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.     

Biphasic effects of ethanol tested with drug discrimination in HAD and LAD rats.

Seventh-generation selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats were trained to make differential responses for ethanol (0.75 g/kg, IP) and saline vehicle, following postadministration intervals (PI) of 2 min (HAD-2 and LAD-2 animals) and 30 min (HAD-30 and LAD-30 animals). ED50 values of 0.395 and 0.352 g/kg, respectively, for HAD-2 and LAD-2 animals and 0.269 and 0.314 g/kg, respectively, for HAD-30 and LAD-30 animals reflect the absence of any phenotypic difference for the discriminative stimulus effects of ethanol. HAD-2 animals were more responsive than LAD-2 animals to the stimulating effects of ethanol as measured by total response rates during training sessions. The differential ethanol response generalized to pentobarbital in all four groups but not to morphine, an alternative CNS depressant. The specific antagonist of 5-hydroxytryptamine3 receptors, 3-tropanyl-3,5-dichlorobenzoate (MDL 72222), up to doses of 14.0 mg/kg failed to antagonize the discriminative effects of ethanol. Ethanol sleep times did not differ between groups.     

LAD rats learn a three-key drug discrimination more rapidly and achieve a higher level of performance than HAD rats.

High-alcohol drinking (HAD1) and low-alcohol drinking (LAD1) rats were trained to discriminate among 0.75 g/kg ethanol, 1.5 g/kg ethanol and saline under a fixed-ratio 10 schedule. LAD rats learned the discrimination more rapidly than HAD rats, and asymptotic performance by LAD rats was better than that of HAD rats. The 0.75 g/kg dose of ethanol failed to control the responding of HAD rats, both when baseline responding stabilized and during the determination of an ethanol dose-response curve. These differences between LAD and HAD rats in ethanol discrimination were not observed in previous experiments using a two-choice procedure. The three-choice procedure may be useful for establishing strain differences in ethanol discrimination. These and previous experiments with alcohol-preferring rats suggest that the learning of an ethanol discrimination may be dissociable from voluntary ethanol consumption in rat strains bred selectively to consume ethanol.     

Daily patterns of ethanol drinking in adolescent and adult, male and female, high alcohol drinking (HAD) replicate lines of rats

The rationale for our study was to determine the pattern of ethanol drinking by the high alcohol-drinking (HAD) replicate lines of rats during adolescence and adulthood in both male and female rats. Rats were given 30 days of 24 h free-choice access to ethanol (15%, v/v) and water, with ad lib access to food, starting at the beginning of adolescence (PND 30) or adulthood (PND 90). Water and alcohol drinking patterns were monitored 22 h/day with a “lickometer” set-up. The results indicated that adolescent HAD-1 and HAD-2 males consumed the greatest levels of ethanol and had the most well defined ethanol licking binges among the age and sex groups with increasing levels of ethanol consumption throughout adolescence. In addition, following the first week of adolescence, male and female HAD-1 and HAD-2 rats differed in both ethanol consumption levels and ethanol licking behavior. Adult HAD-1 male and female rats did not differ from one another and their ethanol intake or licking behaviors did not change significantly over weeks. Adult HAD-2 male rats maintained a relatively constant level of ethanol consumption across weeks, whereas adult HAD-2 female rats increased ethanol consumption levels over weeks, peaking during the third week when they consumed more than their adult male counterparts. The results indicate that the HAD rat lines could be used as an effective animal model to examine the development of ethanol consumption and binge drinking in adolescent male and female rats providing information on the long-range consequences of adolescent alcohol drinking.     

Lack of difference between HAD and LAD rats in the stimulus generalization of ethanol to nicotine

High alcohol drinking (HAD) and low alcohol drinking (LAD) rats were trained to discriminate 0.5 g/kg ethanol from saline. HAD and LAD rats learned the discrimination at the same rate and to the same level of asymptotic performance. In substitution tests, increasing doses of ethanol produced increased responding on the ethanol lever with dose-effect curves that were very similar in HAD and LAD rats. There was no generalization from ethanol to nicotine, or d-amphetamine, in either HAD or LAD rats. These data may be contrasted with data obtained with alcohol preferring rats (P rats) and alcohol non-preferring rats (NP rats), where the ethanol discrimination was learned more rapidly, asymptotic performance was better in P than in NP rats, and ethanol discriminative stimulus generalized to nicotine and partially to d-amphetamine in P, but not in NP rats. These data suggest that the differences in ethanol consumption reported previously by P and HAD rats relative to NP and LAD rats is not necessarily related to strain differences in ethanol discrimination as the differences in ethanol discrimination previously observed between P and NP rats do not occur in HAD and LAD rats.     

Hypofunction of the dorsal hippocampal NMDA receptors impairs retrieval of memory to partially presented foreground context in a single-trial fear conditioning in rats.

In the present study, the effects of N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (AP5) bilaterally infused into the dorsal hippocampus (2.0 microl /5 microg), on the retrieval of fear memory to partial and whole foreground cues were evaluated by using a step-through passive avoidance and Pavlovian fear conditioning. In the both conditioning tasks, following a 30-s preshock exposure period to the shock-associated context, rats received a single shock in a foreground manner for fear memory exhibition by freezing. Rats with AP5 infusion 5 min before the retrieval tests showed profound freezing deficits either immediately or 48 h after the shock in the testing section of the passive avoidance chamber where foreground cues was partially presented. In the Pavlovian conditioning chamber where fear conditioning was tested in the whole of the context that was explicitly paired with the shock, AP5 rats in all infusion schedules exhibited robust freezing responses. These results showed that hypofunction of the hippocampal NMDA receptors impaired the retrieval of fear memory to partial, and not whole, foreground cues. This suggests that NMDA receptors of the hippocampus are involved in the formation of background context representations about foreground events when there is a deficit in perceiving certain sensory properties of the foreground retrieval cues.     

Scopolamine and Pavlovian fear conditioning in rats: dose-effect analysis.

Muscarinic-cholinergic antagonism produces learning and memory deficits in a wide variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia of contextual fear (fear of the place of conditioning), but do not impact fear conditioning to discrete cues (such as a tone). In order to examine the effects of muscarinic antagonism in this paradigm, rats were given 0.01 to 100 mg/kg of scopolamine (or methylscopolamine) either before or after a fear conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone were assessed by measuring freezing in separate tests. It was found that pretraining, but not post-training, scopolamine severely impaired fear conditioning; methylscopolamine was ineffective in disrupting conditioning. Although contextual fear conditioning was more sensitive to cholinergic disruption, high doses of scopolamine also disrupted tone conditioning. Scopolamine did not affect footshock reactivity, but did produce high levels of activity. However, hyperactivity was not directly responsible for deficits in conditioning. It was concluded that scopolamine disrupts CS-US association formation or CS processing, perhaps through an attenuation of hippocampal theta rhythm.     

Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning.     

Ethanol disrupts fear conditioning in C57BL/6 mice

Ethanol has been demonstrated to disrupt numerous forms of learning. For example, ethanol disrupts fear conditioning in rats. Surprisingly, the opposite result was reported for mice. Because of the importance of mouse models in ethanol research and the predominance of transgenic mice generated on a C57BL/6 background, the present study examined the effects of acute ethanol administration on fear conditioning in C57BL/6 mice. Fear conditioning was chosen because of the apparent contradiction in results between mice and rats, because of its popularity in assessing forebrain-dependent learning and because the task examines two types of learning: (i) the hippocampus-dependent contextual learning and (ii) the hippocampus-independent conditioned stimulus-unconditioned stimulus learning. Dose-response curves were generated for ethanol (0.5, 1.0 and 1.5 g/kg) given on either training day, testing day, or both days. Ethanol, in a dose-dependent manner, disrupted fear conditioning when given on training day or given on both training and testing days. Ethanol given on testing day only did not disrupt fear conditioning. The present results demonstrate that ethanol disrupts fear conditioning in C57BL/6 mice.     

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

Objective and rationale Alcohol and nicotine are commonly co-abused; one possible explanation for co-abuse is that each drug ameliorates the aversive effects of the other. Both drugs have dose-dependent effects on learning and memory. Thus, this study examined the interactive effects of acute ethanol and acute, chronic, or withdrawal from chronic nicotine on fear conditioning in C57BL/6J mice. Materials and methods Conditioning consisted of auditory conditioned stimulus-foot-shock unconditioned stimulus pairings. For acute studies, saline or ethanol, then saline or nicotine was administered before training, and saline or nicotine was also administered before testing. For chronic and withdrawal studies, saline or nicotine was administered chronically, and ethanol or saline was administered before training. Results Acute nicotine (0.09 mg/kg) reversed ethanol-induced deficits (1.0 and 1.5 g/kg) in contextual and cued fear conditioning, whereas a low dose of ethanol (0.25 g/kg) reversed nicotine (6.3 mg kg⁻¹ day⁻¹) withdrawal-induced deficits in contextual conditioning. Tolerance developed for the effects of nicotine on ethanol-induced deficits in conditioning and cross-tolerance between chronic nicotine and acute ethanol was seen for the enhancing effects of ethanol on conditioning. Conclusions The complex and sometimes polar actions of ethanol and nicotine on behavior may contribute to co-abuse of these drugs. Specifically, smoking may initially reduce the aversive effects of ethanol, but tolerance develops for this effect. In addition, low doses of alcohol may lessen nicotine withdrawal symptoms.     

Low dose quetiapine reverses deficits in contextual and cued fear conditioning in rats with excitotoxin-induced hippocampal neuropathy

Previous studies have demonstrated that adult rats with excitotoxic lesions of the hippocampus display deficits in memory-related behaviors similar to the memory deficits associated with schizophrenia. In this study, we assessed the sub-chronic effects of quetiapine, risperidone and haloperidol on performance deficits after intracerebroventricular administration of the excitotoxin, kainic acid, using paradigms for contextual and cued fear conditioning and spatial reversal learning in rats. The effects of three doses of quetiapine (5, 10 and 20 mg/kg) and single doses of risperidone (0.5 mg/kg) and haloperidol (0.15 mg/kg) were compared. Quetiapine administration at the lowest dose (5 mg/kg) reversed deficits in contextual and cued fear conditioning, but not deficits in spatial reversal learning, in kainic acid-treated animals. However, the two higher doses of quetiapine, and the single doses of risperidone and haloperidol, did not reverse any of the kainic acid-induced behavioral deficits. These results may be relevant to the effects of quetiapine and other antipsychotic drugs on memory deficits in patients with schizophrenia.     

Acquisition deficit and time-dependent retrograde amnesia for contextual fear conditioning in agmatine-treated rats

Cumulative evidence indicates that the hippocampus plays a time-limited role in contextual learning paradigms. Pharmacological studies have indicated that acquisition of background contextual cues during Pavlovian fear conditioning is dependent upon hippocampal function, whereas early inactivation of the hippocampus after training produces retrograde amnesia. When administered prior to contextual fear conditioning, agmatine (5 and 10 mg/kg, i.p.), an endogenous polyamine and N-methyl-D-aspartate (NMDA) receptor ligand found at excitatory synapses in the hippocampus, impaired the acquisition of contextual fear (measured as defensive freezing 26 hours later) without a reduction in baseline motor activity during training. Furthermore, ascending doses of agmatine were found not to exert analgesic effects on response thresholds to peripheral shock. This negated the possibility that the observed learning deficit resulted from a difference in perceived shock intensity. Post-training agmatine treatment produced a time-dependent impairment of consolidation, with subjects approaching a level of fear equivalent to that of a reference group as the delay of treatment increased (up to 6 hours). Since physiologically high levels of agmatine are able to inhibit NMDA receptor activity, these results suggest that polyamine modulation of NMDA receptors, most likely within the hippocampus, is required for the acquisition and consolidation of contextual fear stimuli.     

Erk activation in the amygdala and hippocampus induced by fear conditioning in ethanol withdrawn rats: Modulation by mk-801

The extracellular signal-regulated kinase (ERK) pathway, which can be activated by NMDA receptor stimulation, is involved in fear conditioning and drug addiction. We have previously shown that withdrawal from chronic ethanol administration facilitated the formation of contextual fear memory. In order to explore the neural substrates and the potential mechanism involved in this effect, we examined: 1) the ERK1/2 activation in the central (CeA) and basolateral (BLA) nuclei of the amygdala and in the dorsal hippocampus (dHip), 2) the effect of the NMDA receptor antagonist MK-801 on fear conditioning and ERK activation and 3) the effect of the infusion of U0126, a MEK inhibitor, into the BLA on fear memory formation in ethanol withdrawn rats.Rats made dependent via an ethanol-containing liquid diet were subjected to contextual fear conditioning on day 3 of ethanol withdrawal. High basal levels of p-ERK were found in CeA and dHip from ethanol withdrawn rats. ERK activation was significantly increased both in control (60 min) and ethanol withdrawn rats (30 and 60 min) in BLA after fear conditioning. Pre-training administration of MK-801, at a dose that had no effect on control rats, prevented the increase in ERK phosphorylation in BLA and attenuated the freezing response 24 h later in ethanol withdrawn rats. Furthermore, the infusion of U0126 into the BLA, but not the CeA, before fear conditioning disrupted fear memory formation. These results suggest that the increased fear memory can be linked to changes in ERK phosphorylation, probably due to NMDA receptor activation in BLA in ethanol withdrawn rats.     

Fluoxetine protects hippocampal plasticity during conditioned fear stress and prevents fear learning potentiation

Rationale Contextual fear conditioning can produce both changes in hippocampal synaptic efficacy and potentiation of subsequent fear learning. Objectives In this study, we tested whether fluoxetine reverses these effects. Materials and methods In the first experiment, we examined alterations of baseline synaptic efficacy and induction of synaptic plasticity in the CA3 region of the hippocampus during re-exposure of rats, treated with fluoxetine (7 mg/kg) or vehicle, in a context where they previously received 15 eyelid shocks or no shock (controls). In the second experiment, fear learning potentiation was examined in rats that were initially submitted to conditioning (15 eyelid shocks) and extinction training and then re-exposed to a less intense stressor (three eyelid shocks). Results Conditioned fear stress decreased synaptic efficacy and blocked the induction of synaptic potentiation in the fimbria–CA3 pathway. Conditioned rats treated with fluoxetine were protected against these electrophysiological changes and did not differ from controls (i.e., no depression and normal induction of potentiation of synaptic efficacy). However, fluoxetine treatment did not suppress conditioned freezing. After fear extinction, exposure of rats to a subconditioning stressor provoked conditioning (fear learning potentiation) in rats treated with vehicle but not in those treated with fluoxetine. Conclusions These findings indicate that fluoxetine treatment, which is ineffective on conditioned fear stress-induced freezing, may have beneficial effects on conditioned fear stress-induced disturbance of hippocampal plasticity. These data also suggest that restoration of hippocampal functioning may contribute to protection against exaggerated reactions to mild stressors reported in patients with post-traumatic stress disorder.     

Learning and memory in rats exposed pre- and postnatally to alcohol. An attempt at pharmacological control

Using conditioned-reflex methods for active and passive avoidance with punishment reinforcement, we found pronounced memory deficits in 12-week old rats exposed perinatally to alcohol (FAS rats). Impairment of memory was observed not only with the high dose of 9 g ethanol/kg body weight (ingested with tap water in a 6% solution) to which dams were exposed during pregnancy and lactation, but also with the ten-fold lower dose of 1 g ethanol/kg body weight (0.6% ethanol). The nootropic drugs citicholine, piracetam and meclofenoxate administered orally for five days before the training session were effective in decreasing memory deficits; particularly pronounced was the effect of piracetam and meclofenoxate. The benzodiazepine tranquilizer diazepam additionally impaired learning and memory in FAS rats. It is suggested that nootropics could be used to decrease the cognitive disturbances in some humans born to alcoholic mothers.     

Pharmacological dissociation of moderate and high contextual fear as assessed by freezing behavior and fear-potentiated startle.

The amplitude of the whole-body acoustic startle response is reliably enhanced when elicited in the presence of foreground signals, such as light, previously paired with footshocks. It has been shown that this enhancement is evident by moderate fear levels, but is less affected by high fear levels. Potentiation of the acoustic startle reflex has also been reported in the presence of background cues previously associated with footshocks. However, the effects of anxiolytic drugs on different levels of fear elicited by moderate and intense contextual fear conditioning associated with startle reflex have not been examined yet. To approach this issue, we examined the effects of the anxiolytic, midazolam, on two intensities of contextual fear; freezing behavior and the startle response to loud noise. First, we compared the magnitude of the freezing behavior and the startle amplitude during the testing sessions in groups of rats submitted to fear conditioning using 0.3 and 0.6 mA as unconditioned stimuli (10 stimuli of 1 s each, intertrial interval from 60 to 180 s). Afterwards, the effects of midazolam (0.5 and 1.0 mg/kg) were assessed in these two conditions. Rats showed a potentiated startle reflex and a significant freezing behavior to moderate fear conditioning, which were both attenuated by midazolam. Higher levels of fear conditioning caused more intense freezing behavior without enhancing the startle reflex. Whereas midazolam reduced this freezing response, the startle response was unaffected. These results are indicative that anxiolytic-sensitive freezing and fear-potentiated startle are triggered by moderate contextual fear conditioning, while contextual conditioning with the use of high footshocks causes a distinct pattern of behavioral responses, which is only partially affected by midazolam. Due to the differential sensitivity to midazolam of these two patterns of startle responses generated as a function of the intensity of contextual fear conditioning, it is proposed that they represent moderate and intense aversive states that may be related to anxiety or panic/phobic conditions, respectively.     

氯胺酮单次注射对创伤后应激障碍模型动物场景恐惧行为的影响及机制

目的在大、小鼠创伤后应激障碍(PTSD)模型上评价氯胺酮单次预防给药对大、小鼠场景恐惧表达的影响,并基于脑源性神经营养因子(BDNF)表达调节研究其作用机制。方法建立小鼠条件性恐惧和大鼠时间依赖性敏化(TDS)2种PTSD动物模型,在条件性恐惧训练前不同时间点进行不同剂量的单次给药,采用僵住行为测试评价氯胺酮在2个模型上对场景恐惧的影响。在小鼠条件性恐惧模型中,训练前0.5 h单次预防性给予氯胺酮10 mg·kg-1,分别于造模训练后24 h和第14天取脑,采用Western印迹法检测大脑皮质BDNF的表达。结果行为学测试结果表明,在小鼠条件性恐惧模型上,氯胺酮10 mg·kg-1分别在训练前第7天、24 h和0.5 h单次预防给药,训练后24 h场景恐惧测试中各组小鼠僵住时间百分率无明显差异;而训练前0.5 h单次预防性ip氯胺酮10 mg·kg-1,在训练后第14天显著降低小鼠僵住时间百分率(P<0.05);在大鼠TDS模型上,条件性恐惧训练前0.5 h单次ip氯胺酮10 mg·kg-1可显著降低TDS大鼠僵住次数百分率(P<0.05)。Western印迹结果显示,在训练后24 h和第14天,与正常对照组相比,模型组小鼠大脑皮质BDNF表达均显著降低(P<0.05);训练前0.5 h给予氯胺酮10 mg·kg-1组,在训练后24 h和第14天小鼠皮质BDNF的表达较模型组均显著升高(P<0.05)。结论氯胺酮单次预防性给药可减少小鼠场景恐惧的表达,该作用与给药剂量有关,且具有延迟起效的特点,但延迟起效作用与恐惧记忆形成后大脑皮质BDNF表达改变在时间上不具有一致性;氯胺酮单次给药可降低TDS增敏的大鼠场景恐惧的表达,此作用与给药时间点密切相关。     

Time-dependent deficits in delay conditioning produced by trimethyltin

Trimethylin (TMT) produces behavioral and cognitive deficits resulting, in part, from limbic system toxicity. To determine whether these effects result from learning deficits or accelerated memory loss, the present experiment examined two delay conditioning paradigms in rats previously treated with either saline or TMT. Saline-treated Long-Evans rats receiving injections of lithium after consuming saccharin-flavored water later avoided saccharin ingestion: the degree of avoidance varied inversely with the time (0.5, 3 or 6 h) separating initial saccharin availability and lithium injection. Rats treated with TMT (8 mg/kg IV, 30 days prior) showed impaired conditioning at the long but not the short or intermediate delay conditions, suggesting that the deficits were mnemonic and not associative. Similar delay-dependent deficits in rats treated with TMT were observed in a passive avoidance task that arranged one of two delays between response emission and shock delivery during training. The effects of TMT on delay conditioning were accompanied by reduced bodyweight and hippocampal pathology. In summary, TMT appears to alter the temporally dependent association of events (entering darkened compartment versus saccharin consumption) and consequences (foot shock versus lithium administration) during acquisition. Furthermore, the observed deficits in delay conditioning produced by TMT did not appear to be task specific, with similar effects determined with tests of both somatosensory and gustatory avoidance learning designed to distinguish between functional alterations due to deficits in memorial processes from those due to altered sensory, motor, or associative processes.Although the research described in this article has been supported by the United States Environmental Protection Agency (through contract 68-02-4450 to NSI — Environmental Sciences), it has not been subjected to Agency review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. A preliminary report of these data was given at the 1987 annual meeting of the Society of Toxicology, Washington, DC     

Effects of acute and subchronic treatments with fluoxetine and desipramine on the memory of fear in moderate and high-intensity contextual conditioning

Selective serotonin and noradrenalin reuptake inhibitors such as fluoxetine and desipramine, respectively, are efficacious in the treatment of depression and chronic stress. Although they inhibit the reuptake of the biogenic monoamines soon after administration, therapeutic improvements occur only after 2 or 3 weeks. Freezing response and potentiated startle are common responses to moderate fear contextual conditioning. However, freezing but not startle is increased in rats that undergo intense fear conditioning. In this study, we evaluated the effects of acute and subchronic administration of fluoxetine and desipramine on these responses in testing sessions, as indices of fear in moderate and high fear conditioning. Fluoxetine did not show any significant effect on the moderate fear conditioning but reduced freezing and restored the startle response in rats under intense fear conditioning. In comparison, desipramine had no effect on the startle response when administered acutely or subchronically while freezing of the intense fear conditioning was reduced. Our findings indicate that intense contextual fear conditioning is sensitive to subchronic treatment with fluoxetine and resistant to desipramine. Fluoxetine appears to restore the serotoninergic function in brain areas recruited by intense contextual fear conditioning. These effects of fluoxetine may underlie its reported efficacy in the pharmacotherapy of panic disorders.     

Mnemonic effects of testosterone and its 5alpha-reduced metabolites in the conditioned fear and inhibitory avoidance tasks

Experiments were conducted to examine whether performance in hippocampally-mediated learning tasks is influenced by testosterone (T) and/or its 5alpha-reduced metabolites, dihydrotestosterone (DHT) and 3alpha-androstanediol (3alpha-diol). Performance in the conditioned fear and inhibitory avoidance tasks were examined in intact and gonadectomized (GDX), androgen-replaced rats. In Experiment 1, the behavior of intact and GDX rats in the conditioned fear paradigm were compared. GDX rats spent more time freezing, an index of increased learning, in the context, hippocampally-mediated task, but not in the cued, amygdala-mediated task. In Experiment 2, GDX rats were administered T, DHT, 3alpha-diol, estrogen (E2), or vehicle 1 mg/kg sc after training in the conditioned fear paradigm. T-, 3alpha-diol-, or E2-, compared with vehicle-administered rats, spent significantly more time freezing in the contextual, but not the cued, condition. In Experiment 3, intact compared with GDX rats had significantly longer crossover latencies, indicating better performance, in the inhibitory avoidance task. In Experiment 4, T, DHT, 3alpha-diol, or vehicle 1 mg/kg sc was administered to GDX rats immediately following training in the inhibitory avoidance task. Rats administered T, DHT, or 3alpha-diol had significantly longer crossover latencies compared with vehicle controls. In Experiment 5, androgen levels in the hippocampus were elevated 1 h following administration, when androgen exposure is essential for consolidation. These data indicate that androgens effects to enhance learning may be mediated in part by actions of 5alpha-reduced metabolites in the hippocampus.