Acoustic startle, conditioned startle potentiation and the effects of 8-OH-DPAT and buspirone in rats selectively bred for differences in 8-OH-DPAT-induced hypothermia.

HDS and LDS rats are the result of selective breeding for differences in the hypothermic effects of the 5-hydroxytryptamine-1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); HDS (high DPAT sensitivity) rats exhibit a much greater hypothermic response than do LDS (low DPAT sensitivity) rats. It is possible that this genetically-based difference in sensitivity to the hypothermic effects of the 5-HT1A agonist is associated with a change in other behaviours modulated by 5-HT neurotransmission. The present study examined the acoustic startle response, the classically conditioned enhancement of startle, and the effects of 8-OH-DPAT and buspirone treatments on these measures, in HDS and LDS rats. On four test sessions, HDS and LDS rats were exposed to 20 acoustic startle stimuli (115 dB; 40 ms in duration). For each test session, 10 trials were presented in the dark (Noise Alone trials) and 10 were presented at the end of a 3500 ms presentation of a 15 W signal light (Light + Noise trials). LDS rats exhibited greater startle amplitude than did HDS rats on Noise Alone trials. Initially, there was no difference in startle amplitude on the Light + Noise versus Noise Alone trials in either LDS or HDS rats. By the end of the first test session, however, and continuing throughout the remainder of the four test sessions, startle amplitude on the Light + Noise trials was significantly greater than in the Noise Alone trials. The magnitude of this startle-potentiated startle (SPS) effect did not differ in HDS versus LDS rats. SPS testing was continued for three additional sessions; in these sessions the effects of acute treatment with the 8-OH-DPAT (125 microg/kg, subcutaneously (s.c.)), the novel anxiolytic buspirone (4 mg/kg, intraperitoneally (i.p.)) or vehicle (distilled water) were determined. Both 8-OH-DPAT and buspirone treatment increased baseline (Noise Alone) startle amplitude in LDS rats but not in HDS rats. With respect to the conditioned enhancement of startle, buspirone reduced the SPS effect in both HDS and LDS rats, whereas 8-OH-DPAT did not change the conditioned enhancement effect in either rat line. These findings suggest that the selective breeding for differences in 8-OH-DPAT-induced hypothermia has resulted in changes in other behaviours and also changes in the response to 5-HT1A agonist treatment. Moreover, these findings are consistent with the hypotheses that: (a) 5-HT1A agonist actions underlie the buspirone-induced and 8-OH-DPAT-induced increases in Noise Alone startle amplitude; whereas (b) the buspirone-induced reduction in potentiated startle is not the result of 5-HT1A agonist actions of this compound.

A nonextinction procedure for long-term studies of classically conditioned enhancement of acoustic startle in the rat.

In the Fear-Potentiated Startle (FPS) paradigm, the reflexive response to a noise burst is enhanced when it is presented with a stimulus (typically a light) that previously had been paired with the presentation of an aversive stimulus, usually an electric shock. In the FPS paradigm, the conditioned effect is demonstrated under conditions of extinction, i.e., the light is not paired with the shock during FPS testing. Because of this, the FPS paradigm is of somewhat limited value as a longitudinal measure for studying classically conditioned enhancement of acoustic startle. The present studies report a simple and reliable nonshock procedure for studying classically conditioned potentiation of acoustic startle in the rat that does not utilize testing under conditions of extinction. Naive rats were exposed to 5-or 3-days/week startle test sessions for up to 20 weeks. Twenty (20) startle stimuli (115 dB noise bursts; 40 ms in duration) were presented during each session. Half of these startle stimuli were presented in darkness and half were immediately preceded by a 3500-ms presentation of a 15-W light. With this paradigm, the effects of pairing the light with the startle noise burst could be studied across many test sessions in the absence of extinction training. The light did not increase startle amplitude on the first few startle trials of the first test session. By the end of the first session, however, and continuing for many weeks of testing, startle responses in the presence of the light were significantly greater (by 30-40%) than in the absence of the light. The finding that the startle stimulus itself can serve as an unconditioned stimulus (UCS) to enhance subsequent startle responses replicates an earlier finding. The persistence of this Startle-Potentiated Startle (SPS) effect across multiple weeks of testing is in contrast to that earlier report.

Conflict behavior and the effects of 8-OHDPAT treatment in rats selectively bred for differential 5-HT(1A)-induced hypothermia.

The high DPAT sensitivity (HDS) and low DPAT sensitivity (LDS) rat lines are the result of selective breeding for differences in the hypothermic response to acute treatment with the 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetralin (8-OHDPAT). The HDS rats exhibit a much greater hypothermic response than do the LDS rats. The present study examined conflict anxiety-like behavior and the effects of acute challenges with 8-OHDPAT and phenobarbital (PhB) on conflict behavior in HDS and LDS rats. Water-restricted (24-h deprivation) HDS and LDS rats were trained to drink from a tube that was occasionally electrified. The 5-s bouts of drinking tube electrification occurred on a fixed interval (FI) 30-s schedule and were signaled by the presence of a tone. Under this schedule, responding is suppressed approximately 10-fold during the tone-on periods compared to the no-tone periods. After two weeks of training in this repeated measures drink suppression conflict paradigm, the effects of acute challenges with 8-OHDPAT (30-500 microg/kg, SC, +10 min) or PhB (20 mg/kg, IP, +10 min) were determined. In control (i.e. , non-drug) conflict test sessions, rats of the HDS line accepted significantly fewer shocks than did rats of the LDS line. Acute treatment with 8-OHDPAT resulted in a modest increase in punished responding (maximum increase: +30-40 shocks/session) in both lines at doses of 60 and 125 microg/kg. Higher doses produced significant general behavioral disruption and substantial reductions in water intake (unpunished responding) in both HDS and LDS rats. Neither the increase in shocks received nor the decrease in water intake produced by these 8-OHDPAT challenges differed between HDS and LDS rats. In both lines, acute PhB treatment resulted in a more dramatic increase in punished responding than did 8-OHDPAT (+55-65 shocks/session) and an increase in water intake. The effects of PhB also did not differ between HDS and LDS rats. These data suggest that the HDS and LDS rats exhibit differences in baseline anxiety-like behavior in the conflict task, but do not differ in their response to acute challenges with PhB or 8-OHDPAT.

Acoustically elicited behaviours in Lister hooded and Wistar rats.

It has been reported previously that experimenter-presented 20-kHz tones at low intensities produce bursts of locomotor running in Lister hooded rats, but reduced locomotion (freezing) in Wistar rats. Because rats emit 20-kHz tones when stressed, it was proposed that this ultrasound-elicited running and freezing behaviour in Lister hooded and Wistar rats, respectively, represents a model for qualitative strain differences in fear behaviour. The present studies examined the acoustic specificity of acoustically elicited locomotor behaviours in Lister hooded and Wistar rats. In Experiment 1, it was found that brief exposure (i.e., 15 s) of Lister hooded rats to tones at frequencies of 7, 12, or 20 kHz and intensities of 85-95 dB SPL, elicited running behaviour characterised by brief bursts of locomotion followed by periods of quiescence. Somewhat surprisingly, the 7- and 12-kHz tones elicited running behaviour at lower intensities than did the 20-kHz tones. In Experiment 2, it was found that exposure of Lister hooded rats to the 20-kHz acoustic stimulus (91-101 dB, SPL) for a much longer duration, up to 9 min, resulted in episodic bursts of locomotion and convulsions in a significant proportion of subjects. Both the maximal velocity of locomotion and the likelihood of occurrence of convulsions was related to the intensity of the acoustic stimulus. Exposure of Lister hooded rats to white noise for up to 9 min also elicited episodic bursts of locomotion and convulsions in an intensity-dependent manner. The white noise stimulus was found to be a more effective stimulus than the 20-kHz stimulus in this regard. In Experiment 3, it was found that Lister hooded rats exhibited reduced locomotion when they were exposed to a low-intensity 20-kHz acoustic stimulus (e.g., 81 dB, SPL). In Experiment 4, it was found that Wistar rats did not exhibit locomotor bursts or convulsions when presented with 20-kHz tones using stimulus parameters equal to and even greater than those that had been shown to be effective in producing locomotor bursts in Lister hooded rats. Rather, Wistar rats exhibited only reduced locomotion. The present data indicate that (1) running behaviour in Lister hooded rats is not specific for the 20-kHz stimulus. Moreover, (2) when compared to Lister hooded rats, Wistar rats are relatively insensitive to the running and convulsions elicited by acoustic stimuli. Finally, (3) both Lister hooded and Wistar rats exhibited reduced locomotion when presented with the 20-kHz tones, although the range of stimulus intensities that produces freezing behaviour is much more limited in Lister hooded rats because of their propensity to exhibit locomotor bursting and convulsions. Thus, it appears that the difference between the two strains with respect to their unconditioned locomotor responses to novel acoustic stimuli relates to the fact that Lister hooded rats are uniquely susceptible to acoustically elicited locomotor bursts and/or convulsions.

Effects of chronic low-level oral lead exposure on prepulse inhibition of acoustic startle in the rat.

Previous work has suggested that the behavioral effects of chronic low-level lead exposure on fixed interval (FI) operant behavior result from enhanced dopaminergic neurotransmission in the nucleus accumbens (Cory-Slechta et al., J Pharmacol Exp Ther 286: 794-805, 1998). The present studies were designed to further characterize the effects of chronic low-level oral lead exposure on another behavior that is modulated by dopaminergic neurotransmission in the nucleus accumbens. In these studies acoustic startle and the prepulse inhibition (PPI) of startle were studied in rats following chronic low-level oral lead exposure. Weanling male rats were treated for 5-6 weeks with lead via drinking water (250 ppm lead acetate; controls drank 250 ppm sodium acetate). Acoustic startle reactivity (95, 105, and 115 dB noise bursts) and PPI (prepulses of 1-8 dB over the 70-dB background) of startle were tested following lead exposure. Lead exposure did not affect body weight. Lead exposure also did not significantly affect baseline [i.e., no prepulse inhibition (NO-PPI)] acoustic startle as measured by 1) startle amplitude on the first startle trial (105 dB), 2) the average startle amplitude for the first ten trials (105 dB), or 3) the average startle amplitude for the NO-PPI trials during PPI testing (95, 105, and 115 dB). Lead exposure also did not affect the latency to onset for the startle response. In contrast, for both the 105 dB and 115 dB acoustic startle stimuli, chronic low-level oral lead exposure significantly attenuated the capacity of an acoustic prepulse to reduce the startle response. This effect was present whether the data were presented and analyzed as raw change from baseline or as the percentage of baseline startle. Given the strong link between the modulation of PPI and dopaminergic neurotransmission in the nucleus accumbens, the present data support the hypothesis that chronic low-level oral lead exposure facilitates dopamine neurotransmission in the nucleus accumbens.

Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects.

RATIONALE: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or monoamine oxidase inhibitor (MAOI) anti-depressants. OBJECTIVE: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments. METHODS: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11-14 ml water/session (unpunished responding) and accepted 25-40 shocks/session (punished responding) during control (i.e., non-drug) 10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5-40 mg/kg) or alprazolam (0.3-2.5 mg/kg) were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined in additional groups of DSP4- or vehicle-pretreated subjects. RESULTS: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect) relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine treatment. CONCLUSIONS: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines.

Strychnine effects on ultrasound-elicited behaviours in Lister hooded rats.

Previous studies have demonstrated that Lister hooded rats will exhibit characteristic bursts of locomotion when exposed to a 20-kHz acoustic stimulus; this ultrasound-induced locomotion has been suggested as a potential model for panic attacks. Although ultrasound presentation rarely induces convulsions, the locomotor bursts exhibited resemble pre-convulsant running. The present studies examined the interactions between strychnine treatment and experimenter-presented ultrasounds on behaviour in male Lister hooded rats. Strychnine was selected because it is a potent and effective convulsion-inducing agent which is not known to induce anxiety in humans. Behaviour in a circular arena (75 cm diameter) was observed live, videotaped and traced electronically. In experiments 1 and 2, moderate (60 s) or relatively brief (15 s) exposure to an ultrasound stimulus (20 kHz, 98 dB, SPL) typically resulted in 5- to 10-s bursts of locomotion in saline-treated subjects; strychnine treatment (0.5, 0.7, 1.0 mg/kg, injected i.p., 10 min prior to testing) significantly increased this ultrasound-induced locomotion in a dose-dependent manner. Experiment 3 demonstrated that the strychnine enhancement of the ultrasound response was not different in naive animals when compared to those subjects which had received occasional strychnine and/or ultrasound treatment previously. Experiment 3 also demonstrated that strychnine treatment can cause at least modest running in subjects exposed to a 2 kHz tone (96 dB SPL). In experiment 4, exposure to the 20 kHz, 98 dB ultrasound stimulus for a much longer period, 9 min, resulted in irregular cycles of bursts of locomotion, followed immediately by periods of relative inactivity in saline-treated animals; approximately 10% of these subjects exhibited tonic-clonic convulsions. No convulsions occurred in strychnine-treated subjects during the period 10-20 min post-injection in the absence of ultrasound exposure; in contrast, the frequency of occurrence of convulsions in strychnine-treated subjects (10-20 min post-injection) exposed to the ultrasound stimulus was greater than 50%; these convulsions typically occurred at the end of a locomotor burst. The results of the present studies suggest that there may be a relationship between ultrasound-induced locomotor bursts and convulsant activity.

The effects of convulsant and anticonvulsant treatments on the behavioural effects of ultrasound presentation in Lister hooded rats.

Lister hooded rats exhibit bursts of locomotion when exposed to a 20 kHz acoustic stimulus; this ultrasound-induced locomotion has been suggested as a potential model for panic attacks. The present studies determined the effects of treatment with the convulsant agents strychnine and pentylenetetrazole and the anticonvulsant agents pentobarbital and ethosuximide on locomotor behaviour elicited by experimenter-presented ultrasounds in Lister hooded rats. Behaviour in a circular arena was viewed live and tracked electronically. In Experiment 1, brief exposure to an ultrasound stimulus typically resulted in short intensity-related bursts of locomotion in control rats. Pentobarbital or ethosuximide treatment reduced this short-term ultrasound-induced locomotion in a dose-related manner, whereas pentylenetetrazole or strychnine treatment increased these locomotor bursts. In Experiment 2, exposure to the ultrasound stimulus for a longer period resulted in irregular cycles of bursts of locomotion followed by periods of relative inactivity in control rats. In addition, approximately 10% of control rats exhibited convulsions associated with this long-duration ultrasound exposure at 98 dB sound pressure level. Sub-convulsant doses of the convulsant treatments increased the frequency of occurrence of convulsions associated with the ultrasound stimulus; pentobarbital or ethosuximide pretreatment significantly reduced this effect. The present findings suggest that a relationship exists between ultrasound-induced locomotor bursts and convulsant activity.

Anxiety-like and depression-like behavior in Maudsley reactive (MR) and non-reactive (NMRA) rats.

1. Female MR ("anxious") and MNRA ("non-anxious") Maudsley rats were tested in the CSD behavioral conflict paradigm (anxiety-like measure) and also in the FST paradigm (depression-like measure). 2. As expected, MNRA rats accepted significantly more shocks in the CSD paradigm than did MR rats (i.e., MNRA rats were less "anxious"), MNRA rats also exhibited significantly less immobility in the FST procedure (i.e., MNRA rats were less easily made "depressed"). 3. When the data were pooled across the two strains, there was a significant correlation between CSD and FST behavioral scores; however, there was no significant correlation between these measures when the data from the two strains were evaluated separately. Multiple regression (independent variables of rat strain and CSD score, dependent variable of FST score) revealed a significant effect of rat strain, but not CSD score, on FST behavior. 4. The relationship of these findings to the apparent relationship between anxiety and depression in humans is discussed.

Multiple within-day conflict testing to define the time course of anxiolytic drug effects.

The present article describes a method for multiple within-day conflict testing to conduct drug treatment time course studies more efficiently. Groups of female Sprague-Dawley rats were trained for conflict testing in a standard one-session/day procedure [conditioned suppression of drinking (CSD)]. In this task, thirsty rats (24 h water-restricted) drink from a tube that is electrified only when a tone is on (approximately 20% of the 10-min session time). In Experiment 1 it was found that there was no significant variation in CSD conflict behavior when subjects were tested at 0600, 1200, or 1800 h using the traditional procedure of one test/day. In Experiment 2, subjects were assigned to treatment groups such that there were three 5-min test sessions per day and the test-retest interval was either 2, 4, or 6 h (centered around 1200 h). Test-retest intervals of 6 h (i.e., tests at 0600, 1200, and 1800 h) resulted in comparable levels of punished responding across the repeated within-day tests, whereas test-retest intervals of 2 h and, to a lesser extent 4 h, resulted in unequal within-day conflict behavior characterized by a greater number of shocks accepted and a greater volume of water consumed during the earliest test periods each day. In another group of rats, it was determined that conflict behavior sampled five times/day in 3-min sessions separated by a 3-h test-retest interval (i.e., tests at 0600, 0900, 1200, 1500, and 1800 h) also resulted in stable conflict behavior across the various within-day test periods. In Experiment 3, it was found that acute IP challenges with anticonflict treatments that exhibit either a long duration of action (phenobarbital: 40 mg/kg) or a significant delay to onset in addition to a long duration (MK-801: 0.20 mg/kg) yielded time course data comparable to those obtained using the traditional one test/day procedure. These findings indicate that the use of multiple within-day conflict testing can greatly increase the efficiency of these procedures, particularly when drug treatment timecourse information is desired.

An electrophysiological evaluation of serotonergic dorsal raphe neurons in Maudsley rats.

Extracellular electrophysiological recording techniques were used to study serotonergic dorsal raphe (DRN) neurons in Maudsley Reactive (MR), Maudsley Non-Reactive (MNRA) and Sprague Dawley (SD; reference control strain) rats. No significant differences were observed in the average discharge rates of DRN neurons from SD, MR AND MNRA rats. The sensitivity of DRN neuron somatodendritic 5-HT1A autoreceptors to the inhibitory effects of i.v. 8-OH-DPAT or alpha 1-adrenoceptors to the excitatory effects of iontophoretic phenylephrine did not differ significantly among strains. These findings are discussed in light of the previously reported strain-dependent differences in anxiety-like behavior and noradrenergic locus coeruleus neurons.

Anticonflict effect of MK-801 in rats: time course and chronic treatment studies.

The present study examined the time course and chronic treatment effects of the noncompetitive N-methyl-D aspartate (NMDA) antagonist, MK-801 (dizocilpine), on conflict behavior in the conditioned suppression of drinking (CSD) paradigm, a repeated-measures conflict task. In daily 10-min sessions, water-restricted rats drank from a tube that was occasionally electrified (0.25- or 0.5-mA shocks signaled by a tone). Trained subjects (4 weeks of CSD testing) exhibited stable baselines for both punished responding and unpunished responding. In the first experiment, the effects of MK-801 administered IP were determined in female and male rats following a range of pretreatment intervals (i.e., 0.5-48 h). In female rats, 0.2 mg/kg MK-801 exerted an anticonflict effect at pretreatment intervals of 10-36 h, but not before 10 h or after 36 h. In male rats, qualitatively similar results were obtained; MK-801 (0.4 mg/kg) exerted anticonflict effects following pretreatment intervals of 6-14 h, but not before 6 or after 14 h. In the second experiment, chronic treatment of female rats with 0.04, 0.01, or 0.2 mg/kg MK-801 resulted in a dose-dependent anticonflict effect in CSD paradigm, which remained stable over the course of 5 weeks of chronic treatment. Punished responding returned to pretreatment levels within 2-3 days after discontinuation of chronic treatment with MK-801. These data suggest that MK-801 exerts a delayed anticonflict effect in both female and male rats with a qualitatively similar pattern, and that there is no tolerance to the anticonflict effect of MK-801 with chronic treatment.

Initial subsensitivity to anxiolytic treatments on conflict behavior in rats: parametric studies across drug classes.

In conflict paradigms, benzodiazepines (BZs) often exhibit maximal anticonflict effects only after three to four BZ exposures (anxiolytic initial subsensitivity; AIS). The present experiments examined 1) whether AIS occurs with non-BZ anxiolytics and 2) whether prior exposure to non-BZs prevents the occurrence of BZ AIS. Female rats were trained to stable responding levels on a repeated-measures punished drinking paradigm. In Experiment 1, dose-response curves for the effects of the BZs chlordiazepoxide and diazepam, the barbiturates (BBs) pentobarbital and amobarbital, and the non-BZ, non-BB agent carbamazepine were determined in five groups of rats (one group/drug); dose-response curves were determined on two occasions for each drug. There was an AIS with both BZs, with the anticonflict effect being significantly greater for dose-response determination #2. There was no AIS with the BBs (robust and dose-dependent increases in punished responding on both determinations) or with carbamazepine (weak anticonflict effect on both determinations). In Experiment 2, the rats from Experiment 1 received a single-dose challenge with chlordiazepoxide (10 mg/kg). This challenge resulted in a robust anticonflict effect in subjects with a history of repeated BZ treatment; in contrast, subjects with a history of repeated BB or carbamazepine treatment exhibited smaller anticonflict responses. These data suggest that 1) the AIS does not occur with non-BZ anxiolytics and 2) the BZ AIS cannot be prevented by repeated exposure to non-BZs.

The effects of selective and non-selective monoamine oxidase (MAO) inhibitors on conflict behavior in the rat.

Conflict behavior in rats was examined over the course of several weeks of chronic treatment with selective and non-selective monoamine oxidase inhibitors (MAOIs). In daily 10min sessions, rats were trained to drink from a tube which was occasionally electrified (0.5mA). Electrification was signalled by the presence of a tone. Within 3-4 weeks, control (i.e. non-drug) conflict behavior had stabilized (30-40 shocks and 8-12ml water/session) and drug testing began. Chronic administration (two injections/day for 8 weeks) with a non-selective (i.e. MAO-A and MAO-B inhibiting) dose of pargyline (15mg/kg) resulted in a time-dependent increase in punished responding. In contrast, chronic administration of the MAO-A selective inhibitor (clorgyline; 1.0mg/kg, 2mg/kg), the MAO-B selective inhibitor deprenyl (5mg/kg) or MAO-B inhibiting doses of pargyline (1.0mg/kg, 5mg/kg) were without effect. Finally, chronic treatment with the combination of a low dose of clorgyline (1.0mg/kg) and a low dose of pargyline (1.0mg/kg) did result in a time-dependent increase in punished responding. These results suggest that inhibition of both MAO-A and MAO-B is required for the eventuation of the anxiolytic effect resulting from chronic MAOI treatment.

Electrophysiological characteristics of locus coeruleus neurons in the Maudsley reactive (MR) and non-reactive (MNRA) rat strains.

Extracellular single-unit recording techniques were used to evaluate the physiological and pharmacological characteristics of noradrenergic locus coeruleus (LC) neurons in urethane-anesthetized Maudsley reactive (MR) and non-reactive (MNRA) rat strains, a presumed genetic model for differences in 'anxiety'. LC neurons from MNRA rats were found to have a significantly higher basal discharge rate than LC neurons from either the MR or Sprague-Dawley (SD) rats. The discharge pattern of MNRA LC neurons also differed significantly from that of LC neurons from SD and MR rats, with LC neurons from MNRA rats exhibiting a burst-like pattern of discharge. Finally, MNRA LC neurons were significantly less sensitive to the inhibitory effects of i.v. clonidine on spontaneous activity.

High-dose subchronic imipramine treatment: effects on anxiety-like (conflict) behavior in rats.

In the management of both anxiety and depression, agents such as imipramine (IMI) are noted for their 3-5 week delay to onset of clinical effect. A similar delay to onset has been reported for the anxiolytic-like (i.e., anticonflict) effect of chronic IMI treatment (2.5 mg/kg, BID for 5 weeks) in the Conditioned Suppression of Drinking (CSD) conflict paradigm; similar effects have been reported with other antidepressants and in other conflict procedures. In contrast, in the Forced Swim Test (FST) model of depression, antidepressant-like effects are reported immediately following subchronic treatment with relatively high doses of these agents (e.g., 30 mg/kg IMI, 3 times in 24 hr). The present study examined the effects of this high-dose, subchronic treatment with IMI on CSD conflict behavior. Conflict-trained female Sprague Dawley rats were divided into three groups with comparable pretreatment baselines for shocks received. Treatments (0, 15, and 30 mg/kg IMI) were administered intraperitoneally (IP) at 23, 5, and 1 hr prior to CSD conflict testing on day 1; CSD conflict behavior was then monitored daily (Mon-Fri) for 5 weeks following treatment. IMI treatment (30 and, to a lesser extent, 15 mg/kg) significantly reduced shocks received (punished responding) and water intake (unpunished responding) on day 1; although water intake was also slightly reduced in both IMI treatment groups for the remainder of test week 1, there was no difference in shocks received between the various treatments for this period. Subjects receiving 30 mg/kg IMI (but not those receiving 15 mg/kg IMI or vehicle) accepted significantly more shocks than controls on weeks 2-4 (maximal increase at week 3) and returned to pretreatment baseline levels by week 5. Thus, subchronic high-dose treatment with IMI (and perhaps other antidepressants) produces anxiolytic-like effects which are delayed in nature and persist for several weeks after treatment.

Conflict behavior in Maudsley reactive and nonreactive rats: effects of noradrenergic neuronal destruction.

The present studies were designed to examine the effects of treatment with the noradrenergic neurotoxin N-(2-chloroethyl)-n-ethyl-2-bromobenzylamine HCl (DSP4; 65 mg/kg, IP) on conflict behavior in the Maudsley reactive (MR) and nonreactive (MNRA) rat strains. In daily 10-min sessions, water-restricted rats were trained to drink water from a tube that was occasionally electrified; electrification was signaled by the presence of a tone (7-s duration; ISI = 30 s). Consistent with previous reports, the number of shocks accepted by rats of the MR and MNRA strains did not differ initially, but MNRA rats exhibited a dramatic increase in punished responding relative to their MR counterparts over the course of several weeks of conflict testing. This MR vs. MNRA strain difference in punished responding did not exhibit extinction following discontinuation of CSD conflict behavior testing for a period of 6 weeks. Whether it was administered after conflict training or before, DSP4 treatment did not reduce the MR vs. MNRA strain difference in conflict behavior; rather, DSP4 treatment tended to increase the magnitude of the MR vs. MNRA difference in conflict behavior. The effects of DSP4 on norepinephrine (NE) and 5-hydroxytrypamine (5-HT) concentrations in the pons medulla region were determined in one group of conflict-experienced MR and MNRA rats (35 weeks after administration) and in a second group of naive MR and MNRA rats (3 weeks after administration). There were no MR vs. MNRA strain differences in NE or 5-HT concentrations in vehicle-treated rats. DSP4 treatment significantly reduced NE, but not 5-HT, concentrations when compared to control values; rats that were sacrificed 3 weeks following DSP4 administration exhibited a greater NE depletion than did rats sacrificed 35 weeks after DSP4 administration. Finally, there were no significant correlations between pons medulla region NE concentrations and conflict behavior in either strain alone or when the data from the two strains were combined. The present results are not consistent with the hypothesis that the MR vs. MNRA strain difference in conflict behavior is the result of strain differences in brain NE function.

Maudsley reactive and nonreactive rats in the forced swim test: comparison in fresh water and soiled water.

Maudsley reactive (MR) and nonreactive (MNRA) and Sprague-Dawley (SD) male rats were tested for their immobility response in the forced swim test when the water was fresh or soiled by a rat of the same or other strain. For all strains, rats tested in soiled water were less immobile than rats in fresh water. The three strains did not differ as producers of soiling substance, but did differ in their response to it. The MR strain was least responsive, whereas the MNRA and SD did not differ from one another. These results support a previous study suggesting that MR rats are more immobile than MNRA rats in the forced swim test. The interpretation of these findings regarding the use of the Maudsley rat strains as an animal model for studying anxiety and/or depression is discussed.

Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) rats: performance in an operant conflict paradigm.

The present studies were designed to characterize the behavior of Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) rats in a modification of the Geller-Seifter operant conflict paradigm. Food-restricted (85% of free-feeding weights) female MR/Har and MNRA/Har rats were trained to lever press for food reinforcement in a multiple-schedule operant conflict paradigm. In the absence of a tone, a fixed ratio-30 (FR-30) schedule for reinforcement only was in effect (i.e., every 30th lever press resulted in the delivery of a 45-mg food pellet). During the presence of a tone, a fixed ratio-1 (FR-1) schedule of both reinforcement (food) and punishment (0.20 mA footshock applied for 500 ms) was in effect (i.e., each lever press resulted in both food and shock delivery). The tone periods were 27 s in duration and were presented on a variable interval (VI)-120-s schedule (approximately 20 tones/40-min session). Behavioral testing was conducted 5 days/week for 35 weeks. Initially, punished responding between the MR/Har and MNRA/Har rat strains did not differ dramatically. However, over the course of many weeks of conflict testing, rats of the MNRA/Har strain came to accept significantly more shocks than did subjects of the MR/Har strain. A direct examination of footshock sensitivity in these rats revealed that this difference in conflict behavior over time was not due to strain differences in shock sensitivity. The mechanism for this time-dependent difference in conflict behavior between the MR/Har and MNRA/Har rats remains undetermined.