Increased response to a 5-HT challenge after discontinuation of chronic serotonin uptake inhibition in the adult and adolescent rat brain

Little is known about the effects of chronic fluoxetine on 5-HT transmission in the adolescent brain, even though it is acknowledged that the neuroplasticity of the brain during childhood and adolescence might influence the neurobiological mechanisms underlying treatment response. Also, possible ongoing effects on monoamine function following drug discontinuation are unidentified. We therefore examined the chronic effects of fluoxetine on extracellular 5-HT and dopamine concentrations in the medial prefrontal cortex and studied their responsiveness to an acute 5-HT challenge after a one-week washout period, both in adolescent and adult rats. Noradrenaline was measured in adult animals only. Fluoxetine increased 5-HT to 200-300% of control and DA and NA to 150% of control. Although there were no lasting effects of chronic fluoxetine on basal monoamine levels, we observed a clear potentiating effect of previous treatment on the fluoxetine-induced increase in extracellular 5-HT and, to a lesser extent, extracellular DA. No differential effect was found for noradrenaline. Age-at-treatment did not influence these results. So, after cessation of chronic fluoxetine treatment 5-HT responsiveness remains heightened. This may be indicative of the continuing presence of 5-HT receptor desensitization, at least until one week after drug discontinuation in rats. No apparent age-at-treatment effects on extracellular monoamine concentrations in the medial prefrontal cortex were detected, but age-related differences in 5-HT transmission further down-stream or in the recovery processes cannot be ruled ou

Graphical overview of probe localization.

<p>A) Membrane positions of microdialysis probes, based upon histological examination. Length of the membrane was 2 mm (black) in the adults and 3 mm (blue) in the adolescent-treated animals. B) Representative example of probe placement in cresyl blue stained sections.</p

Extracellular NA levels in the mPFC before and after acute FLX challenge.

<p>Levels are given as percentage (%) of the average baseline value ( = 100%). NA release after the challenge is significantly enhanced (RM-ANOVA; effect of time (F_10,200 = 12.197, <i>p</i>-value<0.001) and reaches its maximum after approximately 30 minutes.</p

Extracellular 5-HT levels in the mPFC before and after acute FLX challenge.

<p>Levels are given as percentage (%) of the average baseline value ( = 100%). 5-HT release was significantly increased after the acute FLX challenge in all groups (RM-ANOVA; effect of time (F_10,230 = 48.342, <i>p</i>-value<0.001) and this increase was significantly enhanced in the chronically treated animals (RM-ANOVA; effect of time-by-treatment; F_10,230 = 4.417, <i>p</i>-value = 0.007) and reaches its maximum after approximately 30 minutes. The inset shows the AUC-values per group (effect of treatment; F_1,27 = 10.333, <i>p</i>-value = 0.004). Black arrow indicates the time point of the acute FLX challenge (5 mg/kg, i.v.). Error bars represent one S.E.M.</p

Extracellular DA levels in the mPFC before and after acute FLX challenge.

<p>Levels are given as percentage (%) of the average baseline value ( = 100%). DA release was significantly increased after the acute FLX challenge in all groups (RM-ANOVA; effect of time (F_10,190 = 12.037, <i>p</i>-value<0.001) and reaches its maximum after approximately 30 minutes. The AUC values (inset) showed a significant effect of treatment (increased release in treated animals), this was however not confirmed by the RM-ANOVA analysis (no time-by-treatment effect; <i>p</i>-value>0.100). Black arrow indicates the time point of the acute FLX challenge (5 mg/kg, i.v.). Error bars represent one S.E.M.</p

Basal monoamine levels in the mPFC per group.

#<p>No significant effect of age, treatment or age-by-treatment between groups;</p>$<p>Group analysis not performed due to low amount of subjects in the adolescent-treated groups.</p><p>For each monoamine or metabolite, the average baseline concentrations (nM ± SD (n)) are given per group and for all animals together.</p

Differential Effects of Deep Brain Stimulation of the Internal Capsule and the Striatum on Excessive Grooming in Sapap3 Mutant Mice

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for patients with obsessive-compulsive disorder (OCD) that do not respond to conventional therapies. Although the precise mechanism of action of DBS remains unknown, modulation of activity in corticofugal fibers originating in the prefrontal cortex is thought to underlie its beneficial effects in OCD. METHODS: To gain more mechanistic insight into DBS in OCD, we used Sapap3 mutant mice. These mice display excessive self-grooming and increased anxiety, both of which are responsive to therapeutic drugs used in OCD patients. We selected two clinically relevant DBS targets through which activity in prefronto-corticofugal fibers may be modulated: the internal capsule (IC) and the dorsal part of the ventral striatum (dVS). RESULTS: IC-DBS robustly decreased excessive grooming, whereas dVS-DBS was on average less effective. Grooming was reduced rapidly after IC-DBS onset and reinstated upon DBS offset. Only IC-DBS was associated with increased locomotion. DBS in both targets induced c-Fos expression around the electrode tip and in different regions of the prefrontal cortex. This prefronto-cortical activation was more extensive after IC-DBS, but not associated with behavioral effects. Furthermore, we found that the decline in grooming cannot be attributed to altered locomotor activity and that anxiety, measured on the elevated plus maze, was not affected by DBS. CONCLUSIONS: DBS in both the IC and dVS reduces compulsive grooming in Sapap3 mutant mice. However, IC stimulation was more effective, but also produced motor activation, even though both DBS targets modulated activity in a similar set of prefrontal cortical fibers

Evaluation of temperature rise and bonding strength in cements used for permanent head attachments in rats and mice

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Myopia control in Mendelian forms of myopia

Purpose: To study the effectiveness of high-dose atropine for reducing eye growth in Mendelian myopia in children and mice. Methods: We studied the effect of high-dose atropine in children with progressive myopia with and without a monogenetic cause. Children were matched for age and axial length (AL) in their first year of treatment. We considered annual AL progression rate as the outcome and compared rates with percentile charts of an untreated general population. We treated C57BL/6J mice featuring the myopic phenotype of Donnai–Barrow syndrome by selective inactivation of Lrp2 knock out (KO) and control mice (CTRL) daily with 1% atropine in the left eye and saline in the right eye, from postnatal days 30–56. Ocular biometry was measured using spectral-domain optical coherence tomography. Retinal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high-performance liquid chromatography. Results: Children with a Mendelian form of myopia had average baseline spherical equivalent (SE) –7.6 ± 2.5D and AL 25.8 ± 0.3 mm; children with non-Mendelian myopia had average SE −7.3 ± 2.9 D and AL 25.6 ± 0.9 mm. During atropine treatment, the annual AL progression rate was 0.37 ± 0.08 and 0.39 ± 0.05 mm in the Mendelian myopes and non-Mendelian myopes, respectively. Compared with progression rates of untreated general population (0.47 mm/year), atropine reduced AL progression with 27% in Mendelian myopes and 23% in non-Mendelian myopes. Atropine significantly reduced AL growth in both KO and CTRL mice (male, KO: −40 ± 15; CTRL: −42 ± 10; female, KO: −53 ± 15; CTRL: −62 ± 3 μm). The DA and DOPAC levels 2 and 24 h after atropine treatment were slightly, albeit non-significantly, elevated. Conclusions: High-dose atropine had the same effect on AL in high myopic children with and without a known monogenetic cause. In mice featuring a severe form of Mendelian myopia, atropine reduced AL progression. This suggests that atropine can reduce myopia progression even in the presence of a strong monogenic driver

Myopia control in Mendelian forms of myopia

PURPOSE: To study the effectiveness of high-dose atropine for reducing eye growth in Mendelian myopia in children and mice. METHODS: We studied the effect of high-dose atropine in children with progressive myopia with and without a monogenetic cause. Children were matched for age and axial length (AL) in their first year of treatment. We considered annual AL progression rate as the outcome and compared rates with percentile charts of an untreated general population. We treated C57BL/6J mice featuring the myopic phenotype of Donnai-Barrow syndrome by selective inactivation of Lrp2 knock out (KO) and control mice (CTRL) daily with 1% atropine in the left eye and saline in the right eye, from postnatal days 30-56. Ocular biometry was measured using spectral-domain optical coherence tomography. Retinal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high-performance liquid chromatography. RESULTS: Children with a Mendelian form of myopia had average baseline spherical equivalent (SE) -7.6 ± 2.5D and AL 25.8 ± 0.3 mm; children with non-Mendelian myopia had average SE -7.3 ± 2.9 D and AL 25.6 ± 0.9 mm. During atropine treatment, the annual AL progression rate was 0.37 ± 0.08 and 0.39 ± 0.05 mm in the Mendelian myopes and non-Mendelian myopes, respectively. Compared with progression rates of untreated general population (0.47 mm/year), atropine reduced AL progression with 27% in Mendelian myopes and 23% in non-Mendelian myopes. Atropine significantly reduced AL growth in both KO and CTRL mice (male, KO: -40 ± 15; CTRL: -42 ± 10; female, KO: -53 ± 15; CTRL: -62 ± 3 μm). The DA and DOPAC levels 2 and 24 h after atropine treatment were slightly, albeit non-significantly, elevated. CONCLUSIONS: High-dose atropine had the same effect on AL in high myopic children with and without a known monogenetic cause. In mice featuring a severe form of Mendelian myopia, atropine reduced AL progression. This suggests that atropine can reduce myopia progression even in the presence of a strong monogenic driver