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.

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.