Martin Votava

Relation of sex and estrous phase to deficits in prepulse inhibition of the startle response induced by ecstasy (MDMA)

Sensorimotor gating is the ability of a weak sensory event to inhibit the motor response to an intense stimulus. Drugs that act as serotonin releasers, such as MDMA (3,4-methylenedioxymethamphetamine), impair sensorimotor gating, which is measured as a prepulse inhibition (PPI) of the acoustic startle response. The first objective of the present study was to compare the effect of different doses of MDMA on PPI and the acoustic startle response (ASR) in male and female Wistar rats. The second objective was to examine the effect of MDMA on PPI across the estrous cycle in female rats. MDMA was administered in doses of 2.5, 5 and 10 mg/kg s.c. 15 min before the start of the experiment. The controls received saline in equivalent volumes. MDMA dose-dependently decreased PPI in both the male and female rats and produced higher levels of ASR in the male rats compared to the females. In addition, we found that female rats in the diestrous and metestrous phases are more sensitive to MDMA and showed higher deficits in PPI than female rats in the proestrous and estrous phases. Our result showed that female rats in the proestrous and estrous phases were less sensitive to the disruption of PPI by MDMA.

The opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced by MK-801.

The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT(1A)) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025mg/kg and 1mg/kg) of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1mg/kg or 0.3mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT(1A) receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT(1A) receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT(1A) receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT(1A) receptors. In addition, these findings could indicate that activation of the 5-HT(1A) autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.

Experience with a naphthylmedetomidine-ketamine-hyaluronidase combination in inducing immobilization in anthropoid apes.

Background  The aim of the study was to compare the effect of naphthylmedetomidine to medetomidine on the behavior of orangutans and chimpanzees.

Short term pharmacological immobilization in macaque monkeys

OBJECTIVE To develop a safe and effective immobilization protocol in rhesus monkeys, which is not based on dissociative anaesthetic agent. STUDY DESIGN Prospective, randomised, experimental trial. ANIMALS Twenty rhesus monkeys, weighing 2.6-8.0 kg, 1-3 years of age, of both sexes. METHODS The monkeys received 50 μg kg(-1) medetomidine, 0.25 mg kg(-1) midazolam and 5 μg kg(-1) fentanyl with 150 IU hyaluronidase intramuscularly (IM). The animals were closely observed for behavioural changes and reaction to sound stimulus. Pulse rate and oxygen saturation of haemoglobin (SpO(2) ) were monitored every 5 minutes, for 20 minutes. After this period, 250 μg kg(-1) atipamezole or a placebo was administered IM and behavioural changes were closely observed. RESULTS Full immobilization was observed after mean 269 ± SD 116 seconds. Ten minutes after injection mean arterial oxygen saturation of haemoglobin was 94 ± 4%, but did not fall significantly further. The median pulse rate was 116 beats minute(-1) 5 minutes after the administration of the drug. This level further decreased to a median level of 108 beats minute(-1) 20 minutes after the drugs administration. The median time to recover from immobilization was significantly shorter after atipamezole administration when compared to placebo (2.7 versus 55 minutes). All animals awoke smoothly and no side effects such as vomiting or agitation were observed. CONCLUSIONS Short term and reversible pharmacological immobilization was achieved using combination of midazolam, medetomidine, and fentanyl. CLINICAL RELEVANCE The present study demonstrates that 20-minute pharmacological immobilization with a combination of midazolam, medetomidine, and fentanyl is feasible in rhesus monkeys with minimal effect on heart rate.OBJECTIVE To develop a safe and effective immobilization protocol in rhesus monkeys, which is not based on dissociative anaesthetic agent. STUDY DESIGN Prospective, randomised, experimental trial. ANIMALS Twenty rhesus monkeys, weighing 2.6-8.0 kg, 1-3 years of age, of both sexes. METHODS The monkeys received 50 μg kg-1 medetomidine, 0.25 mg kg-1 midazolam and 5 μg kg-1 fentanyl with 150 IU hyaluronidase intramuscularly (IM). The animals were closely observed for behavioural changes and reaction to sound stimulus. Pulse rate and oxygen saturation of haemoglobin (SpO2) were monitored every 5 minutes, for 20 minutes. After this period, 250 μg kg-1 atipamezole or a placebo was administered IM and behavioural changes were closely observed. RESULTS Full immobilization was observed after mean 269 ± SD 116 seconds. Ten minutes after injection mean arterial oxygen saturation of haemoglobin was 94 ± 4%, but did not fall significantly further. The median pulse rate was 116 beats minute-1 5 minutes after the administration of the drug. This level further decreased to a median level of 108 beats minute-1 20 minutes after the drugs administration. The median time to recover from immobilization was significantly shorter after atipamezole administration when compared to placebo (2.7 versus 55 minutes). All animals awoke smoothly and no side effects such as vomiting or agitation were observed. CONCLUSIONS Short term and reversible pharmacological immobilization was achieved using combination of midazolam, medetomidine, and fentanyl. CLINICAL RELEVANCE The present study demonstrates that 20-minute pharmacological immobilization with a combination of midazolam, medetomidine, and fentanyl is feasible in rhesus monkeys with minimal effect on heart rate.

Selective antiaggressive effect of an alpha-2 adrenoceptor agonist naphthylmedetomidine in mice.

Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.

The effect of the novel partial alpha2-adrenoceptor agonist naphthylmedetomidine on the basic cardiorespiratory parameters and behavior in rhesus monkeys.

Background  The aim of this study was to compare cardiorespiratory and behavioral profile of a new alpha 2‐adrenoceptor ligand naphthylmedetomidine with medetomidine in rhesus monkeys.

Ephedrine accelerates psychomotor recovery from anesthesia in macaque monkeys

Background  Ephedrine is used in treatment of hypotension during anesthesia. We investigated its effects on the psychomotor recovery and its potential adverse reactions on cardiorespiratory functions in rhesus monkeys.

The effect of the novel alpha-2-adrenoceptor agonist naphthylmedetomidine on pulse rate, arterial blood pressure and sedation in rabbits.

OBJECTIVE The aim of this study was to investigate the effect of a novel alpha-2-adrenoceptor (alpha(2)-AR) agonist, naphthylmedetomidine, on cardiorespiratory function and sedation in rabbits in comparison with medetomidine. STUDY DESIGN Prospective, randomized, experimental trial. ANIMALS Forty-two chinchilla rabbits of both sexes, weighing 2.5-4.5 kg. METHODS The rabbits received 350 microg kg(-1) naphthylmedetomidine (n = 21) or medetomidine (n = 21) intramuscularly according to a randomization scheme. Arterial blood pressure (AP), oxygen saturation of haemoglobin (SpO(2)), pulse rate (PR) and righting reflex were monitored for 20 minutes after injection. RESULTS Both drugs significantly decreased PR. The effect of medetomidine was significantly greater than that of naphthylmedetomidine and was evident within 1 minute. The decrease in PR after naphthylmedetomidine administration first appeared after 4 minutes. Medetomidine decreased the SpO(2) after 3 minutes but there was no effect after naphthylmedetomidine. Medetomidine decreased the mean, systolic and diastolic AP within 5 minutes of administration but naphthylmedetomidine had no effect. The mean time to loss of righting reflex was 185 and 714 seconds after the administration of medetomidine and naphthylmedetomidine respectively. CONCLUSIONS AND CLINICAL RELEVANCE These results provide the first description of the effects of naphthylmedetomidine on cardiovascular and psychomotor functions in rabbits. Further work is required to reveal the anaesthetic sparing, analgesic or sedative effect of partial naphthylmedetomidine.

Endogenous ligands of benzodiazepine binding site have inverse agonistic properties.

Benzodiazepines have been widely used in clinical praxis for many decades. They act as GABAA receptor agonists and possess muscle-relaxant, hypnotic-sedative, anticonvulsant, and anxiolytic properties. Flumazenil acts as a benzodiazepine receptor antagonist (subunits α1, α2, α3, and α5) or partial agonist (subunits α4 and α6). It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepines. In our experiments, administration of flumazenil in rabbits was surprisingly associated with anxiolytic effects similar to those of midazolam. Additionally, flumazenil significantly and dose-dependently decreased the total number of vocalizations in rats, i.e. it was anxiolytic. These observations seem to be in contrast to the effect of flumazenil in humans, where it is believed to produce mainly anxiogenic effects. It seems that in individuals, who exhibit anxiogenic behavior or in individuals with anticipation anxiety, flumazenil acts as an anxiolytic agent, while in individuals without any signs of anxiety, flumazenil can also act as anxiogenic agent. Thus, we hypothesize that flumazenil is associated with decreased intensity of anticipatory anxiety due to occupancy of benzodiazepine binding sites by an endogenous ligand with inverse agonistic properties.