Tamara G. Amstislavskaya

Female-induced sexual arousal in male mice and rats: behavioral and testosterone response

Exposure of a male mouse to a female mouse separated from it by a holed partition induced specific behavior and an increase in blood testosterone in the male. The male made more approaches to the partition and spent more time at it. The time spent by the male mouse over the first 10 min at the partition, behind which an estrus female was placed, was increased sixfold compared to the time spent by a male mouse exposed to the vacant neighboring compartment; and 1.5-fold compared to that spent by a male mouse exposed to a nonreceptive female or a male. Increased blood testosterone level was detected at 20 min of exposure to a receptive female in winter and at 40 min in summer. No variation in blood testosterone levels in the male mouse exposed to a nonreceptive female or a male was observed. Similar response to a receptive female placed in the neighboring compartment was shown in a male rat. The time spent by the male rat at the partition was 12 times higher when there was an estrus female behind it than in control. Blood testosterone in the male rat increased in response to a female rat and did not change in response to a male rat indicating female-induced motivation. It was concluded that the partition time might serve as a quantitative measure of sexual motivation in the males and that the model of female-induced sexual arousal used was suitable for studying both motivational and hormonal components of sexual arousal in male mice and rats.

Behavioral Characteristics of Mice with Genetic Knockout of Monoamine Oxidase Type A

Transgenic mice of line Tg8 were used to study the effects of deletion of the monoamine oxidase type A gene and the absence of the corresponding enzyme on behavior. These experiments showed that Tg8 mice with genetic knockout of monoamine oxidase type A differed from mice of the parental line C3H/HeJ by lower levels of the startle reflex in response to an acoustic signal, while there was no difference in the prestimulus inhibition of the startle response. Tg8 mice showed decreased investigative activity and decreases in the number of sector crossings in the light-dark anxiety test. There were significant increases in aggression as a motivation in male Tg8 mice, which was manifest as an increase in the number of mice demonstrating aggression and a decrease in the latent period of attack. The intensity of aggression changed to a lesser extent – the number of fights even decreased, though longer periods of keeping mice together resulted in increased numbers of deaths among intruder mice. At the same time, there were no significant differences between mice with genetic knockout of monoamine oxidase type A and control mice in terms of the expression of sexual activation: the behavioral responses of Tg8 males to presentation of females was marked and was no different from that of male C3H/HeJ mice. Knockout of the gene had no effect on movement activity on behavior in an elevated cross-shaped maze or in the test for predisposition to catalepsy.

5-HT2A and 5-HT2C Serotonin Receptors Differentially Modulate Mouse Sexual Arousal and the Hypothalamo-Pituitary-Testicular Response to the Presence of a Female

The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavior and plasma testosterone regulation was studied in male CBA mice exposed to a sexually receptive female separated by a transparent partition. Introduction of the receptive female induced sexual motivation and arousal in males, as evidenced by a prolonged time spent at the partition, unsuccessful attempts to step across it and a significant increase in plasma testosterone levels. Administration of 5-HT2A receptor antagonists ketanserin (1.0 and 2.0 mg/kg i.p.) or cyproheptadine (1.0 and 2.0 mg/kg i.p.) diminished the behavioral components and prevented the hormonal components of male sexual arousal. Administration of the selective 5-HT2C antagonist RS 102221 (1.0 and 2.0 mg/kg) considerably increased the time spent by males at the partition (p < 0.001) and, at the dose of 2.0 mg/kg, increased plasma testosterone levels (p < 0.01). Administration of ritanserin – a nonselective 5-HT2A/2C antagonist and, to a smaller degree, 5-HT2B antagonist – at doses of 0.1 and 0.5 mg/kg did not significantly influence male behavior and the activating effect of the presence of a female on the hypothalamo-pituitary-testicular system, although it increased resting testosterone levels (p < 0.05). The present findings suggest that 5-HT2A/5-HT2C receptors may be involved in the neural control of male sexual motivation and arousal, presumably by exerting reciprocal facilitative (5-HT2A) or suppressive (5-HT2C) influences.

Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A

The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic Tg8 mice on the activity of tryptophan hydroxylase (TPH), the rate‐limiting enzyme in serotonin (5‐HT) biosynthesis, and on the levels of 5‐HT and 5‐hydroxyindoleacetic acid (5‐HIAA) in the midbrain, hypothalamus, hippocampus, striatum, amygdala, and frontal cortex was studied. It was shown that mice with a genetic MAO A knockout differed from mice of the initial C3H/HeJ strain in having a higher level of 5‐HT and a lower level of its metabolite, 5‐HIAA, in all brain regions but the frontal cortex, where the changes were insignificant. Although the 5‐HIAA/5‐HT ratio in various brain regions differed considerably, the decrease of the 5‐HT oxidative deamination index in Tg8 mice was similar in different brain regions (to 41–45% of control values), with the exception of the frontal cortex, where the decrease of the 5‐HIAA/5‐HT was somewhat smaller (to 54%). The presence of the remaining 45% ± 1.9% of the control ratio value indicates rather effective oxidative deamination of 5‐HT in MAO A knockout mice and explains the lack of severe behavioral and pathological consequences in MAO A genetic deficiency. An increase of TPH activity in mice lacking MAO A was found in the frontal cortex, hippocampus, and amygdala. No significant changes were found in the striatum, hypothalamus, and midbrain. The data show an effect of the MAO A gene mutation on TPH and indicate a uniform decrease of 5‐HT catabolism in different brain regions except for the frontal cortex, which is somewhat more resistant to the lack of MAO A than other brain structures. J. Neurosci. Res. 66:423–427, 2001.

Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson's disease rat model.

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinsons disease (PD) and treatment with drugs modulating glutamatergic activity may have beneficial effects. Ceftriaxone has been reported to increase glutamate uptake by increasing glutamate transporter expression. The aim of this study was to determine the effects of ceftriaxone on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Then, starting the next day (day 1), the rats were injected daily with either ceftriaxone (200 mg/kg/day, i.p.) or saline for 14 days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test. The treatment of ceftriaxone decreased the above MPTP-induced cognitive deficits. Furthermore, this study provides evidence that ceftriaxone inhibits MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area. In conclusion, these data support the idea that hyperactivity of the glutamatergic system is involved in the pathophysiology of PD and suggest that ceftriaxone may be a promising pharmacological tool for the development of new treatments for the dementia associated with PD.

Effects of repeated aggressive encounters on approach to a female and plasma testosterone in male mice.

Effects of repeated experience of aggression accompanied by social victories or social defeat in 10 daily agonistic confrontations on testosterone levels in and the behavioral response of CBA/Lac male mice exposed to a receptive female from behind a perforated transparent partition have been examined. Testosterone levels were not changed significantly in the mice that had consistently been victorious over 10 days (winners) or in the mice that had consistently been defeated over 10 days (losers). Losers and controls (mice that had been caged individually for 5 days) responded with increased levels of behavioral activity near the partition and elevated testosterone. Winners showed a significantly poorer behavioral and hormonal response. It is concluded that the repeated display of aggression by male mice led to a reduction in both their behavioral and neuroendocrine responses to an estrous female.

Effect of repeated experience of victory and defeat in daily agonistic confrontations on brain tryptophan hydroxylase activity

The rate‐limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase (TPH), was studied in brain areas of male mice with repeated experience of victory (winners) or defeat (losers) gained in 10 daily agonistic confrontations. A reduction of TPH activity in the midbrain and an increase in the hypothalamus was demonstrated for winners compared with controls. In contrast, repeated defeat in social confrontations was associated with higher TPH activity in the striatum and hypothalamus in losers compared with controls. Agonistic interactions did not affect TPH activity in the amygdala, nucleus accumbens or hippocampus in either winners or losers. The sensory contact technique used in this work for generating winners and losers may be productive in the analysis of TPH gene regulation.

Methoxychlor given in the periimplantation period blocks sexual arousal in male mice

To determine whether pesticide methoxychlor (MXC) alters sexual arousal in male offspring, pregnant ICR mice remained untreated or received daily subcutaneous injections (s.c.) of olive oil, 33.0 mg/kg bw purified (95%) MXC, or 0.33 mg/kg bw estradiol-173 in vehicle on Days 5 to 7 of pregnancy. Live births were recorded in all groups except the estradiol group. At 4 months, untreated or olive oil-treated male offspring exhibited normal sexual arousal. When placed near a plastic partition with an estrus female behind it, these males spent significantly more time near the partition than near a vacant half of the cage and exhibited a sharp increase in plasma testosterone. MXC-exposed males showed no sexual arousal, spent much less time near the partition with an estrus female, and exhibited significantly lower plasma testosterone levels. Exposure to purified MXC close to implantation alters the function of the hypothalamic-pituitary-testicular axis and compromises male sexual behavior in offspring.

Brain serotonin metabolism during water deprivation and hydration in rats.

The effects of two-day water deprivation and hyperhydration (provision of 4% sucrose solution for 48 h) on levels of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain and hypothalamus were studied in Wistar rats. The rates of diuresis (0.05 ± 0.01 and 0.84 ± 0.12 ml/h/100 g in water deprivation and hyperhydration respectively) and urine osmolality (1896 ± 182 and 50 ± 13 mOsm/kg) reflected increases and decreases in blood vasopressin levels. Water deprivation was associated with a significant increase in 5-HIAA levels in the midbrain and hypothalamus, along with a decrease in serotonin levels and a three-fold increase in serotonin catabolism (the 5-HIAA:serotonin concentration ratio). Hyperhydration induced moderate increases in serotonin and 5-HIAA levels in the hypothalamus with no changes in the midbrain. The blood corticosterone level doubled in water deprivation and decreased in hyperhydration. It is suggested that activation of the serotoninergic system induces a complex adaptive reaction in water deprivation, including mechanisms specific for the regulation of water-electrolyte homeostasis and non-specific stress mechanisms (vasopressin and corticoliberin secretion).

Effects of the mitochondria-targeted antioxidant SkQ1 on sexually motivated behavior in male rats

Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress and may be ameliorated by antioxidants. Here we examined effects of mitochondria-targeted antioxidant, SkQ1, on sexual motivation in 12-month-old Wistar and accelerated-senescent OXYS male rats. A change in behavioral activity of a male at a holed transparent partition with a receptive female on the other side was taken as an index of sexual motivation. The social behavior of male in same conditions with ovariectomised (OVXed) female and castrated male was investigated to differentiate sexually and socially motivated behavior. Behavioral response to social stimulus did not depend on age and genotype. No differences were found between 4- and 12-month-old Wistar males when sexual stimulus was presented; however, 12-month-old OXYS males demonstrated a lower propensity for sexual motivation as compared to 4-month-old OXYS rats and 12-month-old Wistar rats. We examined effects of SkQ1 on sexual motivation in 12-month-old male rats following prolonged supplementation begun at 1.5months of age (10, 50 or 250nmol/kg daily), a 45-day supplementation begun at 10.5months of age (50nmol/kg) and a 3-month supplementation begun at 9months of age (250nmol/kg). SkQ1 did not affect locomotor activity; however, it increased the time spent at the partition. A significantly higher measure of the motivational stage of sexual behavior was displayed following chronic preventive treatment at a dose of 50 and 250nmol/kg by OXYS rats. Chronic therapeutic treatment during 3months at a dose of 250nmol/kg was effective in age-accelerated OXYS rats too. These findings suggest an essential role for oxidative stress associated with mitochondrial dysfunction in the decline of sexually motivated behavior of male rats. Recovery from these impairments and/or their prevention enables a fully successful performance of the initial stage of male sexual behavior.