Dose-related facilitation and inhibition of passive avoidance behavior by the ACTH 4-9 analog (ORG 2766)

The effects of "low" and "high" doses of the ACTH 4-9 analog (ORG 2766) were studied on passive avoidance behavior of rats compared to ACTH 4-10 and [D-Phe7] ACTH 4-10. All peptides increased avoidance latency in a dose-dependent manner. However, "high" doses of ORG 2766 (500 and 1000 ng/rat) inhibited passive avoidance retention. "High" amounts of ACTH 4-10 and [D-Phe7] ACTH 4-10 still facilitated passive avoidance behavior. "High" doses of ORG 2766 like "low" amounts of this peptide delayed extinction of active avoidance behavior. "High" doses of [D-Phe7] ACTH 4-10 like "low" amounts of this peptide facilitated extinction of active avoidance behavior. The substituted analog apparently carries a dual effect on passive avoidance behavior.     

The enhanced recovery of sensorimotor function in rats is related to the melanotropic moiety of ACTH/MSH neuropeptides

The recovery of sensorimotor function in female rats was studied using a foot-flick response test after crushing the sciatic nerve. Every other day the animals received a subcutaneous injection of small ACTH/MSH-like peptides. Rats treated with ACTH-(4-10), ACTH-(4-9), ACTH-(4-9) analog ORG 2766, ACTH-(6-10) and alpha-MSH showed a faster recovery of sensorimotor function as compared to vehicle-treated rats. Treatment with ACTH-(4-7) and the tripeptide Phe7-D-Lys8-Phe9 (PDLP, the C-terminal part of the ORG 2766) remained ineffective. The effect of alpha-MSH was even stronger than that of the other peptides. The facilitation of the return of sensorimotor function by the ACTH-like peptides is discussed in relation to the corticotropic and melanotropic properties of these peptides. Furthermore, it was shown that treatment with ORG 2766 was effective not only in young adult animals (2--3 months) but also in one-year-old animals.     

Potency and duration of action of the ACTH 4-9 analog (ORG 2766) as compared to ACTH 4-10 and [D-Phe7] ACTH 4-10 on active and passive avoidance behavior of rats

Experiments were performed to examine the potency and duration of action of various ACTH analogs on active and passive avoidance behavior of rats. ACTH 4-10 and the ACTH 4-9 analog (ORG 2766) delayed extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. [D-Phe7] ACTH 4-10 facilitated extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. [D-Phe7] ACTH 4-10 facilitated extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. ORG 2766 was a thousand times more active than ACTH 4-10. The effect of ORG 2766 on extinction of pole-jumping avoidance behavior and on passive avoidance behavior was of longer duration than that of ACTH 4-10. As determined more precisely in the passive avoidance test it appeared that the action of ACTH 4-10 lasted 3 to 6 hours, while that of ORG 2766 amounted to at least 24 hours. Although [D-Phe7] ACTH 4-10 was a thousand times less active than ORG 2766 in the passive avoidance paradigm, its duration of action was of the same magnitude. In view of this, the marked increase in potency of the ACTH 4-9 analog cannot be explained only on the basis of its metabolic stability but also by an increased intrinsic activity.     

Postnatal treatment with ACTH-(4-9) analog ORG 2766 attenuates N-methyl-D-aspartate-induced excitotoxicity in rat nucleus basalis in adulthood

It has been reported that the ACTH-(4-9) analog H-Met(O(2))-Glu-His-Phe-D-Lys-Phe-OH (ORG 2766) administered in adulthood has trophic effects on neuronal tissue and when given postnatally, it can induce long-lasting changes in brain development. In the present study, we investigated whether early postnatal treatment with ORG 2766 affects adult neuronal vulnerability, i.e. the sensitivity of cholinergic neurons against excitotoxic damage. Wistar rat pups received injections of ORG 2766 or saline on postnatal days 1, 3 and 5 and were then left undisturbed until adulthood. At the age of 6 months, the animals were subjected to unilateral lesion of magnocellular basal nucleus by infusion of high dose of N-methyl-D-aspartate (NMDA). The effects of the excitotoxic insult were studied 28 hours and 12 days after the lesion by measuring both the acute cholinergic and glial responses, and the final outcome of the degeneration process. Twenty eight hours after NMDA infusion, postnatally ACTH-(4-9)-treated animals showed stronger suppression of choline-acetyltransferase immunoreactivity and increased reaction of glial fibrillary acidic protein -immunopositive astrocytes in the lesioned nucleus compared to control animals. However, 12 days post-surgery, the NMDA-induced loss of cholinergic neurons, as well as the decrease of their acetylcholinesterase -positive fibre projections in the cortex, were less in ACTH-(4-9) animals. Our data indicate that the early developmental effects of ACTH-(4-9) influence intrinsic neuroprotective mechanisms and reactivity of neuronal and glial cells, thereby resulting in a facilitated rescuing mechanism following excitotoxic injury.     

ACTH4-9 analog (ORG 2766) facilitates acquisition of an inhibitory avoidance response in rats.

These experiments examined the effects of an ACTH4-9 analog (ORG 2766) on an inhibitory avoidance response in rats. Graded doses of ORG 2766 were administered either 1 hr prior to training, immediately after training, or 1 hr prior to the retention test. The animals were tested 24 hr after training. A 5.0 mg/kg dose was administered prior to training significantly facilitated acquisition of the response. ORG 2766 did not significantly affect retention when administered after training or prior to the retention test. Since ORG 2766 only affected acquisition of the response, it is suggested that the drug acts by influencing sensory, motivationl or attentional variables rather than directly affecting memory consolidation or retrieval processes.     

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.     

Possible consequence of ACTH-like peptides for human mental performance (author's transl)]

ACTH affects behavior of rats. The results of the reported experiments suggest that ACTH effects on conditioned behavior are the result of an improved motivation or attention. The ACTH fragments, ACTH 4--10 and ACTH 4--9, have the behavioral effects of ACTH but are devoid of endocrine activities. The ACTH 4--9 analog H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH (Org 2766) has behavioral activity after oral administration. ACTH-like-peptides restore the behavioral deficiencies of hypophysectomised rats and delay extinction of conditioned behavior of normal rats independent of the type of conditioning. So is extinction of pole jump avoidance and extinction of conditioned tast aversion delayed after Org 2766. Moreover ACTH-like peptides reduce the behavioral deficit in rats with amnesia even when the treatment is given two weeks after the induction of amnesia. In man the administration of a single dose of ACTH 4--10 on Org 2766 reduces the duration of lapses as well as the number of errors of volunteers in a continuous performance task. These and similar observations suggest that ACTH-like peptides may be of practical consequence for the therapy of patients with impairments of cognitive processes.     

N alpha-acetyl-[Arg8]vasopressin antagonizes the behavioral effect of [Cyt6]vasopressin-(5-9), but not of vasopressin

It has been found recently that N alpha-acetyl-[Arg8]vasopressin (Ac-VP) is present in the brain of rats. The physiological significance of this peptide is as yet unknown. Therefore, the central nervous system effects of this peptide were investigated, namely, its effects on passive avoidance behavior, exploratory behavior and body temperature. The interaction of Ac-VP with the central nervous system effects of vasopressin (VP) was also studied. Ac-VP had a slight agonistic effect on passive avoidance behavior, i.e. it facilitated passive avoidance behavior at a dose 100 times higher than that of VP. Relatively low doses (3-10 ng) of Ac-VP attenuated passive avoidance behavior, which suggests that Ac-VP interfered with an endogenous compound involved in the control of passive avoidance responding. Ac-VP was also able, albeit in higher doses (30 ng), to competitively antagonize the effect of [Cyt6]VP-(5-9), a highly potent, putative endogenous metabolite of vasopressin in the rat brain. This antagonism could be due to an interaction of Ac-VP with sites other than the V1 vasopressin receptor. Ac-VP had no significant influence on other central nervous system effects of the hormonally active nonapeptide VP, such as exploratory behavior and body temperature. These effects were readily antagonized by the V1 vasopressin receptor antagonist d(CH2)5Tyr(Me)VP. Ac-VP may be competitive antagonist of behaviorally active vasopressin metabolite(s) in the brain.     

A dose-response analysis of the beneficial effects of the ACTH-(4-9) analogue, Org 2766, on behavioural recovery following unilateral labyrinthectomy in guinea-pig.

1. After removal of the peripheral vestibular receptors in one inner ear (unilateral labyrinthectomy, UL), oculo-motor and postural symptoms occur but disappear over time in a process of recovery known as vestibular compensation. 2. ACTH-(4-10), a fragment of the adrenocorticotrophic hormone (ACTH) molecule, which is devoid of corticotrophic activity, has been shown to enhance vestibular compensation. The present study investigated the effect of the ACTH-(4-9) analogue, Org 2766, on vestibular compensation in guinea-pig. Org 2766 is reported to be more potent behaviourally than ACTH-(4-10). 3. After UL, Org 2766 was delivered via an osmotic minipump implanted s.c. to 30 animals randomly assigned to one of five conditions: 1, 5, 10, 20 or 40 nmol kg-1 Org 2766, every 4 h for 52 h post-UL. Although infusion was continuous, in the present study the doses are expressed as nmol per 4 h in order to compare the results to a previous study in which animals received a discrete dose of ACTH-(4-10) at the end of each 4 h period. All animals were compared to saline controls (n = 6). 4. Three symptoms of UL, spontaneous ocular nystagmus, roll head tilt and yaw head tilt, were measured every 4 h for 52 h, beginning at 10 h post-UL. 5. Rates of infusion of 1, 5 and 10 nmol kg-1 accelerated spontaneous nystagmus compensation; 20 nmol kg-1 produced a significant decrease in the frequency of spontaneous nystagmus, as well as accelerating its compensation; 40 nmol kg-1 had no significant effect on spontaneous nystagmus compensation.(ABSTRACT TRUNCATED AT 250 WORDS)     

David and Goliath - the slingshot that started the neuropeptide revolution

This review in honor of David de Wied summarizes the work done in my laboratory that first indicated that adrenocorticotropic hormone (ACTH) has a direct effect on the neuromuscular system. Cold stress or ACTH and its related peptides alpha-melanocyte-stimulating hormone (alpha-MSH ) and beta-lipotropin improve the electromechanical characteristics of adrenalectomized and hypophysectomized rats. ACTH-(1-39) accelerates the return of motor and sensory function and improves the morphological characteristics of the motor endplate after peripheral nerve crush. The non-corticotropic fragments ACTH-(4-10), alpha-MSH, the ACTH-(4-9) analogue Organon 2766 (Org 2766) or the ACTH-(4-10) analogue Biomeasure 22015 (BIM 22015) improve electrophysiological and morphological parameters of the regenerating neuromuscular system. ACTH-(4-10) immunoreactivity, present in ventral horn motor neurons in low levels, is decreased ipsilaterally following ipsilateral nerve crush but increases both ipsilaterally and contralaterally if injured animals are treated with ACTH-(4-10) indicating a neuroprotective action. Similarly, Org 2766 appears to have a protective action in the brain following nigrostriatal lesions. In developmental studies, perinatal exposure to ACTH peptides improves the structure of the neuromuscular junction, accelerates the maturation of electromechanical properties and enhances nerve-muscle integration and nerve regeneration. Perinatal exposure to these peptides decreases adult male sexual behavior, a change correlated with increased serotinergic input within the medial preoptic area. Similar changes occur in female rats and appear to be long-lasting. In tissue culture studies, both Org 2766 and BIM 22015 promote neurite outgrowth in the absence of nerve growth factor, indicating a neurotrophic role for these peptides.     

Comparative effects of the ACTH 4-9 analogue (ORG 2766), ACTH 4-10 and [D-Phe7] ACTH 4-10 on medial septal self-stimulation behaviour in rats

Experiments were performed to examine the effects of various analogues of ACTH on electrical self-stimulation behaviour elicited from the medial septal area using an ascending or descending sequence of stimulus intensities within a session. When an ascending sequence of threshold multiples was used ACTH 4-10 and the ACTH 4-9 analogue (ORG 2766) enhanced level pressing for low intensity stimulation but attenuated self-stimulation at greater current intensities. The analogue ORG 2766 appeared to be a thousand times more potent than ACTH 4-10; [D-Phe7] ACTH 4-10 inhibited the response rate at threshold level but was inactive at greater current intensities. The same effect was found following administration of ORG 2766 in a dose which was 20 times greater (1 microgram/rat) than that used in the first experiments. Lever pressing was not affected by treatment with ACTH 4-10 or ORG 2766 when a descending sequence of stimulus intensities was used within a session. Thus, ACTH-related peptides may affect motivational processes involved in self-stimulation rather than the reward of the stimulation per se. It is suggested that although ORG 2766 mimicked the action of ACTH 4-10 this synthetic peptide may have additional behavioural properties.     

Neuroleptic activity of the neuropeptide beta-LPH62-77 ([Des-Tyr1]gamma-endorphin; DT gamma E).

In contrast to β-endorphin, α-endorphin, β-LPH_61–69 and Met-enkephalin which delay extinction of pole-jumping avoidance behavior (De Wied et al., 1978), γ-endorphin given either subcutaneously (30 ng/rat) or intraventricularly (0.3 ng/rat) facilitated extinction. Removal of the N-terminal amino acid residue tyrosine — yielding the neuropeptide [Des-Tyr¹]γ-endorphin (DTγE) — which destroys the opiate-like activity as determined on the electrically driven guinea pig ileum, potentiated the facilitating effect of γ-endorphin on pole-jumping avoidance behavior. Observations on passive avoidance behavior gave essentially the same results. Whereas α-endorphin facilitated this behavior. DTγE attenuated passive avoidance behavior. Amounts of γ-endorphin and DTγE which were highly active on extinction of pole-jumping avoidance behavior (0.3 μg s.c. per rat) were without effect on gross behavior in an open field. Much higher amounts (10–50 μg s.c. per rat) also failed to affect the rate of ambulation in an open field. In relatively high doses (20 μg i.v.t. or 50 μg s.c. per rat), γ-endorphin and in particular DTγE were positive in the various “grip tests”. Haloperidol given s.c. (0.03–0.1 μg/rat) facilitated extinction of pole-jumping avoidance behavior and attenuated passive avoidance behavior. The same amounts decreased ambulation in an open field. In higher doses haloperidol was active in the “grip tests” but in addition caused severe immobility, ptosis and extension of the lower limbs. Intraventricularly administered morphine or β-endorphin induced wide open eyes, exophthalmus, rigidity and reduced reflexes, in contrast to γ-endorphin and DTγE which did not produce such effects. These results are interpreted to indicate that DTγE or a closely related peptide is an endogenous neuroleptic. It may be that a reduced availability as a result of an inborn error in the generation of DTγE is an etiological factor in psychopathological states for which neuroleptic drugs are beneficial.     

alpha-MSH and Org.2766 in peripheral nerve regeneration: different routes of delivery

The efficacy of melanocortins (alpha-MSH and an ACTH-(4-9) analog, Org.2766) in accelerating functional recovery from sciatic nerve damage following various types of subcutaneous and oral administration was assessed in the rat. Furthermore, the effectiveness of the local delivery of melanocortins to the site of injury was examined. An accelerated recovery was evident following subcutaneous constant delivery of Org.2766 from an osmotic mini-pump and from biodegradable polymere microspheres, and was as effective as repeated subcutaneous injections of alpha-MSH or Org.2766. Oral administration of Org.2766 was ineffective. Local application of Org.2766, achieved by wrapping a peptide-impregnated biodegradable gelatine foam matrix around the site of injury, facilitated recovery as well. The biodegradable microspheres and gelatine foam matrix may be of importance in eventual clinical use as effective vehicles for administration of melanocortins in the treatment of peripheral nerve damage.     

Effect of high doses of naloxone on shuttle avoidance acquisition in rats

Administration of high doses of naloxone intraperitoneally (2.5-10.0 mg/kg) resulted in a dose-related impairment of avoidance response acquisition in a shuttle avoidance paradigm in rats. Naloxone in this dose range produced a significant decrease in the number of intertrial responses but did not result in a significant dose-response. Escape latencies were not affected by naloxone administration at any dose tested. The effect of naloxone on activity and nociception are implicated as possible causes of the observed behavior. The results are discussed as behavioral evidence supporting theories postulating multiple opiate receptors.     

3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and phencyclidine produce a deficit of passive avoidance retention in rats

3-((+-)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), phencyclidine (PCP) and diazepam were evaluated for their ability to produce a deficit for a single trial step-through passive avoidance response in rats. Pretraining administration with CPP at doses ranging from 2.0 to 10.0 mg/kg s.c. significantly decreased retention latencies 24 h after passive avoidance training. Similar effects were found with PCP at doses ranging from 0.5 to 1.7 mg/kg s.c. and diazepam at doses between 5.0-18.0 mg/kg s.c. Pretraining administration with the benzodiazepine antagonist, RO15-1788 at doses between 0.1-15 mg/kg s.c., did not alter retention latencies. Co-administration of RO15-1788 (0.01-15.0 mg/kg s.c.) with CPP (6.0 mg/kg s.c.) or PCP (1.0 mg/kg s.c.) failed to block decreases in latencies. However, when RO15-1788 was co-administered with diazepam (9.0 mg/kg s.c.) a dose-related antagonism of diazepam's effects were found. These results suggest that the behavioral actions of CPP and PCP on passive avoidance retention are not mediated via the benzodiazepine receptor complex.     

Cellular distribution of cis-diamminedichloroplatinum(II)-DNA binding in rat dorsal root spinal ganglia: effect of the neuroprotecting peptide ORG.2766

The in situ binding of the anticancer drug cis-diamminedichloroplatinum(II) (cisDDP) to DNA was studied in the rat dorsal root spinal ganglion (DRG), using an antiserum against cisDDP-modified calf thymus DNA in a quantitative immunocytochemical assay. Rats received a dose of cisDDP (1 mg/kg), two times a week, up to a cumulative dose of 15 mg/kg (group I) or 34 mg/kg (group II). Rats of group III were given a single dose of 15 mg/kg. Rats were killed 48 hr (groups I and II) or 6 hr (group III) after the last injection. In groups I and II cisDDP-induced neurological damage was assessed by measuring both motor and sensory nerve conduction velocities (MNCV and SNCV). Whereas the MNCV was not influenced by the treatment with cisDDP, the SNCV decreased significantly. The level of cis-DDP-DNA binding in DRG satellite cells equalled that in liver cells, but binding could not be shown in DRG neuron nuclei. The level of cisDDP-DNA binding in spinal cord and brain was very low. The neuroprotecting peptide ORG.2766, an ACTH4-9 analog, was given sc (10 micrograms/rat) four times a week concomitantly with cisDDP to some rats of groups I and II. ORG.2766 prevented the decrease of the SNCV, but did not change the extent of cisDDP-DNA binding in satellite or liver cells. It is concluded that the amelioration of cisDDP toxicity by ORG.2766 is not directly related to the cisDDP-DNA binding in satellite cells.     

Neuronal peptide (enkephalin) receptors in the ear artery of the rabbit.

Methionine-enkephalin methylester (MEM) and leucine-enkephalin (LE) inhabit the vasoconstrictor responses of the rabbit ear artery to nerve stimulation by acting on a specific neuronal peptide (enkephalin)-receptor insensitive to opiate agonists. The tetrapeptide: H-Tyr-Gly-Phe-Leu-OCH3 is ineffective. This is the first instance of enkephalins acting in an organ devoid of receptors. In a new test for the analysis of opiate receptors, MEM (ID50=6.9 X 10(-9) M) was a potent inhibitor of transmission. The presence was shown of opiate receptors in the brain which were insensitive to high i.v. or intraventricular doses of enkephalins. It is concluded that enkephalins are not natural ligands to the opiate receptors, but that some of the receptors confuse these structures because of similar characteristics which determine the binding of both opiates and peptides.     

Putative neurotrophic factors in the protection of cisplatin-induced peripheral neuropathy in rats.

One of the major side effects of cisplatin is its neurotoxicity. In rats, this neurotoxicity can be measured as a slowing of the H-reflex-related sensory nerve conduction velocity. In this study the ability of the neurotrophic peptide ORG 2766 (an ACTH4-9 analog) to prevent this neurotoxic side effect was investigated in rats subjected to a high-dose cisplatin regime (2 mg/kg, 2/wk). Furthermore, the efficacy of nimodipine (a calcium entry blocker of the 1,4-dihydropyridine type with presumed neurotrophic or neuroprotective activity) to prevent the neuropathy induced by both a low (1 mg/kg, 2/wk) and a high (2 mg/kg, 2/wk) dose cisplatin regime was studied. In cisplatin-treated rats concurrently treated with vehicle (saline for ORG 2766, polyethylene glycol for nimodipine) a significant slowing of the H-related sensory nerve conduction velocity was observed whereas in rats treated with both cisplatin and ORG 2766 or nimodipine, no decrease of this conduction velocity occurred. The possibility that nimodipine hampers the antitumor activity of cisplatin was investigated in an immunocytoma model in the LOU/M rat. Similar tumor regression was observed in cisplatin-treated rats concurrently treated with nimodipine or vehicle. These data suggest that both ORG 2766 and nimodipine protect from the induction of a cisplatin-induced neuropathy, at least in this animal model, and thus warrant investigation of their neuroprotective efficacy in humans subjected to a cisplatin-based chemotherapy.     

Time-related memory effects of vasopressin analogues in rats

The present study was designed to investigate critical time periods for the memory modulating effect of vasopressin and several analogues in rats using a passive avoidance test as the behavioral paradigm. AVP, AVP-(4-8) and AVP-(5-8) were more effective when given immediately after the learning trial (consolidation), while AVP-(1-8) (DGAVP) and AVP-(5-9) were more active when administered one hour prior to the retention test (retrieval). DDAVP and AVP-(4-9) were highly active both when given immediately after the learning trial or 1 hour before the retention test. The period between 12 and 18 hr after the learning trial appeared to be another sensitive period. Administration, in particular of DGAVP, and AVP-(5-9) at 12, 15, and 18 hr after the learning trial induced marked retention of the avoidance response at the 24 hr retention test. Injection at 6 and 21 hr after the learning trial was the least effective in facilitating passive avoidance latencies. The more stable analogue DDAVP facilitated avoidance latencies irrespective of the time of administration. Vasopressin and related peptides exert a long term effect on avoidance behavior. However, DGAVP and AVP-(5-9) facilitated passive avoidance behavior at the 24, 48, and 72 hr retention test if administered immediately after the learning trial. If injection was postponed till 15 hr after the learning trial, passive avoidance behavior was facilitated at the 24 hr retention test only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral activity of a short chain ACTH analog

The behavioral activity of ACTH1-17 analog (beta-Ala1, Lys17) ACTH1-17-4 -amino-n-butilamide (Ala1-Lys17-ACTH1-17) has been studied in the rat. Acquisition of shuttle-box active avoidance behavior was facilitated by Ala1-Lys17-ACTH1-17 administered both subcutaneously (SC) and intracerebroventricularly (ICV), and this effect was suppressed by peripheral administration of haloperidol or naltrexone. Extinction of pole jumping active avoidance behavior was delayed by SC administration of the peptide in a dose-dependent manner. Retention of a step-through passive avoidance behavior was facilitated SC or ICV injection of Ala1-Lys17-ACTH1-17. Adrenalectomy failed to modify the effects of the peptide on the retention of passive avoidance behavior. Furthermore, ICV injection of graded doses of Ala1-Lys17-ACTH1-17 induced excessive grooming, and this effect was totally prevented by intraperitoneal (IP) injection of haloperidol or naltrexone SC administration of Ala1-Lys17-ACTH1-17 induced a slight but significant increase in negative responses in a test for behavioral responsiveness to electrical footshock. This effect was totally prevented by IP injection of naltrexone. It is concluded that Ala-Lys17-ACTH1-17 shares some of the behavioral effects of ACTH4-10 and some ACTH1-24, but it seems to be more potent than the latter peptides. Both dopamine and opioid transmission seem to be involved in the behavioral activity of Ala1-Lys17-ACTH1-17.