H. M. Greven

Neuroleptic activity of the neuropeptide β-LPH62–77 ([Des-Tyr1]γ-endorphin; DTγE)

In contrast to β-endorphin, α-endorphin, β-LPH61–69 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.

Dissociation of the behavioural and endocrine effects of lysine vasopressin by tryptic digestion

1 . Lysine vasopressin induces resistance to extinction of active avoidance behaviour (De Wied, 1971). 2 . Digestion of lysine vasopressin with trypsin almost completely destroys the pressor‐, antidiuretic‐, oxytocic‐ and corticotrophin‐releasing factor activities of lysine vasopressin, but does not materially influence its effect on the maintenance of an avoidance response.

The influence of peptides derived from corticotrophin (ACTH) on performance. Structure activity studies.

Publisher Summary This chapter describes the influence of peptides derived from corticotrophin (ACTH) on performance. In the study reported in the chapter, two approaches are followed. First, it sought the small peptide sequence of ACTH that possesses essentially the same behavioral effects as ACTH itself. Second, the chapter tries to increase the behavioral potency of the sequence ACTH 4-9 by introducing certain structural modifications. Attention is focused on the dissociation between behavioral activity and melanocyte stimulating hormone (MSH)-like potency. The influence of peptides derived from ACTH on acquisition and extinction of conditioned avoidance behavior in rats was studied. The tetrapeptide ACTH 4-7 is found to be the short peptide that still bears the essential elements required for the behavioral effects. The improved performance of hypophysectomized rats treated with ACTH or fragments of ACTH is neither due solely to improved motor and/or sensory capacities nor to an increase in the level of general activity.

Behavioral profile of ψ-MSH: Relationship with acta and β-endorphin action

Abstract In view of the close structural similarity of the pro-opiocortin fragment γ-MSH and of ACTH/MSH type peptides, the behavioral profile of γ-MSH was explored. Attention was first focussed on behavioral procedures in which ACTH/MSH related neuropeptides have been found effective. Using different procedures to test avoidance behavior, it was found that γ-MSH and ACTH-like neuropeptides had opposite effects. In this respect the activity of γ-MSH resembles that of opiate antagonists rather than that of β-endorphin. Accordingly, ACTH 1–24 -induced excessive grooming which is blocked by opiate antagonists, is attenuated by γ-MSH. In addition, γ-MSH injected into the periaqueductal gray matter of the brainstem of opiate naive rats elicited symptoms reminiscent of those seen after opiate withdrawal. γ-MSH attenuated more or less several effects of intracerebroventricularly administered β-endorphin (e.g. antinociception, hypothermia, α-MSH release) and decreased acquisition of heroin self-administration. Although γ-MSH at rather high doses displaced naloxone from its specific binding sites in brain homogenates, it did not interfere with β-endorphin-induced effects on in vitro muscle preparations (guinea pig ileum, rat rectum). Interestingly, γ-MSH induced relaxation of the rat rectum in vitro . It is postulated that γ-MSH may attenuate β-endorphin-induced effects by acting via γ-MSH receptor sites (functional antagonism), although a pharmacological antagonism cannot be excluded as yet.