A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear.

BACKGROUND: Though drugs binding to serotonergic 5-HT2A receptors have long been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety promoting or anxiety dampening. Whereas conditioned fear expressed as freezing in rats is modified by application of 5-HT2A-acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behavior remain sparse. METHODS: We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI)-per se or in combination-on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they received foot shocks 7 days earlier. RESULTS: The 5-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect. CONCLUSIONS: The results indicate that 5-HT2A receptor activation is not a prerequisite for normal conditioned freezing in rats but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.

Serotonin depletion reduces both acquisition and expression of context-conditioned fear.

OBJECTIVE: Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear. METHODS: Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only. RESULTS: The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear. CONCLUSION: Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.

Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing.

OBJECTIVE: Whereas long-term administration of selective serotonin reuptake inhibitors (SSRIs) is effective for the treatment of anxiety disorders, acute administration of these drugs may exert a paradoxical anxiogenic effect. The aim of the present study was to explore the possible effect of an SSRI in situations of unconditioned or limited conditioned fear. METHODS: Male Sprague Dawley rats were administered a single dose of an SSRI, escitalopram, before acquisition or expression of context conditioned fear, where noise bursts were used as the unconditioned stimulus. Freezing was assessed as a measure of unconditioned fear (=the acute response to noise bursts) or conditioned fear (=the response to the context), respectively. RESULTS: Noise bursts elicited an acute increase in freezing but no robust conditioned response 7 days after exposure. Administration of escitalopram before testing exacerbated the freezing response during presentation of the unconditioned stimulus and also unmasked a conditioned response; in contrast, administration of escitalopram prior to acquisition did not influence the conditioned response. CONCLUSION: The data suggest that freezing in rats exposed to a stimulus inducing relatively mild fear may be enhanced by acute pretreatment with an SSRI regardless of whether the freezing displayed by the animals is an acute unconditioned response to the stimulus in question or a conditioned response to the same stimulus.

Serotonin depletion eliminates sex differences with respect to context-conditioned immobility in rat.

RATIONALE: Previous studies have shown that male rats display more anxiety-like behavior than females as assessed using the elevated plus maze and that serotonin depletion abolishes this difference by exerting an anxiolytic-like effect in males only. OBJECTIVES: To compare male and female rats with respect to immobility and startle responses to sudden noise bursts after contextual fear conditioning and to explore to what extent any possible sex difference in this regard is influenced by serotonin depletion during testing (but not acquisition). RESULTS: In line with previous studies, males displayed more immobility following contextual conditioning induced by previous exposure to foot shocks than females. In males but not females, the immobility response was reduced by administration of the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA) between shock exposure and testing, the consequence being that males and females no longer differed in this regard. Untreated males but not females displayed a negative correlation between fear-conditioned startle and immobility, suggesting that the latter behavior, when excessive, interferes with the former. In line with this assumption, the reduction in immobility following administration of PCPA in males coincided with an increase in startle that was not observed in females, hence revealing a sex difference in startle not seen in untreated controls. CONCLUSION: The greater display of context-conditioned immobility in males compared with females appears to be serotonin-dependent.

Differences in Anxiety-Like Behavior within a Batch of Wistar Rats Are Associated with Differences in Serotonergic Transmission, Enhanced by Acute SRI Administration, and Abolished By Serotonin Depletion.

BACKGROUND: The anxiety-reducing effect of long-term administration of serotonin reuptake inhibitors is usually seen only in subjects with anxiety disorders, and such patients are also abnormally inclined to experience a paradoxical anxiety-enhancing effect of acute serotonin reuptake inhibition. These unique responses to serotonin reuptake inhibitors in anxiety-prone subjects suggest, as do genetic association studies, that inter-individual differences in anxiety may be associated with differences in serotonergic transmission. METHODS: The one-third of the animals within a batch of Wistar rats most inclined to spend time on open arms in the elevated plus maze were compared with the one-third most inclined to avoid them with respect to indices of brain serotonergic transmission and how their behavior was influenced by serotonin-modulating drugs. RESULTS: "Anxious" rats displayed higher expression of the tryptophan hydroxylase-2 gene and higher levels of the tryptophan hydroxylase-2 protein in raphe and also higher levels of serotonin in amygdala. Supporting these differences to be important for the behavioral differences, serotonin depletion obtained by the tryptophan hydroxylase-2 inhibitor p-chlorophenylalanine eliminated them by reducing anxiety in "anxious" but not "non-anxious" rats. Acute administration of a serotonin reuptake inhibitor, paroxetine, exerted an anxiety-enhancing effect in "anxious" but not "non-anxious" rats, which was eliminated by long-term pretreatment with another serotonin reuptake inhibitor, escitalopram. CONCLUSIONS: Differences in an anxiogenic impact of serotonin, which is enhanced by acute serotonin reuptake inhibitor administration, may contribute to differences in anxiety-like behavior amongst Wistar rats.

Acute escitalopram but not contextual conditioning exerts a stronger "anxiogenic" effect in rats with high baseline "anxiety" in the acoustic startle paradigm.

RATIONALE: Acute administration of selective serotonin reuptake inhibitors (SSRIs) may enhance anxiety in humans, those with anxiety disorders being more susceptible than others. Fear-conditioned or unconditioned acoustic startle and freezing are common measures of fear and/or "anxiety" in rodents that may be used to study this effect of SSRIs preclinically. OBJECTIVES: Our aim was to shed further light on the effect of acute administration of an SSRI, escitalopram (10 mg/kg), on startle and freezing in the absence or presence of prior contextual conditioning. Repeated testing also enabled us to evaluate (i) if there are stable inter-animal variations with respect to these parameters in a batch of outbred Wistar rats, (ii) the possible relationship between the two and (iii) if baseline behaviour predicts the response to escitalopram. RESULTS: Inter-animal test-retest correlations were found for both startle and freezing at baseline, and the two parameters also correlated with each other. Both escitalopram and contextual conditioning increased freezing and startle but without exerting any synergistic effect. While animals displaying high startle at baseline showed higher susceptibility to respond to escitalopram, the effect of conditioning was more pronounced in those with low baseline startle. CONCLUSIONS: The results support the usefulness of both conditioned and non-conditioned startle and freezing to capture an "anxiogenic" influence of SSRIs. Also, they suggest that baseline non-conditioned startle may predict this response in a manner reflecting the clinical situation in the sense that subjects with high baseline "anxiety" are particularly prone to respond with enhanced "anxiety" following acute SSRI administration.

Posture strategies generated by constrained optimization.

For people with motion disorders, posture can impact fatigue, discomfort or deformities in the long term. Orthopedic treatments such as orthoses or orthopedic surgeries which change geometric properties can improve posture in these individuals. In this study, a model has been created to study posture strategies in such situations. A 3D mechanical model consisting of eight rigid segments and 30 muscle groups is used in which varying moment arms along the ranges of motion and biarticular muscles are considered. The method is based on static optimization, both to solve the load sharing in the muscle system and to choose posture strategy. The optimization computes the specific posture with minimal required effort (level of muscle activations), while fulfilling constraints containing subject specific ranges of motion, muscle strength/weakness and external support if present. Anthropometry and strength were scaled to each individual, based on reported pediatric anthropometry and strength values, combined with each individual's physical assessment. A control group of 10 able-bodied subjects as well as three subjects with motion disorders were studied, and simulated posture was compared with experimental data. The simulation showed reasonable to good agreement and ability to predict the effect of motion disorders and of external support. An example of application in parameter studies was also presented wherein ankle orthosis angles were varied. The model allows the user to study muscle activity at the muscle group level, position of center of mass and moments at joints in various situations.

Personality traits and the R668Q polymorphism located in the MMP-9 gene.

Matrix metalloproteinases (MMPs) are enzymes involved in degradation of proteins in the extracellular matrix and have been shown to contribute to neuroinflammation by several mechanisms such as blood-brain barrier breakdown. Among the MMPs, MMP-9 (gelatinase B) has been suggested to be of relevance also for synaptic and behavioural plasticity. In order to explore the role of MMP-9 for mental functions a polymorphism in MMP-9 was analysed with respect to personality traits. The two studied populations consisted of women and men, respectively, both recruited from the population registry and assessed by means of the Karolinska Scales of Personality. The non-synonymous single nucleotide polymorphism (R668Q, rs17577) studied is located in the coding region of MMP-9 and is believed to affect the activity of the enzyme. The present study found that an amino acid change from arginine (R) to glutamine (Q) was associated with higher scores of the personality trait inhibition of aggression in the female population whilst this substitution was associated with higher scores of verbal aggression and irritability in men. These findings give support for an influence of MMP-9 on mental functions.

Influence of heel lifts during standing in children with motor disorders.

Heel wedges may influence standing posture but how and to what extent are unknown. Thirty-two children with motor disorders - 16 with arthrogryposis multiplex congenita (AMC) and 16 with cerebral palsy (CP) - and 19 control children underwent a three-dimensional motion analysis. Unassisted standing during 20s with shoes only and with heel lifts of 10, 20 and 30mm heights was recorded in a randomized order. The more weight-bearing limb or the right limb was chosen for analysis. In both the AMC and CP groups, significant changes were seen between various heel lifts in ankle, knee and pelvis, and in the control group in the ankle only. Between orthosis and non-orthosis users significant differences were seen between different heel lift conditions in ankle, knee and trunk in the AMC group and in the ankle in the CP group. Pelvis position changed toward less anterior tilt with increasing heel height, but led to increasing knee flexion in most of the children, except for the AMC Non-Ort group. Children with AMC and CP represent different motor disorders, but the heel wedges had a similar influence on pelvis, hip and knee positions in all children with CP and in the AMC orthosis users. A challenge is to apply heel heights adequate to each individual's orthopaedic and neurologic conditions to improve biomechanical alignment with respect to all body segments.