Pre-exposed Rats Research Articles

Audible pain squeaks can mediate emotional contagion across pre-exposed rats with a potential effect of auto-conditioning

Footshock self-experience enhances rodents’ reactions to the distress of others. Here, we tested one potential mechanism supporting this phenomenon, namely that animals auto-condition to their own pain squeaks during shock pre-exposure. In Experiment 1, shock pre-exposure increased freezing and 22 kHz distress vocalizations while animals listened to the audible pain-squeaks of others. In Experiment 2 and 3, to test the auto-conditioning theory, we weakened the noxious pre-exposure stimulus not to trigger pain squeaks, and compared pre-exposure protocols in which we paired it with squeak playback against unpaired control conditions. Although all animals later showed fear responses to squeak playbacks, these were weaker than following typical pre-exposure (Experiment 1) and not stronger following paired than unpaired pre-exposure. Experiment 1 thus demonstrates the relevance of audible pain squeaks in the transmission of distress but Experiment 2 and 3 highlight the difficulty to test auto-conditioning: stimuli weak enough to decouple pain experience from hearing self-emitted squeaks are too weak to trigger the experience-dependent increase in fear transmission that we aimed to study. Although our results do not contradict the auto-conditioning hypothesis, they fail to disentangle it from sensitization effects. Future studies could temporarily deafen animals during pre-exposure to further test this hypothesis.

Pre-Exposure to Environmental Enrichment Protects against Learning and Memory Deficits Caused by Infrasound Exposure.

With the development of industrialization in recent years, infrasound has become an important component of public noise. To date, diverse studies have revealed the negative effects of infrasound on the central nervous system (CNS), especially the learning and memory ability. It is widely reported that environmental enrichment (EE) ameliorates the learning and memory deficits in different models of brain injury. Therefore, the present study was designed to determine the possible benefits of pre-exposure to EE in preventing functional deficits following infrasound exposure and their related mechanism. Adult male rats were given enriched or standard housing for 30 days. Following enrichment, the rats were exposed to 16 Hz, 130 dB infrasound for 14 days, and then their learning and memory ability was assessed. Changes to neuroinflammation, apoptosis, and oxidative stress in the hippocampus were also detected. Our results showed that the infrasound-induced deficit in learning and memory was attenuated significantly in EE pre-exposed rats. Pre-exposure to EE could induce a decrease in proinflammatory cytokines and increased anti-inflammatory cytokines and antioxidant properties in the hippocampus. Moreover, pre-exposure to EE also exerted antiapoptosis functions by upregulating the B-cell lymphoma/leukemia-2 (Bcl-2) level and downregulating the P53 level in the hippocampus. In conclusion, the results of the present study suggested that EE is neuroprotective when applied before infrasound exposure, resulting in an improved learning and memory ability by enhancing antioxidant, anti-inflammatory, and antiapoptosis capacities.

Transfer of Odor Perception From the Retronasal to the Orthonasal Pathway.

Although orthonasal odorants are often associated with the external environment, retronasal odorants are accompanied by consummatory behaviors and indicate an internal state of an animal. Our study aimed to examine whether the same odorants may generate a consistent perceptual experience when 2 olfactory routes potentiate variations in concentration in the nasal cavity and orosensory activation. A customized lick spout with vacuum removing odorants around the animal's nares was used to render a pure retronasal exposure experience. We found that pre-exposing rats to odorants retronasally with positive or negative reinforcers (sweet or bitter) lead to a significant learning rate difference between high- and low-vapor-pressure odorants. This effect was not observed for novel odorants, suggesting that odorants may generate similar perceptual quality in a volatility-dependent manner.

Oleic Acid Prevents Isoprenaline-Induced Cardiac Injury: Effects on Cellular Oxidative Stress, Inflammation and Histopathological Alterations.

The present study was designed to assess the cardio-protective role of oleic acid in myocardial injury (MI) induced by intra-peritoneal injection of isoprenaline (ISO) in rats for 2 consecutive days. Oleic acid (OA) was administered orally (@ 5mg/kg b.wt and 10mg/kg b.wt) for 21days before inducing MI. Pre-exposure to OA at higher dose significantly improved the HW/BW ratio, myocardial infarct size, lipid profiles (total cholesterol, HDL-C) and cardiac injury biomarkers (LDH, CK-MB, cardiac troponin-I, MMP-9), thus suggesting its cardio-protective role. The ameliorative potential of the higher dose of OA was further substantiated by its ability to reduce the cardiac oxidative stress as evidenced by significant decrease in lipid peroxidation coupled with increase in superoxide dismutase activity and reduced glutathione level. Significant decrease in heart rate as well as increase in RR and QT intervals in oleic acid pre-exposed rats were also observed. OA pre-treatment also reduced the histopathological alterations seen in myocardial injury group rats. The mRNA expression of cardiac UCP-2 gene, a regulator of reactive oxygen species (ROS) generation, was significantly increased in oleic acid pre-exposure group compared to the ISO-induced myocardial injury group. Thus increase in expression of UCP-2 gene in cardiac tissue seems to be one of the protective measures against myocardial injury. Based on the above findings, it may be inferred that oleic acid possesses promising cardio-protective potential against myocardial injury due to its anti-oxidative property and ability to modulate cardiac metabolic processes.

Repeated Cocaine Exposure Attenuates the Desire to Actively Avoid: A Novel Active Avoidance Runway Task.

Drug addiction is a disorder in which drug seeking persists despite aversive consequences. While it is well documented in animal models of drug sensitization that repeated drug exposure enhances positive incentive motivation for drug and natural reinforcers, its effect on negative incentive motivation, defined here as the motivation to avoid a cued aversive outcome, remains an open question. In the present study, we designed a novel active avoidance (AA) runway paradigm to assess the effects of repeated cocaine exposure on the motivation to avoid an aversive outcome. Cocaine and saline pre-exposed rats were first trained to perform a conditioned AA lever press response to prevent the occurrence of foot shock administrations. The rats were subsequently tested in a runway apparatus, wherein they were required to traverse the length of a straight alley maze to reach the lever and emit a conditioned AA response. Run times were measured as an indication of negative incentive motivation. Cocaine pre-exposed rats demonstrated longer latencies to emit the conditioned AA response but showed no differences in latency to initiate runway behavior, nor in their acquisition of the AA response compared to the saline pre-exposed controls. Subsequent testing in an elevated plus maze revealed no differences in the expression of anxiety in cocaine pre-exposed rats compared to saline pre-exposed controls. Our results indicate that prior repeated cocaine exposure attenuated cued negative incentive motivation, which suggests that drug addiction may be attributable to a decrease in motivation to avoid aversive consequences associated with drug use.

Effects of amphetamine exposure during adolescence on behavior and prelimbic cortex neuron activity in adulthood

Repeated exposure to psychostimulants during adolescence produces long-lasting changes in behavior that may be mediated by disrupted development of the mesocorticolimbic dopamine system. Here, we tested this hypothesis by assessing the effects of amphetamine (AMPH) and dopamine receptor-selective drugs on behavior and neuron activity in the prelimbic region of the medial prefrontal cortex (PFC). Adolescent male, Sprague-Dawley rats were given saline or 3 mg/kg AMPH between postnatal day (P) 27 and P45. In Experiment 1, locomotor behavior was assessed during adulthood following challenges with a dopamine D1 (SKF 82958) or D2 (quinpirole) receptor-selective agonist. In Experiment 2, pre-exposed rats were challenged during adulthood with AMPH and a D1 (SKF 83566) or D2 (eticlopride) receptor-selective antagonist. In Experiment 3, the activity of putative pyramidal cells in the prelimbic cortex was recorded as rats behaved in an open-field arena before and after challenge injections with AMPH and one of the antagonists. We found that compared to controls, adolescent pre-exposed rats were more sensitive to the stimulant effects of AMPH and the dopamine receptor agonists, as well as to the ability of the antagonists to reverse AMPH-induced stereotypy. Prelimbic neurons from AMPH pre-exposed rats were also more likely to respond to an AMPH challenge in adulthood, primarily by reducing their activity, and the antagonists reversed these effects. Our results suggest that exposure to AMPH during adolescence leads to enduring adaptations in the mesocorticolimbic dopamine system that likely mediate heightened response to the drug during adulthood.

Behavioral predictors of alcohol drinking in a neurodevelopmental rat model of schizophrenia and co-occurring alcohol use disorder

Alcohol use disorder commonly occurs in patients with schizophrenia and contributes greatly to its morbidity. Unfortunately, the neural and behavioral underpinnings of alcohol drinking in these patients are not well understood. In order to begin to understand the cognitive and reward-related changes that may contribute to alcohol drinking, this study was designed to address: 1) latent inhibition; 2) conditioning; and 3) extinction of autoshaping in a neurodevelopmental rat model with relevance to co-occurring schizophrenia and alcohol use disorders, the neonatal ventral hippocampal lesioned (NVHL) rat. NVHL lesions (or sham surgeries) were performed on post-natal day 7 (PND7) and animals were given brief exposure to alcohol during adolescent (PND 28–42). Latent inhibition of autoshaping, conditioning and extinction were assessed between PND 72–90. On PND90 animals were given alcohol again and allowed to establish stable drinking. Latent inhibition of autoshaping was found to be prolonged in the NVHL rats; the NVHL rats pre-exposed to the lever stimulus were slower to acquire autoshaping than sham pre-exposed rats. NVHL rats that were not pre-exposed to the lever stimulus did not differ during conditioning, but were slower to extinguish conditioned responding compared to sham controls. Finally, the NVHL rats from both groups drank significantly more alcohol than sham rats, and the extent of latent inhibition predicted future alcohol intake in the pre-exposed animals. These findings suggest that the latent inhibition of autoshaping procedure can be used to model cognitive- and reward-related dysfunctions in schizophrenia, and these dysfunctions may contribute to the development of co-occurring alcohol use.

Antipsychotic drug-like facilitation of latent inhibition by a brain-penetrating neurotensin-1 receptor agonist.

Latent inhibition (LI) is a measure of cognitive gating and refers to reduced conditioned learning when there is pre-exposure to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (US). Dysregulation of LI is associated with some neuropsychiatric disorders, including schizophrenia, and the ability to facilitate LI in rodents is a reasonably good predictive test for antipsychotic drugs. Converging evidence supports neurotensin-1 receptor (NTS1) agonists as novel drugs for schizophrenia. Therefore, we investigated the ability of a brain-penetrating, selective NTS1 agonist, PD149163, to facilitate LI in heterozygous Brattleboro rats, a strain that exhibits naturally low LI. Conditioned taste aversion to flavored water (FW; 0.1% saccharin) was induced by pairing it with malaise-inducing injections of lithium chloride (LiCl). Prior to LiCl-FW pairing, rats received subcutaneous injections of saline, or PD149163 (100 µg/kg or 200 µg/kg). Half the rats in each drug group had been allowed to drink FW the day before the LiCl-FW pairing (pre-exposed rats). Two days after pairing, the amount of FW each rat consumed was recorded. LI, defined as significantly greater FW drinking in the pre-exposed group compared with the non pre-exposed group, was exhibited only among rats that received 200 µg/kg of PD149163. These results further support NTS1 agonists as potentially novel drugs for the treatment of schizophrenia.

Effects of oxytocin on methamphetamine-seeking exacerbated by predator odor pre-exposure in rats.

The endogenous oxytocin system has emerged as an inhibitor of drug-seeking and stress in preclinical models. The goal of this study was to examine whether systemic oxytocin administration attenuated methamphetamine (METH)-seeking in rats pre-exposed to a predator odor threat. In Experiment 1, rats were exposed for 5 days to the predator odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), or saline before METH self-administration began. After extinction training, rats were injected with 1 mg/kg, ip oxytocin (OXT) or saline 30 min before a cue-induced reinstatement test followed by re-extinction and a TMT-induced reinstatement test. In Experiment 2, TMT pre-exposure was followed by 10 days of 1 mg/kg OXT or saline injections before METH self-administration, extinction, and a TMT-induced reinstatement test. In Experiment 1, TMT pre-exposed rats that were injected with saline 30 min before reinstatement exhibited greater drug-seeking induced by conditioned cues or TMT than that exhibited by saline pre-exposed rats. A single injection of OXT 30 min before reinstatement suppressed METH-seeking in both saline- and TMT pre-exposed rats. In Experiment 2, TMT pre-exposed rats that received saline injections for 10 days prior to METH self-administration exhibited enhanced drug-seeking induced by TMT during stress-induced reinstatement. OXT injections for 10 days prior to METH self-administration blocked only the stress-induced exacerbation of drug-seeking in TMT pre-exposed rats. These results support further research on the development of oxytocin as a novel therapeutic drug that has enduring effects on drug-seeking exacerbated by stress.

Potentiation of the expression of cocaine-induced sensitization by a conditioned stressor

Repeated exposures to physical stressors cross-sensitize to the locomotor activating effects of psychostimulants in rodents. In the present study, we examined the effect of a conditioned stressor on expression of cocaine-induced sensitization in rats. We determined whether a mint odor cue previously paired with footshock stress (FS) would elicit a sensitized locomotor response in cocaine pre-exposed rats. Rats were given once daily injections of cocaine (30mg/kg, i.p.) or saline for 6 days in activity monitoring chambers. Subsequently, and in a different and distinct context, equal numbers of rats in each drug condition were exposed to 10min of brief, intermittent FS or no FS, either in the presence or absence of the mint odor cue. Upon re-exposure to the activity chambers (in which cocaine exposures had been given), all rats previously exposed to cocaine showed robust conditioned locomotion. In response to a cocaine challenge (10mg/kg, i.p.), cocaine relative to saline pre-exposed rats showed a sensitized locomotor response. Finally, in those cocaine pre-exposed rats that had been given prior odor-FS pairings, concurrent delivery of the cocaine challenge and presentation of the odor cue markedly potentiated the expression of sensitization. To our knowledge, this is the first report of a facilitation of cocaine-induced locomotor sensitization by a conditioned stressor.

Effects of circadian disruption on methamphetamine consumption in methamphetamine-exposed rats.

A substantial number of clinical studies indicate associations between sleep abnormalities and drug abuse; however, the role played by the circadian system in the development of addiction is largely unknown. The aim of this study was to examine the effects of experimentally induced chronic jet lag on methamphetamine consumption in a rat model of methamphetamine drinking. Male Sprague-Dawley rats (n = 32) were housed in running wheel cages in a 12:12h light:dark cycle. One group of rats (n = 16) was given 2weeks of forced methamphetamine consumption (0.01% in drinking water; meth pre-exposed) while a second group (n = 16, not pre-exposed) received water only. This was followed by a 2-week abstinence period during which half of the animals from each group were exposed to four consecutive 6-h advancing phase shifts of the light:dark cycle, while the other half remained on the original light:dark cycle. Methamphetamine consumption was assessed in all rats following the deprivation period using a two-bottle choice paradigm. Methamphetamine consumption was initially lower in methamphetamine pre-exposed versus not pre-exposed rats. However, during the second week following abstinence, consumption was significantly higher in phase-shifted rats of the methamphetamine pre-exposed group compared to all other groups. These data reveal an effect of circadian rhythm disturbance on methamphetamine consumption and suggest that dysregulation of the circadian system be considered in the etiology of relapse and addiction.

Impulsive choice, alcohol consumption, and pre-exposure to delayed rewards: II. Potential mechanisms.

In a prior study (Stein et al., 2013), we reported that rats pre-exposed to delayed rewards made fewer impulsive choices, but consumed more alcohol (12% wt/vol), than rats pre-exposed to immediate rewards. To understand the mechanisms that produced these findings, we again pre-exposed rats to either delayed (17.5 s; n=32) or immediate (n=30) rewards. In posttests, delay-exposed rats made significantly fewer impulsive choices at 15- and 30-s delays to a larger, later food reward than the immediacy-exposed comparison group. Behavior in an open-field test provided little evidence of differential stress exposure between groups. Further, consumption of either 12% alcohol or isocaloric sucrose in subsequent tests did not differ between groups. Because Stein et al. introduced alcohol concentration gradually (3-12%), we speculate that their group differences in 12% alcohol consumption were not determined by alcohol's pharmacological effects, but by another variable (e.g., taste) that was preserved as an artifact from lower concentrations. We conclude that pre-exposure to delayed rewards generalizes beyond the pre-exposure delay; however, this same experimental variable does not robustly influence alcohol consumption.

Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs

BackgroundPeripherally administered oxytocin (OT) has produced antipsychotic drug (APD)-like effects in animal tests that are predictive of APD efficacy. However, these effects have mainly been demonstrated using animal models of schizophrenia-like deficits in prepulse inhibition (PPI) of the startle reflex. Another schizophrenia-relevant abnormality that is the basis of a predictive animal test for APD efficacy is deficient latent inhibition (LI). LI is the normal suppression of a classically conditioned response when the subject is pre-exposed to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (UCS). Conditioned taste aversion (CTA), the normal avoidance of ingesting a food or liquid by animals when its taste is associated with an aversive experience, was used to test whether OT facilitates LI consistent with APDs. MethodsBrown Norway rats, known to naturally display attenuated LI, were aversively conditioned on two consecutive exposures to flavored drinking water (0.1% saccharin) by pairing it with malaise-inducing lithium chloride injections. Concurrent with conditioning, rats received subcutaneous OT (0.02, 0.1, 0.5mg/kg) or saline. Some rats were pre-exposed to the flavored water prior to its aversive conditioning (pre-exposed) while others were not (non pre-exposed). Two days after aversive conditioning the amount of flavored water consumed during a 20-min session was recorded. ResultsAs expected, LI, defined as greater consumption by pre-exposed vs. non pre-exposed rats was only weakly exhibited in Brown Norway rats and OT enhanced LI by reducing CTA in pre-exposed rats in a dose-dependent manner, with the 0.02mg/kg dose producing the strongest effect. ConclusionsThe facilitation of LI by OT is consistent with the effects produced by APDs and provides further support for the notion that OT has therapeutic potential for schizophrenia.

Age of exposure-dependent effects of amphetamine on behavioral flexibility

Drug use typically begins during adolescence, which is a period of ongoing neurobiological development that may confer heightened vulnerability to develop drug dependence. Previously, our lab has shown that amphetamine (AMPH)-induced deficits in a medial prefrontal cortex (mPFC)-sensitive working memory task are greater in rats exposed to the drug during adolescence compared to adulthood. Here, we examine potential age-dependent effects of AMPH exposure on behavioral flexibility tasks that are sensitive to disruptions in mPFC and orbitofrontal cortex (OFC) function. Male Sprague-Dawley rats were injected (i.p.) with saline or 3mg/kg AMPH every other day between postnatal days (PNDs) 27–45 and PNDs 85–103. Starting around PND 125, rats were tested in an attentional set-shifting task and a subset of those was then tested in an operant strategy shifting task. Following completion of the operant task, rats were challenged with 3mg/kg AMPH and monitored in open field chambers. Our results demonstrate that AMPH-exposed rats were faster to acquire simple and compound discriminations, but were impaired during the first stimulus-reward reversal when compared to controls. In the operant strategy shifting task, adolescent-exposed rats shifted more rapidly between strategies and completed reversals faster than adult-exposed and control rats, respectively. The final AMPH challenge revealed evidence for sensitization in drug pre-exposed rats, with adult-exposed animals exhibiting the most significant effects. Together, these results suggest that AMPH induces long-lasting changes in behavioral flexibility that are at least partially dependent on age of exposure and may be due to adaptations in OFC function.

Environmental enrichment protects against functional deficits caused by traumatic brain injury

Environmental enrichment (EE) increases cortical weight, neuronal density, dendritic branching, and angiogenesis, all of which may be critical for functional recovery following insult. Our study was designed to determine possible benefits of pre-exposure to EE in preventing functional deficits following traumatic brain injury (TBI) to the prefrontal cortex. To examine the benefit of EE, adult male rats were placed in an enriched environment for 15 days. Enrichment was provided through social interaction, exercise, olfactory stimulation, and new objects/toys to explore. Following enrichment, experimental and age-matched controls were subjected to a moderate medial prefrontal cortex injury via controlled cortical impact (CCI). After 1 week recovery, animals were behaviorally tested to assess memory, anxiety, and sensory neglect. Lesion-induced deficits in spatial memory [Morris water maze (MWM)] were significantly attenuated in EE pre-exposed rats 18–21 days following injury. In addition, TBI-induced sensory neglect was significantly reduced in EE rats relative to non-enriched animals. No differences in anxiety-like behavior on the elevated plus maze (EPM) were detected. The behavioral data suggest that EE is neuroprotective when applied prior to TBI, resulting in improved recovery following injury.

Lesion of medial prefrontal dopamine terminals abolishes habituation of accumbens shell dopamine responsiveness to taste stimuli

Taste stimuli increase extracellular dopamine (DA) in the nucleus accumbens (NAc) and in the medial prefrontal cortex (mPFC). This effect shows single-trial habituation in NAc shell but not in core or in mPFC. Morphine sensitization abolishes habituation of DA responsiveness in NAc shell but induces it in mPFC. These observations support the hypothesis of an inhibitory influence of mPFC DA on NAc DA. To test this hypothesis, we used in vivo microdialysis to investigate the effect of mPFC 6-hydroxy-dopamine (6-OHDA) lesions on the NAc DA responsiveness to taste stimuli. 6-OHDA was infused bilaterally in the mPFC of rats implanted with guide cannulae. After 1 week, rats were implanted with an intraoral catheter, microdialysis probes were inserted into the guide cannulae, and dialysate DA was monitored in NAc shell/core after intraoral chocolate. 6-OHDA infusion reduced tissue DA in the mPFC by 75%. Tyrosine hydroxylase immunohistochemistry showed that lesions were confined to the mPFC. mPFC 6-OHDA lesion did not affect the NAc shell DA responsiveness to chocolate in naive rats but abolished habituation in rats pre-exposed to the taste. In the NAc core, mPFC lesion potentiated, delayed and prolonged the stimulatory DA response to taste but failed to affect DA in pre-exposed rats. Behavioural taste reactions and motor activity were not affected. The results indicate a top-down control of NAc DA by mPFC and a reciprocal relationship between DA transmission in these two areas. Moreover, habituation of DA responsiveness in the NAc shell is dependent upon an intact DA input to the mPFC.

Effects of acupuncture on stress-induced relapse to cocaine-seeking in rats

Cocaine addiction is associated with high rates of relapse, and stress has been identified as a major risk factor. We have previously demonstrated that acupuncture reduces drug self-administration and dopamine release in the nucleus accumbens (NAc), a brain structure implicated in stress-induced reinstatement of drug-seeking behavior. This study was conducted to investigate the effects of acupuncture on footshock-induced reinstatement of cocaine-seeking and the expression of c-Fos and the transcription factor cAMP response element-binding protein (CREB) in the NAc, used as markers of neuronal activation in conditions of stress-induced reinstatement to cocaine. Male Sprague-Dawley rats were trained to self-administer cocaine (1.0 mg/kg) for 14 days, followed by extinction and then footshock stress. Acupuncture was applied at bilateral Shenmen (HT7) points for 1 min after footshock stress. Acute footshock stress reinstated cocaine-seeking behavior and enhanced c-Fos expression and phosphorylated CREB (pCREB) activation in the NAc shell in cocaine pre-exposed rats. On the other hand, acupuncture at HT7, but not at control point (LI5), markedly reduced reinstatement of cocaine-seeking (86.5 % inhibition vs. control value), c-Fos expression (81.7% inhibition), and pCREB activation (79.3% inhibition) in the NAc shell. These results suggest that acupuncture attenuates stress-induced relapse by regulating neuronal activation in the NAc shell.

Opioid-induced latent sensitization in a model of non-inflammatory viscerosomatic hypersensitivity

Exposure to opioids can induce a state of “latent sensitization” characterized by long-lasting enhanced responses to subsequent cutaneous injury. Here, we explored the possibility that prior treatment with morphine could induce a state of latent sensitization to visceral pain conditions. Following butyrate enemas to induce non-inflammatory visceral pain, acute morphine administration produced dose-related inhibition of referred viscerosomatic hypersensitivity. Treatment with morphine for a period of six days resulted in a persistent hyperalgesia that resolved many days after termination of drug administration. In morphine pre-exposed rats, butyrate-induced referred hypersensitivity was enhanced and extended in duration. No differences were observed in the morphine dose–response curve in suppression of acute nociception (i.e., the hot-plate assay) when morphine pre-exposed rats were compared to naïve rats indicating that opioid antinociceptive tolerance was not present. However, the morphine dose–response curve to suppress evoked viscerosomatic hypersensitivity was displaced to the right by approximately 4-fold in morphine pre-exposed rats. Induction of viscerosomatic hypersensitivity resulted in an increased labeling of CGRP-, but not substance P-positive cells in the lumbar dorsal root ganglia; increased labeling was not affected by prior exposure to morphine. The data indicate that a period of morphine exposure can induce a state of “latent sensitization” to subsequent visceral pain characterized by extended duration of hypersensitivity. This condition likely reflects enhanced visceral “pain” intensity as a consequence of persistent pronociceptive adaptive changes.

Repeated exposure attenuates the behavioral response of rats to static high magnetic fields

Exposure of rats to high strength static magnetic fields of 7 T or above has behavioral effects such as the induction of locomotor circling, the suppression of rearing, and the acquisition of conditioned taste aversion (CTA). To determine if habituation occurs across magnetic field exposures, rats were pre-exposed two times to a 14 T static magnetic field for 30 min on two consecutive days; on the third day, rats were given access to a novel 0.125% saccharin prior to a third 30-min exposure to the 14 T magnetic field. Compared to sham-exposed rats, pre-exposed rats showed less locomotor circling and an attenuated CTA. Rearing was suppressed in all magnet-exposed groups regardless of pre-exposure, suggesting that the suppression of rearing is more sensitive than other behavioral responses to magnet exposure. Habituation was also observed when rats underwent pre-exposures at 2–3 h intervals on a single day. Components of the habituation were also long-lasting; a diminished circling response was observed when rats were exposed to magnetic field 36 days after 2 pre-exposures. To control for possible effects of unconditioned stimulus pre-exposure, rats were also tested in a similar experimental design with two injections of LiCl prior to the pairing of saccharin with a third injection of LiCl. Pre-exposure to LiCl did not attenuate the LiCl-induced CTA, suggesting that 2 pre-exposures to an unconditioned stimulus are not sufficient to explain the habituation to magnet exposure. Because the effects of magnetic field exposure are dependent on an intact vestibular apparatus, and because the vestibular system can habituate to many forms of perturbation, habituation to magnetic field exposure is consistent with mediation of magnetic field effects by the vestibular system.

Phenotype of hepatic xenobiotic metabolizing enzymes and CYP450 isoforms of sanguinarine treated rats: Effect of P450 inducers on its toxicity

Catalytic and immunochemical activities of cytochrome P450 (CYP) isoforms were investigated in argemone alkaloid, sanguinarine (SAN) intoxicated rats, pre-treated with different CYP inducers. SAN treated control (CON) and ethanol (ET), 3- methylcholantherene (MC) or dexamethasone (DEX) pre-exposed rats, resulted in 48, 64, 47 and 33% decrease in CYP content. SAN exposure to CON, and DEX, MC or ET pre-treated animals caused a decrease (22-37%) in glutathione-S-transferase (GST) activity, however, quinone reductase (QR) activity decreased (26–45%) in the MC pre-exposed group. Similarly, western-blot analysis of hepatic CYP1A1 and CYP1A2 showed a decrease (27–37%) in MC pre-treated SAN exposed animals. Further, a decrease in mortality in the SAN+MC (25%) group compared to SAN treated animals was also observed. The results suggest that inhibition of CYP 1A1, 1A2, 2D1, 2E1, 3A1, and Phase II enzymes by SAN augments its toxicity, whereas attenuation of SAN toxicity by MC may be due to removal of parent compound/metabolites from the body.