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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.

The behavioral effects of two peptides (HOE 427) and ORG 31433) related to the ACTH-(4-9) analog ORG 2766 were investigated in Wistar rats in a number of tests in which Org 2766 is active. Subcutaneous administration of HOE 427 in a dose of 0.5 ng/kg or ORG 31433 in doses of 0.5-5.0 ng/kg facilitated passive avoidance behavior whereas these peptides attenuated the avoidance response in doses of 25 ng/kg and 250 ng/kg respectively. ORG 31433 (0.1 - 1.0 microgram/kg) decreased motor activity of group housed rats tested under low light conditions. Furthermore subcutaneous (1.0- 10.0 ng/kg) or oral (10 microgram/kg) administration of ORG 31433 accelerated functional recovery from 6-hydroxydopamine (6-OHDA)-induced lesions in the nucleus accumbens which cause motor hypoactivity. The experiments show that as compared to ORG 2766 the peptides HOE 427 and ORG 31433 induce qualitatively similar responses but are approximately 10 to 100 times more potent. These data may imply that substitution of the C-terminal COOH group of ORG 2766 yields neuropeptides with increased potency.

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.

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.

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.

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.

Subcutaneous treatment with the neuropeptide ACTH-(4-10) induced hypokinesia in rats subjected to a mild stress induced by placing the animals on a non-functional "hot" plate (21 degrees C) for 30 sec, but not in control animals not exposed to this stress-inducing environment. The lowest effective dose of ACTH-(4-10) was 5 micrograms/kg, administered 50 min before testing. The combination of peptide treatment and the mild stress-inducing procedure mimicked the effect of a short intense stress induced by placing the rats on a hot plate (57 degrees C) for 30 sec, suggesting that this stress-induced hypokinesia is mediated by ACTH neuropeptides. Structure-activity relationship studies revealed that the active core for the ACTH-(4-10)-induced hypokinesia is located in the C-terminal tetrapeptide Phe-Arg-Try-Gly (ACTH-(7-10)). Pretreatment with the opioid antagonist naltrexone did not influence the effect of ACTH-(4-10) indicating that activation of opioid systems is not implicated in this behavioral effect of the peptide.

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.

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.

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.

Rats housed individually for 7 days showed a marked decrease in motor activity when tested under intense light conditions in a novel environment as compared to group-housed rats tested under low light conditions. The ACTH analogue ORG 2766 administered into the amygdala decreased the motor activity of group-housed rats tested under low light conditions and increased the motor activity of 7-days isolated rats tested under intense light conditions (ED50: 1-10 pg). Injection of the peptide into the nucleus accumbens was not effective, suggesting that ORG 2766 affects the integration of sensoric stimuli rather than the specific motor output systems. Pretreatment of the rats with the opiate antagonist naltrexone in the amygdala completely blocked the effect of ORG 2766. A similar blockade of the ORG 2766-induced effect could be induced by pretreatment with endorphin antibody suggesting that the "normalizing" activity of ORG 2766 on environmentally induced behavioral changes is mediated by the release of endogenous opioid peptides.