beta-endorphin 6-17) as well as with the neuroleptic drugs haloperidol, sulpiride and clozapine injected into the accumbens. Dose-response studies revealed that a dose of 100 pg DE gamma E completely inhibited the apomorphine-induced hypomotility. The influence of DE gamma E appeared to be specific for gamma-type endorphins, since alpha-type endorphins were inactive in this respect. Treatment with DE gamma E injected into the accumbens for 4 days resulted in an enhancement of apomorphine-induced hypoactivity. It is concluded that gamma-type endorphins may control the activity of dopaminergic transmission in the nucleus accumbens, a suggestion which may be of significance for the purported neuroleptic-like and antipsychotic action of gamma-type endorphins.

Animals↗

Non-opiate beta-endorphin fragments and dopamine-IV. gamma-Type endorphins may control dopaminergic systems in the nucleus accumbens.

Chronic treatment with des-enkephalin-gamma-endorphin (DE gamma E, beta-endorphin 6-17) twice daily for 10 days into the nucleus accumbens of rats resulted in hypoactivity, while similar treatment with gamma-endorphin antiserum led to a marked hyperactivity. This enhanced activity persisted for at least 3 days following discontinuation of treatment. Rats chronically treated with gamma-endorphin antiserum into the nucleus accumbens habituated at a slower rate when tested repeatedly for locomotor activity, as well as for nociception. Passive avoidance behaviour was attenuated in the treated rats, when they were trained during treatment, but not when the learning trial was given before treatment and testing was performed during treatment. Treatment with gamma-endorphin antiserum did not affect the diurnal rhythm in locomotion, the responsiveness to nociceptive stimulation and the basal and novelty stress induced-plasma corticosteroid levels. It is concluded that chronic treatment with gamma-endorphin antiserum into the nucleus accumbens, which may lead to bio-inactivation of gamma-type endorphins, causes hyperactivity and disturbances in habituation and cognitive functions. It is suggested that gamma-type endorphins are physiologically involved in the control of distinct dopaminergic systems in the nucleus accumbens. The findings are discussed in relation to the role of mesolimbic dopaminergic systems in schizophrenic psychosis.

Animals↗