Chlordiazepoxide microinjected into the region of the dorsal raphe nucleus eliminates the interference with escape responding produced by inescapable shock whether administered before inescapable shock or escape testing.

Systemic administration of benzodiazepines before exposure to inescapable shock (IS) blocks the enhanced fear conditioning and escape learning deficits that follow exposure to IS, whereas administration before the subsequent behavioral testing eliminates the enhanced fear but not the interference with escape (N?=?44 male rats). The failure of benzodiazepines to reduce the IS-produced escape learning deficit when given before testing is inconsistent with a recent proposal that interference with escape is mediated by an IS-induced sensitization of dorsal raphe nucleus (DRN) activity. The present experiments demonstrate that chlordiazepoxide will block both the enhancement of fear and interference with escape responding when given before either IS or testing if microinjected in the region of the DRN. This suggests that systemic benzodiazepines fail to block escape deficits when given before testing because action at a site distant from the DRN counters the effect of the drug at the DRN. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The dorsal raphe nucleus is a site of action mediating the behavioral effects of benzodiazepine receptor inverse agonist DMCM.

Systemic administration of benzodiazepine receptor inverse agonists leads to behavioral changes similar to those produced by inescapable shock (IS). The dorsal raphe nucleus (DRN) is a critical structure mediating IS effects. The present experiments determined whether the DRN is a site mediating the behavioral changes produced by benzodiazepine receptor inverse agonists. Microinjection of the inverse agonist Methyl 6,7-Dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in the region of the DRN produced enhancement of fear conditioning as assessed by the amount of freezing in the presence of shock cues as well as interference with shuttlebox escape learning assessed 24 hr later. Furthermore, lesion of the DRN blocked the effects of systemic DMCM on fear conditioning and escape learning. These data suggest that the DRN is indeed critical in mediating these behavioral consequences of DMCM and further support a role for the DRN in producing the behavioral changes induced by IS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inescapable shock-induced potentiation of morphine analgesia in rats: involvement of opioid, GABAergic, and serotonergic mechanisms in the dorsal raphe nucleus

Exposure of rats to inescapable shock (IS) potentiated the analgesic response to a low dose (1 mg/kg) of morphine 24 hr later. This effect was blocked by naltrexone (10 micrograms), diazepam (5 micrograms), or 8-hydroxy-2-(di-n-propylamine)-tetralin (8-OH-DPAT; 1 microgram) microinjected into the dorsal raphe nucleus (DRN) 15 min before IS. When microinjected into the DRN at the time of tail-flick testing, 8-OH-DPAT also effectively prevented this effect. Further, intra-DRN administration of a beta-carboline mimicked the effects of IS, because rats treated with methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (1 microgram) and simply restrained displayed potentiated morphine analgesia 24 hr later. These data suggest that this phenomenon shares mechanisms in common with other effects of IS at the level of the DRN.     

Role of fear in mediating shuttle escape learning deficit produced by inescapable shock.

The relation between the shuttlebox escape deficit produced by prior inescapable shock (IS) and fear during shuttlebox testing as assessed by freezing was investigated in rats. IS rats learned to escape poorly and were more fearful than either escapably shocked subjects or controls, both before and after receiving shock in the shuttlebox. However, fear and poor escape performance did not covary with the manipulation of variables designed to modulate the amount of fear and the occurrence of the escape deficit. A 72-hr interval between IS and testing eliminated the escape deficit but did not reduce preshock freezing. Diazepam before testing reduced both preshock and postshock fear in the shuttlebox but had no effect on the escape deficit. Naltrexone had no effect on fear but eliminated the escape deficit. This independence of outcome suggests that the shuttlebox escape deficit is not caused by high levels of fear in IS subjects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock

It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hr after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the escape learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed.     

Corticosterone is involved in foot shock-induced inactivity in rats

Inescapable shock (IS) exposure induces behavioral inactivity, related to behavioral alterations in subsequent tests (i.e., escape failure, and inactivity during shuttle box task). Metyrapone (150 mg/kg, IP), a corticosterone (CS) synthesis inhibitor, administered 3 h prior to IS reduced inactivity during this aversive experience. Forty-eight hours later, when these rats were submitted to a shuttle box task, a reduction in both escape failure and inactivity was observed. These effects were reversed by CS (20 mg/kg, SC) and dose dependent of the synthetic glucocorticoid dexamethasone, both administered 1 h before IS. When metyrapone was administered 3 h before the shuttle box task to IS-exposed animals, escape failures and inactivity were markedly reduced. This effect was subsequently reversed by CS. The dynamics of changes in serum CS concentrations after both IS and shuttle box task paralleled behavioral changes. Animals injected with metyrapone before IS, which displayed active behavior, showed serum CS levels stable at their basal levels after shock, and their secretion pattern was quite attenuated after the shuttle box task, whereas vehicle-, CS alone-, and metyrapone + CS-injected animals showed higher serum CS concentrations post-IS, which slowly decreased to their corresponding basal levels. CS secretion after the shuttle box task was similar for the three groups: it had the same magnitude as after IS, though the decrease was faster. In all groups, animals displayed passive behavior. These results indicate that glucocorticoids are involved in the onset and expression of passive behaviors induced by uncontrollable stressors. Therefore, it is possible to suggest a functional relationship between CS released by exposure to inescapable stressor and the behavioral strategies adopted by rats under this stressful condition.     

Effects of Exercise on Pavlovian Fear Conditioning.

Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic immobilization stress alters aspects of emotionality and associative learning in the rat.

Chronic stress significantly alters limbic neuroarchitecture and function, and potentiates emotionality in rats. Chronic restraint stress (CRS) increases aggression among familiar rats, potentiates anxiety, and enhances fear conditioning. Chronic immobilization stress (CIS) induces anxiety behavior and dendritic hypertrophy in the basolateral amygdala, which persist beyond a recovery period. However, little else is known about the emotional impact of CIS as a model of chronic stress or depression. Therefore, the authors present two experiments examining emotional and learned responses to CIS. In Experiment I, the authors examine individual differences in behaviors during and after CIS, specifically: struggling, aggression, learned helplessness, inhibitory avoidance, and escape behavior. In Experiment II, the authors confirm the effects of CIS on aggression and struggling during immobilization, and correlate individual responses with aspects of conditioned fear. Here the authors report significant effects of CIS on aggression, inhibitory avoidance, escape, as well as learned aspects of fear (i.e., fear conditioning) and inescapable stress (i.e., struggling and helplessness). These results emphasize the emotional and learned responses to CIS evident during and after the stress treatment, as well as the importance of individual differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Studies on the neuronal circuits involved in the discriminative stimulus effects of 5-hydroxytryptamine1A receptor agonists in the rat

Rats were trained to discriminate 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, 1.25 mg/kg i.p.), a selective and nonselective 5-hydroxytryptamine1A (5-HT, serotonin) receptor agonist, respectively, from saline in a two-lever procedure. The selective 5-HT1A receptor agonist ipsapirone substituted completely for 8-OH-DPAT (ED50, 1.52 mg/kg) and 5-OMe-DMT substituted partially for 8-OH-DPAT, whereas 8-OH-DPAT (ED50, 0.07 mg/kg) and ipsapirone (ED50, 4.15 mg/kg) substituted completely for 5-OMe-DMT. These results suggest that the discriminative stimulus properties of both 8-OH-DPAT and 5-OMe-DMT are 5-HT1A receptor mediated, although 5-OMe-DMT may involve an additional interaction with other 5-HT receptor subtypes. 5-OMe-DMT substituted for 8-OH-DPAT after application in the lateral ventricle (ED50, 3.0 micrograms/rat) and the dorsal raphe nucleus (DRN, 1.1 micrograms/rat). After application in the DRN (ED50 range, 1.4-5.0 micrograms/rat) and the median raphe nucleus (2.3 micrograms/rat), and after bilateral application into the CA-4 region of the dorsal hippocampus (4.1 micrograms/rat), 8-OH-DPAT also produced responding on the 8-OH-DPAT lever. Ipsapirone also substituted for 8-OH-DPAT after application into the DRN and the hippocampus (ED50S, 38 and 62 micrograms/rat, respectively). The 5-HT1A mixed agonist-antagonist (1-(2-methoxyphenyl) 4-[4-(2-pthalimido)butyl]piperazine, i.p. NAN-190) attenuated the discriminative stimulus effects of 8-OH-DPAT injected i.p. (0.1 mg/kg), into the DRN (10 micrograms) or into the hippocampus (2 x 10 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chemical Lesion of the Bed Nucleus of the Stria Terminalis Blocks the Behavioral Consequences of Uncontrollable Stress.

Uncontrollable or inescapable shock (IS) produces behavioral changes that are characterized by a sensitized fear system and a deficit in fight-flight responding. These behavioral changes have been argued to represent an anxiety-like state produced by the uncontrollability of the stressor. The bed nucleus of the stria tenninalis (BNST) has been implicated in the mediation of long-duration responses to unpredictable stressors, which have also been argued to represent anxiety. In the present study, the effects of BNST chemical lesion on the IS-induced sensitization of freezing to an environment previously paired with shock and the IS-induced impairment of escape responding were investigated. BNST chemical lesion blocked the potentiation of freezing and the increases in escape latency that normally follow IS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of intra-amygdaloid infusions of a D? dopamine receptor antagonist on Pavlovian fear conditioning.

The present study examined the effects of bilateral intra-amygdaloid infusions of the D? receptor antagonist, eticlopride, on the acquisition and expression of Pavlovian fear conditioning as measured by freezing to acoustic and background contextual stimuli in the rat. Infusions of eticlopride before acquisition or before both acquisition and retention testing significantly attenuated conditioned freezing to tone presentations during the retention test 24 hr later. No effects, however, were observed on freezing that emerged during acquisition. Furthermore, these effects were not attributable to state-dependent learning effects or alterations in baseline activity or shock reactivity. In conclusion, these results suggest that amygdaloid dopamine transmission at D? receptors contributes to the formation and/or consolidation of fear memories (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modafinil and memory: Effects of modafinil on Morris water maze learning and Pavlovian fear conditioning.

Modafinil has been shown to promote wakefulness and some studies suggest the drug can improve cognitive function. Because of many similarities, the mechanism of action may be comparable to classical psychostimulants, although the exact mechanisms of modafinil's actions in wakefulness and cognitive enhancement are unknown. The current study aims to further examine the effects of modafinil as a cognitive enhancer on hippocampus-dependent memory in mice. A high dose of modafinil (75 mg/kg ip) given before training improved acquisition on a Morris water maze. When given only before testing, modafinil did not affect water maze performance. We also examined modafinil (0.075 to 75 mg/kg) on Pavlovian fear conditioning. A low dose of pretraining modafinil (0.75 mg/kg) enhanced memory of contextual fear conditioning (tested off-drug 1 week later) whereas a high dose (75 mg/kg) disrupted memory. Pretraining modafinil did not affect cued conditioning at any dose tested, and immediate posttraining modafinil had no effect on either cued or contextual fear. These results suggest that modafinil's effects of memory are more selective than amphetamine or cocaine and specific to hippocampus-dependent memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Shock controllability and opioid substrates of escape performance and nociception: Differential effects of peripherally and centrally acting naltrexone.

In 2 experiments with 104 male albino rats, Ss exposed to inescapable shock (IS) exhibited analgesia and a significant impairment of shock-escape learning in a shuttlebox situation 24 hrs later. In contrast, Ss exposed to escapable shock (ES) or to no shock (NS) displayed neither effect. Subcutaneous naltrexone HCl (10 mg/kg) significantly reduced the analgesia and completely eliminated the escape deficit in IS Ss, but it induced hyperalgesia and hampered escape performance in ES and NS Ss. The same dose of naltrexone methylbromide (quaternary naltrexone), which has low ability to cross the blood-brain barrier, had no effect on either the antinociception or the escape deficit produced by IS, although it also induced escape impairment and hyperalgesia in Ss preexposed to ES or to NS. Both the escape interference and the antinociceptive consequences of IS could be reduced partially by a much lower dose (1 mg/kg) of naltrexone, but 50 times this amount of quaternary naltrexone was still without effect. Results imply that the consequences of exposure to IS are mediated by activation of central opioid processes, whereas naltrexone-induced effects in ES and NS Ss may be peripherally mediated. (64 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential regulation of somatodendritic serotonin 5-HT1A receptors by 2-week treatments with the selective agonists alnespirone (S-20499) and 8-hydroxy-2-(Di-n-propylamino)tetralin: microdialysis and autoradiographic studies in rat brain

Single treatment with the serotonin (5-hydroxytryptamine) 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and alnespirone (S-20499) reduces the extracellular 5-HT concentration (5-HText) in the rat midbrain and forebrain. Given the therapeutic potential of selective 5-HT1A agonists in the treatment of affective disorders, we have examined the changes in 5-HT1A receptors induced by 2-week minipump administration of alnespirone (0.3 and 3 mg/kg/day) and 8-OH-DPAT (0.1 and 0.3 mg/kg/day). The treatment with alnespirone did not modify baseline 5-HText but significantly attenuated the ability of 0.3 mg/kg s.c. alnespirone to reduce 5-HText in the dorsal raphe nucleus (DRN) and frontal cortex. In contrast, the ability of 8-OH-DPAT (0.025 and 0.1 mg/kg s.c.) to reduce 5-HText in both areas was unchanged by 8-OH-DPAT pretreatment. Autoradiographic analysis revealed a significant reduction of [3H]8-OH-DPAT and [3H]WAY-100635 [3H-labeled N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexa necarboxamide x 3HCl] binding to somatodendritic 5-HT1A receptors (but not to postsynaptic 5-HT1A receptors) of rats pretreated with alnespirone but not with 8-OH-DPAT. In situ hybridization analysis revealed no change of the density of the mRNA encoding the 5-HT1A receptors in the DRN after either treatment. These data indicate that continuous treatment for 2 weeks with alnespirone, but not with 8-OH-DPAT, causes a functional desensitization of somatodendritic 5-HT1A receptors controlling 5-HT release in the DRN and frontal cortex.     

Laryngeal tuberculosis and laryngeal cancer

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT could be prevented by either selective D1-type or D2-type dopamine receptor antagonists. In three experiments, male Wistar rats (250-350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D2-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D1-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D2-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms.     

Factors governing single-trial contextual fear conditioning in the weanling rat.

Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The authors adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that N-methyl-D-aspartate (NMDA) receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intrahippocampal infusions of a metabotropic glutamate receptor antagonist block the memory of context-specific but not tone-specific conditioned fear.

The role of metabotropic glutamate receptors (mGluRs) in the acquisition of learning and memory using fear conditioning as a behavioral model was examined. The mGluR antagonist (R,S)-α-methyl-4-carboxyphenylglycine (MCPG) was infused into the hippocampus 30 min before fear conditioning, and freezing was measured during both acquisition and retention tests. The results show that pretraining antagonism of MCPG-sensitive mGluRs in the hippocampus impaired context-specific memory for an aversive event during testing. The memory for tone-specific fear, however, remained intact despite pretraining infusion of MCPG. Treating rats with MCPG did not affect context- or tone-specific fear during acquisition. Results suggest that mGluR activation may play an important role in hippocampally mediated memory consolidation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of the behavioral effects of 8-OH-DPAT by estrogen and DOI

The effects of female gonadal hormones on 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced flat body posture, hypothermia, and eating behavior were examined. Ovariectomized rats were injected with estradiol benzoate, estradiol benzoate, and progesterone, progesterone or vehicle on each of 2 consecutive weeks. On each week, the behavioral effects of the 5-HT1A receptor agonist, 8-OH-DPAT, or the combination of both 8-OH-DPAT and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2 receptor agonist, were examined. 8-OH-DPAT produced flat body posture, hypothermia, and eating behavior on each week of the experiment. Female gonadal hormones modulated eating behavior (e.g., rats treated with estradiol benzoate showed less eating after 8-OH-DPAT), but had no effect on either flat body posture or hypothermia. The 5-HT2 receptor agonist, DOI, attenuated 8-OH-DPAT's effect on flat body posture and on hypothermia, but not on eating behavior. 8-OH-DPAT's effect on all behaviors declined during the second week of the experiment.     

Modeling signal features of escape response: Effects of cessation conditioning in "learned helplessness" paradigm.

Six experiments examined the effects of signaling the termination of inescapable shock (cessation conditioning) or shock-free periods (backward conditioning) on later escape deficits in the learned helplessness paradigm, using rats (Sprague-Dawley and Bantin–Kingman). A cessation signal prevented later performance deficits when highly variable inescapable shock durations were used during pretreatment. The inclusion of short minimum intertrial intervals during pretreatment did not alter the benefits of cessation conditioning but eliminated the protection afforded by a safety signal. The beneficial effects of both cessation and backward signals were eliminated when a single stimulus signaled shock termination and a shock-free period. Finally, a combination of cessation and backward signals was found to be most effective in immunizing against the effects of subsequent unsignaled, inescapable shock on later escape performance. These data suggest that cessation conditioning may be crucial to the prophylactic action of an escape response. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Predator odor-induced conditioned fear involves the basolateral and medial amygdala.

The basolateral (BLA) and medial nucleus (MeA) of the amygdala participate in the modulation of unconditioned fear induced by predator odor. However, the specific role of these amygdalar nuclei in predator odor-induced fear memory is not known. Therefore, fiber-sparing lesions or temporary inactivation of the BLA or MeA were made either prior to or after exposure to cat odor, and conditioned contextual fear behavior was examined the next day. BLA and MeA lesions produced significant reductions in cat odor-induced unconditioned and conditioned fear-related behavior. In addition, temporary pharmacological neural inactivation methods occurring after exposure to cat odor revealed subtle behavioral alterations indicative of a role of the BLA in fear memory consolidation but not memory retrieval. In contrast, the MeA appears to play a specific role in retrieval but not consolidation. Results show that the BLA participates in the conditioned and unconditioned cat odor stimulus association that underlies fear memory, underscore a novel role of the MeA in predator odor contextual conditioning, and demonstrate different roles of the BLA and MeA in modulating consolidation and retrieval of predator odor fear memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)