carbetocin and atosiban

Topics: Antidiuretic Hormone Receptor Antagonists; Drug Design; Female; Humans; Oligopeptides; Oxytocin; Pregnancy; Receptors, Oxytocin; Vasotocin

Oxytocin (OT) and arginine vasopressin (AVP), in their capacities as neuromodulators, are believed to play an important role in mood control, including regulation of the anxiety response. In the present study, the contributions of oxytocin and vasopressin receptor modulation to anxiety-like behaviors were examined in male Sprague-Dawley rats. The behavioral effects of the OT receptor agonist, carbetocin (intracerebroventricular, intravenous and intraperitoneal routes), the AVP receptor agonist desmopressin (intravenous route), and the OT/AVP(1A) receptor antagonist atosiban (intravenous route) were evaluated in the elevated plus maze. The benzodiazepine diazepam was included as a positive control. Central but not systemic administration of carbetocin produced pronounced anxiolytic-like behavioral changes comparable to those measured following systemic diazepam treatment. The anxiolytic efficacy of carbetocin was maintained following 10 days of once-daily treatment, contrasting with the effects of diazepam which were no longer distinguishable from saline treatment. Systemic administration of desmopressin produced anxiogenic-like effects whereas systemic atosiban produced anxiolytic-like effects. Co-administration of desmopressin with atosiban resulted in saline-like behavioral responses, implicating an AVP(1A) receptor mechanism in the anxiolytic and anxiogenic effects of these neuropeptides following systemic administration. A peripherally-mediated antidiuretic effect of desmopressin on water consumption was also demonstrated. These results highlight the potential therapeutic utility of AVP(1A) receptor blockade in the modulation of anxiety-related behaviors; AVP(1A) receptor blockade appears to be a more promising pharmacological target than does OT receptor activation following systemic drug administration.

Topics: Animals; Anti-Anxiety Agents; Deamino Arginine Vasopressin; Diazepam; Ligands; Male; Maze Learning; Oxytocin; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Receptors, Vasopressin; Vasotocin

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') use results in distinctive mood changes of a prosocial nature, most likely through its enhancement of serotonin (5HT) neurotransmission. Activation of 5HT-1A postsynaptic receptors has been shown to stimulate the release of oxytocin in the central nervous system where it regulates aspects of mood and behavior. Using a drug discrimination paradigm, we examined whether modulation of oxytocin receptor activity would affect conditioned behavioral responses to MDMA. Male and female Sprague Dawley rats (n=24) were trained to reliably differentiate between MDMA and a related stimulant, amphetamine (AMP), and saline using a three-lever drug discrimination paradigm. The extent to which substitution with carbetocin (an oxytocin analog) or co-administration with atosiban (an oxytocin receptor antagonist) affected drug-appropriate responding was evaluated. The tricyclic antidepressant imipramine was included as a negative control. The results supported the hypotheses that substitution with an oxytocin analog (carbetocin) would partially generalize to the MDMA training cue, whereas blocking oxytocin receptors with atosiban would result in a selective disruption of MDMA--but not AMP-appropriate responding. These findings were specific to the oxytocin receptor ligands as imipramine pre-treatment did not affect drug-appropriate responding. The results of this study implicate oxytocin receptor activation as a key MDMA-specific interoceptive cue in male and female rats and support the conclusion that this is one of the features of MDMA's subjective effects that distinguishes it from AMP.

Topics: Adrenergic Uptake Inhibitors; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amphetamine; Amphetamine-Related Disorders; Animals; Antidepressive Agents, Tricyclic; Brain; Conditioning, Psychological; Cues; Discrimination Learning; Excitatory Amino Acid Antagonists; Female; Hormone Antagonists; Imipramine; Male; Motivation; N-Methyl-3,4-methylenedioxyamphetamine; Oxytocin; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Synaptic Transmission; Vasotocin

Oxytocin (OXY) in addition to peripheral actions has many central regulatory functions which can be studied on animal models. In the present study we examined in rats, which behavioral actions of OXY and long-acting carba-analog of OXY carbetocin (CBT) in the open-field can be inhibited by OXY-receptor antagonists. Our interest focused on the behavioral patterns considered indicative of anxiety-related behavior. To determine what is the participation of OXY receptor on OXY and CBT induced behavioral changes, we used two peptide and one nonpeptide OXY antagonists differing in selectivity for OXY receptor.. OXY, CBT as well as OXY antagonists were injected intraperitoneally, and spontaneous behavior (horizontal and vertical activity, grooming) of Wistar rats was observed in the circular open-field arena 60 min after application of drugs; in some experiments testing was performed without treatment few days after drug administration.. OXY at the dose 0.05 mg/kg increased locomotion indicating anxiety attenuation, but 1.0 mg/kg reduced both locomotion and rearing. CBT in the dose range 0.1-3.0 mg/kg either did not change or increased horizontal activity. The increase in exploration after both peptides persisted for several days. A marked difference in the behavioral effects of the two peptides was grooming enhancement induced by OXY compared with the absence of this effect after CBT. The increase of the activity induced by OXY and CBT indicating anxiolytic-like action was blocked by OXY antagonists. However, the reduction of exploration induced by 1.0 mg dose of OXY was only partially reversed. The OXY induced enhanced grooming was completely antagonized by all used antagonists.. Behavioral effects of OXY and its antagonists after their i.p. application indicate that they penetrate blood brain barrier. The diversity in potency of OXY antagonists to inhibit grooming and other behaviors induced by OXY suggests that receptors participating in these behaviors may differ in brain localization, receptor conformation and/or in the utilized signaling pathways.

Topics: Analysis of Variance; Animals; Behavior, Animal; Camphanes; Dose-Response Relationship, Drug; Grooming; Hormone Antagonists; Male; Motor Activity; Oxytocics; Oxytocin; Piperazines; Rats; Rats, Wistar; Receptors, Oxytocin; Restraint, Physical; Stress, Physiological; Stress, Psychological; Vasotocin