Aversive properties of bombesin in rats.

Aversive properties of bombesin were determined in the conditioned place-preference paradigm in rats and compared with the effects on spontaneous behavior. Bombesin induced excessive grooming and/or scratching behavior at doses of 80 ng, 400 ng, and 2.0 micrograms ICV. In the conditioned place-preference paradigm, doses of 400 ng and 2.0 micrograms ICV induced a profound aversion to the environment in which the animals had received peptide treatment. Eighty ng were partially effective, and 16 ng did not induce a significant change in preference. The grooming/scratching behavior was attenuated by pretreatment with 4 mg/kg morphine-sulfate. These results show that bombesin is strongly aversive at doses that induce grooming/scratching behavior. Although the relationship between these different effects is not known, the similarity in their dose-response relationship suggests that they may be mediated by a common mechanism.

Specific antagonists of the acute behavioral response to centrally-administered vasopressin in mice.

Vasopressin and related peptides cause behavioral excitation after intracerebroventricular injection in mice. This behavioral excitation is characterized by excessive scratching and grooming behavior in the unrestrained animal and enhanced escape-directed activity in stressful situations. These effects of vasopressin were found to be blocked by the administration of analogs which act as competitive antagonists of the pressor-activity of vasopressin. The potencies of these analogs in suppressing the behavioral effect paralleled the pressor antagonist potencies. The antagonists did not cause the characteristic behavioral alterations by themselves, nor did they block grooming and/or scratching behavior induced by the structurally-unrelated substances, mescaline, bombesin and substance P. It is suggested that these antagonists provide useful tools for studying the role of endogenous vasopressin in behavior.

Behavioral alterations induced by substance P, bombesin, and related peptides in mice.

Bombesin, substance P and several structurally related peptides cause excessive grooming behavior after intracerebroventricular injection in mice. The present study describes the behavioral characteristics of these effects after acute administration. Substance P caused an elevation of grooming behavior which was short-lasting (less than 15 minutes), while bombesin induced both grooming and scratching behavior with a duration of action of about 2.5 hours. After repeated injections of high doses of either bombesin or a metabolically stable substance P analog, no tolerance-formation to these peptide-induced effects could be observed. Morphine partially antagonized bombesin-induced behaviors at a dose of 7.5 mg/kg subcutaneously while the same dose did not attentuate substance P-induced grooming. These results suggest that the behavioral changes induced by substance P and bombesin are mediated by distinct mechanisms. The lack of tolerance formation, together with the partial antagonism by morphine, suggests that the bombesin-induced behaviors may be related to a stimulation of nociceptive mechanisms.

Motor hypoactivity induced by neurotensin and related peptides in mice.

The tridecapeptide neurotensin (NT) induces a variety of behavioral changes in animals. The present study characterizes the behavioral hypoactivity observed after intracerebroventricular (ICV) injection in mice. At doses higher than 25 ng, NT induced a reduction of general motor activity and increases in immobility which lasted for about one hour. The NT-related amphibian skin peptide xenopsin was about 70-fold more potent than NT itself. After repeated NT-injections, tolerance developed within 2-4 days and disappeared within 2-4 days after cessation of the treatment. The motor hypoactivity induced by NT was not attenuated by pretreatment with naloxone (5 mg/kg, SC). Furthermore, amphetamine-induced locomotor activity was not blocked by NT or xenopsin. These results suggest that the NT-effect is not mediated by a stimulation of opioid mechanisms or attenuation of dopamine-mediated events.

Hypothermia induced by centrally administered vasopressin in rats. A structure-activity study.

Vasopressin and related peptides cause short-lasting hypothermia when injected into the lateral ventricle of the rat. In the present study, the structure-activity relationships for the induction of this effect were examined. For the agonist peptides studies, the structural requirements were found to be similar to those required to cause peripheral vasoconstriction ant to induce behavioral excitation in mice. However, an antagonist of the pressor and behavioral effects of vasopressin was ineffective in antagonizing the hypothermic response. Moreover, this analog and another pressor antagonist themselves caused hypothermia. Comparison with the structure-activity relationships for other effects on the central nervous system strongly suggests that the hypothermic response is unrelated to the effects of vasopressin on consolidation of memory, development of tolerance to drugs, and mechanisms of reinforcement.

Amastatin potentiates the behavioral effects of vasopressin and oxytocin in mice.

Vasopressin and oxytocin cause behavioral excitation after intracerebroventricular injection in mice. This effect is short-lasting, suggesting that the peptides are rapidly inactivated in the brain. Co-injection of microgram amounts of amastatin, an aminopeptidase inhibitor, prolonged the effect of both vasopressin and oxytocin. Amastatin did not induce large vasopressin-like behavioral effects by itself, nor did it significantly potentiate the action of 1-deamino[1,6-dicarba, 8-arginine] vasopressin (Asu-AVP), an analog that lacks the N-terminal amino group. The effect of Asu-AVP, but not that of vasopressin, was potentiated by phosphoramidon, an inhibitor of neutral metalloendopeptidase ("enkephalinase A"). These results support previous suggestions that vasopressin and oxytocin are inactivated mainly by aminopeptidase action following intracerebroventricular injection.

Factors involved in the inactivation of vasopressin after intracerebroventricular injection in mice.

Behavioral excitation induced by intracerebroventricularly administered vasopressin in mice is very short-lasting, suggesting a half-life of the injected peptide of only a few minutes. The results of the present study suggest that vasopressin and related peptides are too hydrophilic to penetrate lipid membranes readily by passive diffusion and that passive diffusion from the extracellular space into cells or the bloodstream is an unlikely mechanism of inactivation. Pharmacological desensitization (tachyphylaxis) occurs after higher doses, but does not seem to be the major factor responsible for the short duration of action. Some deaminoanalogs of vasopressin, however, show a prolonged action, suggesting that degradation by (an) aminopeptidase(s) is a major route of inactivation. These results also suggest that vasopressin-degrading aminopeptidases are accessible from the extracellular space.

Effects of catecholamine-related mammalian alkaloids on spontaneous and vasopressin-induced behavior in mice.

Heterocyclic catechol derivatives (tetrahydroisoquinoline alkaloids) are known to be formed endogenously via condensation of the catecholamines with carbonyl compounds. In this study, the effects of a variety of representative simple isoquinolines, benzyl isoquinolines, bicyclic isoquinoline-derived alkaloids (pavines and isopavines), an aporphine and berberine were investigated after intracerebroventricular injection in mice. Most (thirteen) of the alkaloids studied were found to induce significant alterations in three behavioral parameters (immobility, grooming and scratching behavior). In addition, the stereotypic scratching behavior elicited by central injection of arginine-vasopressin (AVP) was significantly antagonized by only one of these, 6-O-methyl-tetrahydropapaveroline (6-O-methyl-THP). To a lesser extent, (-)THP and the pavine, (+/-)bisnorargemonine, were also effective. That this rather specific effect did not involve opioid receptors was indicated by the failure of naloxone to reverse the antagonism by 6-O-methyl-THP.

Minireview. Peptides and the blood-brain barrier.

Most neuropeptides are known to occur both in the central nervous system and in blood. This, as well as the occurrence of central nervous peptide effects after peripheral administration, show the importance of studying the relationships between the peptides in the two compartments. For many peptides, such as the enkephalins, TRH, somatostatin and MIF-1, poor penetration of the blood-brain barrier was shown. In other cases, including beta-endorphin and angiotensin, peptides are rapidly degraded during or just after their entry into brain or cerebrospinal fluid. Some peptides, such as insulin, delta-sleep-inducing peptide, and the lipotropin-derived peptides, enter the cerebrospinal fluid to a slight or moderate extent in the intact form. Many peptide hormones, such as insulin, calcitonin and angiotensin, act directly on receptors in the circumventricular organs, where the blood-brain barrier is absent. Oxytocin, vasopressin, MSH, and an MSH-analog alter the properties of the blood-brain barrier, which may result in altered nutritient supply to the brain. In conclusion, the diffusion of most peptides across the brain vascular endothelium seems to be severely restricted. There are, however, several alternative routes for peripheral peptides to act on the central nervous system. The blood-brain barrier is a major obstacle for the development of pharmaceutically useful peptides, as in the case of synthetic enkephalin-analogs.

Centrally mediated effects of neurohypophyseal hormones.

The neurohypophyseal hormones oxytocin and vasopressin cause a variety of biological effects in animals which are mediated by central nervous system mechanisms. Among the best studied of these effects is the modulation of both memory processes and the development of drug tolerance and dependence. Neurohypophyseal hormones have also been shown to alter various physiological parameters such as heart rate and body temperature following central administration. In addition, these peptides can profoundly alter spontaneous, unlearned behavior in several rodent species. Many of the centrally mediated effects of neurohypophyseal hormones have been shown to be elicited at sites within the brain stem and the limbic system where vasopressin and oxytocin occur in cell bodies, axons and nerve terminals, suggesting a physiological role for these peptide effects. The various central effects of neurohypophyseal hormones involve different mechanisms which can be distinguished from one another on the basis of required dose, time-course of action, and structure-activity relationships. Thus, alterations of spontaneous behavior are mediated by putative receptors closely related to vasopressin receptors in blood vessels responsible for the peripheral pressor response while the effects on memory processes are mediated by a mechanism which is not closely related to those involved in the peripheral hormonal effects of the peptides. The influence of neurohypophyseal hormones on memory and attention may be useful clinically. A potential role for these peptides in mental disorders is discussed.

Behavioral effects of intracerebroventricularly administered neurohypophyseal hormone analogs in mice.

The neurohypophyseal hormones oxytocin and vasopressin evoke characteristic behavioral changes after intracerebroventricular injection in mice. These included the induction of excessive grooming and scratching in an unrestricted environment and of escape behavior in stressful situations. The structure-activity relations of 33 neurohypophyseal hormones and hormone analogs in the induction of these behavioral changes were examined. The results demonstrate that these effects generally parallel the vasoconstrictory effects of th peptides. It is suggested that the behavioral effects are mediated by a receptor that is closely related biochemically to the vasopressin receptors in blood vessels. They are not related to the long-term effects of neurohypophyseal hormones on learned behavior. A competitive antagonist of the short-term behavioral effects of these peptides is described. This analog also antagonizes some of the hormonal effects of vasopressin and related peptides.

Short-term behavioural effects of neurohypophyseal hormones: pharmacological characteristics.

Neurohypophyseal hormones and related peptides cause behavioural alterations after intracerebroventricular injection in mice. In the present study, these effects, consisting of excessive grooming and scratching, and of escape-directed activity in stressful situations, could easily be distinguished from those of other centrally acting peptides and drugs by means of two different behavioural bioassays. The effects were not antagonized by drugs that block cholinergic or adrenergic receptors, but they were powerfully suppressed by some potent psychotropic agents. Some compounds with strong vasoconstrictor or vasodilatory actions did not mimick or antagonize the behavioural alterations, suggesting that vasoconstriction is not essential for the induction of these effects. A considerable degree of tolerance could be induced and cross-tolerance was observed between different neurohypophyseal hormones. In rats, behavioural alterations caused by oxytocin and vasopressin could be demonstrated as well, but they were by far less pronounced than those observed in mice. For comparison, some data on the behavioural effects of bombesin are included. This peptide caused behavioural alterations similar to those of the neurohypophyseal hormones, but these were apparently mediated by different mechanisms. It is suggested that centrally-released oxytocin and/or vasopressin might be physiologically involved in the regulation of animal behaviour.

Short-term behavioral effects of posterior pituitary peptides in mice.

The acute behavioral effects of some neurohypophyseal hormones after intracerebroventricular injection in mice were examined. The effects, consisting mainly of a dose-dependent stimulation of certain behaviors, were demonstrated in three different behavioral tests. The type of the induced behaviors was dependent on the experimental conditions: If the mice were placed into a cage after the injection of the peptides, excessive scratching and grooming behaviors were induced. If they were exposed to stressful environmental influences, however, escape-directed activity was markedly stimulated with only minimal elevation of scratching and grooming behaviors. Very low doses down to less than 1 nanogram per mouse were effective. The effects can be observed after central, but not after peripheral application of the peptides and are mediated by a mechanism that displays some degree of specificity. An activity unit for the behavior-altering potency of the peptides was defined. A role of neurohypophyseal hormones or related peptides in the regulation of motivation and behavioral arousal is suggested.