Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray.

The amygdala is an important filter for unconditioned and conditioned aversive information. The amygdala synthesizes the stimuli input from the environment and then signals the degree of threat that they represent to the dorsal periaqueductal gray (dPAG), which would be in charge of selecting, organizing and executing the appropriate defense reaction. In this study, we examined the influence of fluoxetine microinjections (1.75 and 3.5 nmol/0.2 microL) into the lateral (LaA) and basolateral (BLA) amygdaloid nuclei on the freezing and escape responses induced by electrical stimulation of the dPAG. Freezing behavior was also measured after the interruption of the electrical stimulation of the dPAG. On the following day, these rats were also submitted to a contextual fear paradigm to examine whether these microinjections would affect the conditioned freezing to contextual cues previously associated with foot shocks. Fluoxetine injections into both amygdaloid nuclei did not change the freezing and escape thresholds, but disrupted the dPAG-post-stimulation freezing. Moreover, the conditioned freezing was enhanced by fluoxetine. Whereas 5-HT mechanisms in the amygdala facilitate the acquisition of conditioned fear they inhibit the dPAG-post-stimulation freezing. However, the unconditioned fear triggered by activation of the dPAG is produced downstream of the amygdala. These findings have important implications for the understanding of the neurochemical substrates that underlie panic and generalized anxiety disorders.     

Apomorphine enhances conditioned responses induced by aversive stimulation of the inferior colliculus.

Consistent evidence has shown that learning may be produced in paradigms using electrical stimulation of the inferior colliculus (IC) as unconditioned stimulus (UCS). Recent reports have also demonstrated that aversive stimulation of the IC, at the escape threshold, enhances dopamine (DA) release in the prefrontal cortex. The purpose of the present study was to determine whether dopaminergic mechanisms are involved in the Pavlovian conditioning and latent inhibition using IC stimulation as UCS and light as conditioned stimulus (CS). Rats were placed inside a shuttle box and subjected to a two-way avoidance paradigm. IC aversive electrical stimulation was used as UCS and shuttle box illumination as CS. The rats quickly learned to avoid or interrupt the IC stimulation. Apomorphine injections produced a dose-dependent increase in the number of avoidance responses. On the other hand, chlorpromazine administration promoted a dose-dependent reduction of the avoidance responses. Previous injections of chlorpromazine inhibited the effects of apomorphine. Also, previous exposure to unreinforced light weakened the strength of the conditioning. Apomorphine blocked this latent inhibition effect, which was antagonized by previous injections of chlorpromazine. These findings bring evidence for the involvement of DA in the setting up of adaptive responses to aversive states generated at the IC level, which may underlie stressful situations present in anxiety.     

Effects of ketamine on different types of anxiety/fear and related memory in rats with lesions of the median raphe nucleus.

The aim of the present study was to determine the involvement of the median raphe serotonergic system in the effects of ketamine on anxiety behaviours and related memory. The effects of ketamine pretreatment (3 and 10 mg/kg, i.p.) on three types of fear-motivated behaviours, unconditioned one-way escape, conditioned avoidance and freezing were tested. Experiments were performed with the inhibitory avoidance apparatus in rats with ibotenic acid lesions of the median raphe nucleus. It was found that 10 mg/kg ketamine had an anxiogenic-like effect on one-way escape type of fear and anxiolytic-like effect on conditioned freezing-related fear; these effects were unaffected by median raphe lesions. Both ketamine doses impaired freezing-related fear memory. Ketamine (10 mg/kg) also produced an anxiolytic-like effect on avoidance type of fear and impaired avoidance memory. The median raphe lesions attenuated the anxiolytic action of the drug on the avoidance type of fear and prevented ketamine-induced avoidance memory impairment. These results suggest that the anxiolytic-like effect of ketamine on avoidance-type fear is mediated through the median raphe serotonergic system.     

Effect ofd-fenfluramine on human experimental anxiety

To investigate the role of 5-HT in human anxiety, the 5-HT releaser and uptake blockerd-fenfluramine (FEN) was administered to healthy volunteers under two models of experimental anxiety. The first was a simulated public speaking (SPS) test consisting of talking in front of a video camera, anxiety being evaluated mainly by self-rating scales. The second was a conditioned fear test, in which the changes in skin electrical conductance caused by a tone associated once with an aversive white noise were measured. The doses of 15 and 30 mg FEN, PO, decreased anxiety induced by SPS in a dose-dependent way, as indicated by the anxiety factor of Norris Visual Analogue Mood Scale. In the conditioned fear test, however, the amplitude and level of skin conductance responses to the conditioned aversive stimulus were not significantly changed by FEN. The differential effects of FEN in these human experimental models of anxiety, together with similar results reported in rats, support the view that 5-HT exerts a dual action on brain mechanisms regulating anxiety, facilitating conditioned while inhibiting unconditioned fear. The presumed reduction in unconditioned fear caused by FEN may have implications for the treatment of panic disorder.     

Neurobiology of anxiety disorders and implications for treatment

The neurobiology of the anxiety disorders, which include panic disorder, post-traumatic stress disorder (PTSD), and specific phobias, among others, has been clarified by advances in the field of classical or Pavlovian conditioning, and in our understanding of basic mechanisms of memory and learning. Fear conditioning occurs when a neutral conditioned stimulus (such as a tone) is paired with an aversive, or unconditioned stimulus (such as a footshock), and then in the absence of the unconditioned stimulus, causes a conditioned fear response. Preclinical studies have shown that the amygdala plays a key role in fear circuitry, and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Drugs such as glutamate N-methyl-D-aspartate (NMDA) antagonists, and blockers of voltage-gated calcium channels, in the amygdala, may block these effects. There is also preliminary evidence for the use of centrally acting beta-adrenergic antagonists, like propranolol, to inhibit consolidation of traumatic memories in PTSD. Finally, fear extinction, which entails new learning of fear inhibition, is central to the mechanism of effective anti-anxiety treatments. Several pharmacological manipulations, such as D-cycloserine, a partial NMDA agonist, have been found to facilitate extinction. Combining these medication approaches with psychotherapies that promote extinction, such as cognitive behavioral therapy (CBT), may offer patients with anxiety disorders a rapid and robust treatment with good durability of effect.     

Moderate doses of ethanol partially reverse avoidance learning deficits in high-alcohol-drinking rats

We previously reported that ethanol-naive high-alcohol-drinking (HAD1 and HAD2) rats exhibited selective deficits in active avoidance learning, as compared to low-alcohol-drinking (LAD1 and LAD2) rats, in a signaled bar-pressing task [Alcohol. Clin. Exp. Res. 24 (2000) 1778]. In the current study, we used appetitive and aversive learning tasks to assess whether administration of ethanol influences approach and avoidance learning in HAD and LAD rats. Rats were administered 0.0, 0.5, 1.0, or 1.5 g ethanol/kg body weight during appetitive and aversive conditioning sessions. We found that ethanol impaired acquisition of the appetitive conditioned response in a dose-dependent manner in both HAD and LAD rats, with 1.5 g/kg ethanol producing the greatest deficits. Notably, moderate doses of ethanol (0.5 and 1.0 g/kg) partially reversed avoidance learning deficits in HAD rats, but only when appetitive conditioning preceded aversive conditioning. The highest dose (1.5 g/kg EtOH) abolished avoidance responding altogether in HAD rats. Avoidance responding in LAD rats was not affected by any dose of ethanol. These results are consistent with previous studies suggesting that alcohol preference may be associated with increased fear or anxiety, but the conditions under which ethanol produces a reduction of fear and anxiety in HAD rats appear to be relatively complex.     

Anxiolytic effect of intra-amygdala injection of midazolam and 8-hydroxy-2-(di-n-propylamino)tetralin in the elevated T-maze

The effects of intra-amygdala injection of midazolam (20 nmol) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 8 and 16 nmol) were investigated in rats submitted to the elevated T-maze, a new animal model of anxiety. This test allows the measurement, in the same rat, of conditioned and unconditioned fear/anxiety responses. Both drugs impaired inhibitory avoidance of the open arms of the T-maze (task representing conditioned fear), indicating an anxiolytic effect, but did not change escape performance from one of the open arms (representing unconditioned fear). The results further implicate gamma-aminobutyric acid (GABA)/benzodiazepine and serotonergic systems within the basolateral/lateral amygdala in the modulation of conditioned anxiety responses.     

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats

Rationale Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear.Objectives To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning.Methods For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task.Results The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task.Conclusions These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.Part of this study was presented at the 18th European College of Neuropsychopharmacology Congress, Amsterdam, The Netherlands, 22–26 October 2005.     

Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice

GABA(A) receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABA(A) receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABA(A) receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABA(A) receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABA(A) receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABA(A) receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABA(A) receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored.     

Effect of sex on fear conditioning is similar for context and discrete CS in Wistar, Lewis and Fischer rat strains

Enhanced fear in males relative to females, both innate and conditioned, is a well-described characteristic of behavior in the laboratory rat. In the case of aversive conditioning to foot shock in Long-Evans rats, it has been described that conditioning to general (nondiscrete) contextual cues is greater in male rats relative to female rats, whereas conditioning to a discrete, predictive stimulis (CS) is not. These findings have been combined with evidence for greater levels of hippocampal LTP in males in Sprague-Dawley rats to derive a model of hippocampal-LTP-mediated contextual and not CS, fear conditioning. The present study reports on an analysis of the effect of sex in contextual and discrete CS conditioning to foot shock, assessed via measurement of freezing behavior in a novel automated paradigm, in three rat strains: Wistar, Fischer, and Lewis. In Wistar rats, there was a consistent but nonsignificant tendency for males to demonstrate both more contextual and more CS conditioning than females; in Fischer rats, males demonstrated both more contextual and more CS conditioning than females; in Lewis rats, a markedly enhanced acquisition of freezing in males did not translate into a sex difference in either context or CS conditioning at expression. Therefore, within each strain the effect of sex was consistent between context and CS conditioning. These findings, taken together with the hippocampal LTP evidence, suggest that the latter mediates both contextual and discrete CS aversive conditioning, and contributes to sex differences in both these forms of conditioning, in those strains where these sex differences exist.     

Effect of d-fenfluramine on human experimental anxiety

To investigate the role of 5-HT in human anxiety, the 5-HT releaser and uptake blockerd-fenfluramine (FEN) was administered to healthy volunteers under two models of experimental anxiety. The first was a simulated public speaking (SPS) test consisting of talking in front of a video camera, anxiety being evaluated mainly by self-rating scales. The second was a conditioned fear test, in which the changes in skin electrical conductance caused by a tone associated once with an aversive white noise were measured. The doses of 15 and 30 mg FEN, PO, decreased anxiety induced by SPS in a dose-dependent way, as indicated by the anxiety factor of Norris Visual Analogue Mood Scale. In the conditioned fear test, however, the amplitude and level of skin conductance responses to the conditioned aversive stimulus were not significantly changed by FEN. The differential effects of FEN in these human experimental models of anxiety, together with similar results reported in rats, support the view that 5-HT exerts a dual action on brain mechanisms regulating anxiety, facilitating conditioned while inhibiting unconditioned fear. The presumed reduction in unconditioned fear caused by FEN may have implications for the treatment of panic disorder.     

Lack of consistent behavioural effects of Maudsley reactive and non-reactive rats in a number of animal tests of anxiety and activity

RATIONALE: A number of previous studies have reported that the Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) strains of rats show behavioural and physiological differences consistent with the hypothesis that these strains differ in emotionality and could therefore be considered a model of trait anxiety in humans. OBJECTIVES: We sought to confirm this observation by determining their behaviour in various animal models of conditioned and unconditioned fear. METHODS: Both strains were evaluated in the open field (OF), conditioned avoidance (CA), elevated plus maze (EPM) and fear-potentiated startle (FPS) tests. In the OF the behaviour of both strains was consistent with previous results showing that reactive rats had significantly higher levels of defecation and lower levels of activity than the non-reactive rats. However, there were no significant strain differences in CA responses or in the time spent on the open arms of the EPM. In addition, the full benzodiazepine receptor agonist, chlordiazepoxide, induced quantitatively similar effects in both strains of rats. In the FPS test, MNRA/Hars had a higher baseline level of startle and fear potentiation than the MR/Har rats. CONCLUSIONS: These data show that the behaviour of MR/Har and MNRA/Har rats in some models of conditioned and unconditioned fear is inconsistent with that predicted by their behaviour in the OF test, suggesting that they are not a model of trait fear.     

Dopaminergic mechanisms in the conditioned and unconditioned fear as assessed by the two-way avoidance and light switch-off tests

The involvement of dopaminergic mechanisms in fear and anxiety is still unclear. Behavioral studies aimed to disclose the involvement of dopamine in anxiety have reported anxiolytic-like, anxiogenic-like and lack of effects with the use of dopaminergic agonists and antagonists in animal models of anxiety. This work was an attempt to contribute to this field by providing evidence that these discrepancies may be due to the kind of aversive situation the animals experience in these models. The present study examined the effects of a dopaminergic agonist apomorphine, a dopaminergic D(1) antagonist SCH 23390 and a D(2) receptor antagonist sulpiride on the two-way avoidance response test (CAR) and on the switch-off responses to light (SOR). In both tests, learning was assessed by the performance of the animals across four blocks of 10 trials in which light was paired to footshocks (CAR) or only light was presented to the animals (SOR). The obtained data show that rats learn to make a shuttling response to avoid the shock in the CAR test and maintain a regular pace of switch-off responses in the SOR. While sulpiride and SCH 23390 administrations prevented learning of the avoidance responses, apomorphine injections produced a dose-dependent enhancement in the conditioned learning in the CAR test. The number of escape responses was unchanged by these drugs. In the light-induced switch-off test, apomorphine reduced the number of switch-off responses whereas sulpiride increased these responses. These findings suggest that the involvement of dopaminergic mechanisms in threatening situations depends on the nature of the aversive stimulus. Activation of D(1) and D(2) receptors seems to be implicated in the heightened aversiveness to conditioned stressful situations, as assessed by the CAR test. Thus, blockade of D(1) and D(2) receptors may be necessary for attenuating the aversiveness triggered by these conditioned fear stimuli. In contrast, mechanisms mediated by D(2) receptors seem to be involved in the setting up of adaptive responses to innate fear reactions. Therefore, the signal of the modulatory dopaminergic mechanisms on defensive behavior will depend on the type of emotional stimuli triggering the coping reaction.     

MK-801 produces a reduction in anxiety-related antipredator defensiveness in male and female rats and a gender-dependent increase in locomotor behavior

The present study investigated the effects of the non-competitive NMDA antagonist MK-801 (0.04–0.16 mg/kg), on antipredator defensive reactions of male and female rats in three paradigms comprising the Anxiety/Defense Test Battery (A/DTB). In order to facilitate interpretation of data from the above study, the behavioral effects of the compound were also assessed in the non-threatening environment of the home cage. The data indicate a marked gender difference in the locomotor effects of the compound with females, but not males, showing a dose-dependent increase in general locomotor activity, a decrease in freezing, and a loss of balance at the highest dose, in both non-threatening and threatening contexts. The behavioral profile for males in the A/DTB included decreased orientation to and proxemic avoidance of the cat stimulus or stimulus site, and increased transits and eating in the cat situation. Contacts with the cat odor stimulus were increased, as was normal, curved back, locomotion in this test. In the absence of non-specific locomotor effects for males, this profile for the A/DTB provides convincing evidence for anxiety/fear reduction with MK-801. While locomotor effects tended to mask the putative anxiolytic properties of the compound in females, evidence remains from behavioral changes not attributable to a locomotor influence to indicate anxiety/fear reduction in this sex.Supported by NIH Grants MH42803 and RR03061     

High-alcohol-drinking rats exhibit persistent freezing responses to discrete cues following Pavlovian fear conditioning

We previously reported that high-alcohol-drinking (HAD) rats exhibited selective deficits in active avoidance learning and that those deficits were partially reversed by moderate doses of ethanol under certain training conditions [Pharmacol. Biochem. Behav. 75 (2003) 89]. In that study, we hypothesized that HAD deficits resulted from exaggerated fear in the conditioning context and that the anxiolytic properties of ethanol, along with prior exposure to the conditioning apparatus, were responsible for the facilitated avoidance learning that was observed in HAD rats following moderate doses of ethanol. The current study was designed to test whether HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts. We used a standard Pavlovian fear conditioning paradigm to assess behavioral freezing in HAD (HAD-1 and HAD-2) and low-alcohol-drinking (LAD; LAD-1 and LAD-2) rats. No significant differences were observed between HAD-1 and HAD-2 or between LAD-1 and LAD-2 rats, indicating that the replicate lines performed similarly in this study. Both HAD and LAD rats exhibited robust fear conditioning during training. Although no differences were observed between HAD and LAD rats during fear training, HAD rats failed to extinguish freezing behavior in response to the discrete tone conditional stimulus during subsequent fear retention tests. Thus, HAD rats demonstrated prolonged cue-elicited fear that was resistant to extinction.     

The use of cognitive enhancers in animal models of fear extinction

In anxiety disorders, such as posttraumatic stress disorders and phobias, classical conditioning pairs natural (unconditioned) fear-eliciting stimuli with contextual or discrete cues resulting in enduring fear responses to multiple stimuli. Extinction is an active learning process that results in a reduction of conditioned fear responses after conditioned stimuli are no longer paired with unconditioned stimuli. Fear extinction often produces incomplete effects and this highlights the relative permanence of bonds between conditioned stimuli and conditioned fear responses. The animal research literature is rich in its demonstration of cognitive enhancing agents that alter fear extinction. This review specifically examines the fear extinguishing effects of cognitive enhancers that act on gamma-aminobutyric acid (GABA), glutamatergic, cholinergic, adrenergic, dopaminergic, and cannabinoid signaling pathways. It also examines the effects of compounds that alter epigenetic and neurotrophic mechanisms in fear extinction. Of these cognitive enhancers, glutamatergic N-methyl d-aspartate (NMDA) receptor agonists, such as D-cycloserine, have enhanced fear extinction in a context-, dose- and time-dependent manner. Agents that function as glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonists, alpha2-adrenergic receptor antagonists (such as yohimbine), neurotrophic factors (brain derived neurotrophic factor or BDNF) and histone deacetylase inhibitors (valproate and sodium butyrate) also improve fear extinction in animals. However, some have anxiogenic effects and their contextual and temporal effects need to be more reliably demonstrated. Various cognitive enhancers produce changes in cortico-amygdala synaptic plasticity through multiple mechanisms and these neural changes enhance fear extinction. We need to better define the changes in neural plasticity produced by these agents in order to develop more effective compounds. In the clinical setting, such use of effective cognitive enhancers with cue exposure therapy, using compounds derived from animal model studies, provides great hope for the future treatment of anxiety disorders.     

Male and female C57BL/6 mice respond differently to diazepam challenge in avoidance learning tasks

Benzodiazepines (BZ) impair learning and memory performance of animals. The goal of this study was to examine sex differences in the effects of diazepam on learning and memory of C57BL/6 mice in avoidance paradigms. Male and female C57BL/6 mice were tested in the one-way active avoidance, step-down passive avoidance, and foot-shock pain threshold tasks, following administration of vehicle or diazepam (1 mg/kg). No substantial sex or drug effects on the threshold of the pain response to shock were found. There were no significant differences in avoidance performance between vehicle-treated male and female mice while 1 mg/kg of diazepam produced opposite effects on performance of males and females in both tasks. Diazepam-treated females learned faster in the active avoidance task and showed stronger retention in the passive avoidance task. In contrast, diazepam impaired learning of males in the active avoidance task and had no effect on their performance in the passive avoidance task. Diazepam-induced impairment in males was not due to higher sensitivity to the sedative effect of diazepam as females were more sedated than males on the first trial of the passive avoidance task. Our data showed that sedative and amnesic effects of BZs are not tightly linked. This study also suggests that cognitive effects of BZs in rodents could be sex dependent and highlight the importance of using both sexes in studies on behavioral effects of psychoactive drugs.     

The disruptive effects of the CB<Subscript>1</Subscript> receptor antagonist rimonabant on extinction learning in mice are task-specific

Rationale Disruption of CB₁ receptor signaling through the use of CB₁ (−/−) mice or the CB₁ receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB₁ (−/−) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task. Objectives The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks. Materials and methods Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session. Results Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task. Conclusions These results support the hypothesis that the CB₁ receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.     

Regulation of conditioned and unconditioned fear in rats by 5-HT1A receptors in the dorsal periaqueductal gray

Studies on the involvement of 5-HT1-mediated mechanisms in the dorsal periaqueductal gray (dPAG) of animals with past stressful experiences have not been conducted so far. We investigated the role of 5-HT1 receptors in the dPAG of rats previously submitted to contextual fear conditioning. Defensive behaviors induced by activation of the dPAG were assessed by measuring the lowest electric current applied to this structure (threshold) able to produce freezing and escape responses during testing sessions of contextual fear conditioning, in which animals were placed in a context previously paired to footshocks. The 5-HT1A function of the dPAG was evaluated by local injections of 8-OH-DPAT (4 and 8 nmol/0.2 microL) and WAY-100635 (10 nmol/0.2 microL), selective agonist and antagonist of 5-HT1A receptors, respectively. In accordance with previous studies, 8-OH-DPAT increased aversive thresholds (antiaversive effects) but injections of WAY 100635 into the dPAG did not produce significant effects on the aversive thresholds in naive rats. However, the aversive thresholds of animals exhibiting contextual fear remained unchanged with both treatments. Moreover, 8-OH-DPAT and WAY 100635 did not change the dPAG post-stimulation freezing. The present results suggest that the stressful experience of being fear conditioned has an effect on the role of the 5-HT1A receptors in mediating unconditioned fear. Also, the reduction in the regulation of the defensive behaviors by 5-HT1A-mediated mechanisms in the dPAG of these animals may underlie the stress precipitated psychopathology associated with the neural substrates of aversion of the dPAG.