Electrolytic, but not 5,7-dihydroxytryptamine, lesions of the nucleus medianus raphe impair acquisition of a radial maze task

We have previously reported that electrolytic lesions of the nucleus medianus raphe (MR) produce a deficit in the acquisition of an 8-arm radial maze task (Wirtshafter and Asin 1983). In an attempt to determine whether or not this deficit is secondary to serotonin depletion resulting from the lesion, we investigated and compared the effects of electrolytic and 5,7-dihydroxytryptamine (5,7-DHT) lesions of the MR on the acquisition of the radial maze task. Although forebrain serotonin levels after 5,7-DHT injections were reduced as much as those following electrolytic lesions, only rats with an electrolytic MR lesion were impaired on the acquisition of both a free-running maze task and on a related task, where animals were replaced into the same arm between arm choices. In contrast, 5,7-DHT-treated rats were unimpaired on both tasks compared to an ascorbate-injected control group. These findings provide further evidence that most of the profound behavioral deficits shown by rats with electrolytic MR damage are not due to serotonin depletion and are consistent with the results of other studies indicating strong similarities between the behavioral effects of limbic and MR lesions.     

Depletion of serotonin selectively impairs short-term memory without affecting long-term memory in odor learning in the terrestrial slug Limax valentianus

The terrestrial slug Limax is able to acquire short-term and long-term memories during aversive odor-taste associative learning. We investigated the effect of the selective serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) on memory. Behavioral studies indicated that 5,7-DHT impaired short-term memory but not long-term memory. HPLC (high-performance liquid chromatography) analysis revealed that 5,7-DHT significantly reduced serotonin content in the central nervous system. The present study suggests that acquisition, retention, and/or retrieval of short-term memory involves serotonin, and neither acquisition nor retrieval of long-term memory requires serotonin at a level as high as that required for short-term memory.     

Behavioral effects of neurotoxic lesions of the ascending monoamine pathways in the rat brain

Intracranial microinjections of 6-hydroxydopamine or 5,6-dihydroxytryptamine into six ascending monoamine pathways produced the expected patterns of depletion of telencephalic serotonin, dopamine, and norepinephrine. Serotonin level was specifically lowered after dorsal or median raphe lesions but not after mesolimbic or nigrostriatal system lesions which lowered both norepinephrine and dopamine. Lesions in the locus coeruleus or ventral nor-adrenergic bundle lowered only norepinephrine, and locus coeruleus lesions elevated serotonin level. Behavior was examined in an open field, one-way active avoidance, and two passive avoidance tasks, and measures were taken of water consumption and body weight. Dorsal raphe lesions had no effect on any of the measures; the other five lesion groups exhibited deficient acquisition of the one-way active avoidance task. In the appetitive passive avoidance task, only the substantia nigra lesion group exhibited a deficiency. In the step-through passive avoidance task, both the substantia nigra and the median raphe groups exhibited a deficit, with the median raphe group exhibiting hyperactivity in the start box during testing. Water consumption was decreased by lesions in the ventral noradrenergic bundle during the first postoperative week and was increased in the median raphe group by the fourth postoperative week. Lastly, lesions in the locus coeruleus dramatically decreased activity in the open field. The results are discussed in regard to the search for specificity of behavioral functions of the distinct ascending monoamine pathways.     

The behavioral effects of enriched housing are not altered by serotonin depletion but enrichment alters hippocampal neurochemistry

To assess a possible role for serotonin in the mediation of the behavioral changes induced by enriched housing conditions (EC), adult female Long-Evans rats sustaining a serotonin depletion (150 microg of 5,7-dihydroxytryptamine, icv) and sham-operated rats were housed postoperatively for 30 days in enriched (12 rats/large cage containing various objects) or standard housing conditions (2 rats/standard laboratory cage). Thereafter, anxiety responses (elevated plus-maze), locomotor activity (in the home-cage), sensori-motor capabilities (beam-walking task), and spatial memory (eight-arm radial maze) were assessed. Monoamine levels were subsequently measured in the frontoparietal cortex and the hippocampus. Overall, EC reduced anxiety-related responses, enhanced sensori-motor performance and improved the memory span in the initial stage of the spatial memory task. Despite a substantial reduction of serotonergic markers in the hippocampus (82%) and the cortex (74%), these positive effects of EC were not altered by the lesion. EC reduced the serotonin levels in the ventral hippocampus (particularly in unlesioned rats: -23%), increased serotonin turnover in the entire hippocampus (particularly in lesioned rats: +36%) and augmented the norepinephrine levels in the dorsal hippocampus (+68% in unlesioned and +49% in lesioned rats); no such alterations were found in the frontoparietal cortex. Our data suggest that an intact serotonergic system is not a prerequisite for the induction of positive behavioral effects by EC. The neurochemical changes found in the hippocampus of EC rats, however, show that the monoaminergic innervation of the hippocampus is a target of EC.     

Injection of 5,7-dihydroxytryptamine into the B3 raphe region of neonatal rat pups induces hyperalgesia but only slight alterations in ingestion-related behaviors.

The effects of intrabrainstem injections of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the B3 raphe region (nucleus raphe magnus and nucleus reticularis paragigantocellularis) on early ingestive behavior and nociception were assessed in Sprague-Dawley rat pups during the first postnatal week. Lesions resulted in a marked depletion of serotonin (5HT) in hindbrain without influencing 5HT levels in forebrain. Pretreatment with desipramine (DMI) resulted in a sparing of noradrenergic neurons from neurotoxic effects. The B3 lesion resulted in significant hyperalgesia as reflected by decreased latencies in tail flick testing. Although nipple attachment latencies in suckling tests were slightly increased by the lesion, no notable effects on mouthing or other ingestive-related behaviors were observed in testing conducted in an independent ingestion paradigm. These results suggest that whereas B3 serotonergic neurons may be functioning in an adult-typical manner to regulate analgesia during the early postnatal period, this raphe region may play only a slight role in the modulation of ingestion-related behaviors early in life.     

Mouse killing in rats induced by lesions of the medial hypothalamus or medial accumbens: short-term preoperative exposure to a mouse does not suppress the killing

Rats were either exposed or not exposed to a mouse in their living cage for a 48-hr period. At the end of this time a bilateral lesion was made in the medial accumbens region or in the medial hypothalamus. When tested 2 days postoperatively, the killing frequency among rats that had been exposed to mice preoperatively was not significantly lower than that of rats that were not preoperatively exposed. The ineffectiveness of preoperative experience in suppressing the mouse killing induced by medial accumbens and medial hypothalamic lesions is similar to that found previously with dorsal-median raphe lesions and olfactory bulb lesions and is in contrast to the ease with which preoperative experience prevents mouse killing induced by septal lesions and serotonergic lesions induced by 5,7-dihydroxytryptamine.     

Differential effects of dorsal raphe lesions and intraraphe GABA and benzodiazepines on conflict behavior in rats

Both reductions in brain serotonin activity and injections of benzodiazepine drugs increase punished responding in rats, but the evidence is conflicting on the role of serotonin pathways in the benzodiazepine effect. Therefore a series of studies were carried out using a Geller-Seifter procedure with three components, to examine drug effects on rewarded, nonrewarded, and punished responding. Using male hooded Lister rats and chronic indwelling cannulae, it was found that neither chlordiazepoxide (1.5 and 5.0 micrograms in 0.5 microliter), midazolam (1.0 and 10.0 micrograms in 0.5 microliter), nor GABA (100, 500, 1000, and 5000 ng in 0.5 microliter), exerted significant anticonflict activity when injected into the dorsal raphe. Lesions of the dorsal raphe produced by injections of 5,6-dihydroxytryptamine significantly increased punished responding, and there were significant correlations between lesion size, extent of forebrain serotonin depletion, and increases in punished responding. Peripheral injections of chlordiazepoxide (5.0 and 10.0 mg/kg) and midazolam (1.25, 2.5, and 5.0 mg/kg) significantly increased punished responding both before and after raphe lesions. The increase in lesioned animals was significantly greater than after drug or lesion alone and represented a powerful additive effect which was specific to punished responding. As intraraphe benzodiazepines did not exert significant anticonflict activity, and raphe lesions did not attenuate the anticonflict activity of peripheral benzodiazepines, it is concluded that increases in punished responding seen after serotonin depletion and after benzodiazepine drugs may be dissociable.     

Serotonin Depletion Does Not Prevent Intrinsic Sensitization in the Leech

Intrinsic sensitization is a form of behavioral facilitation that is distinct from the extrinsic sensitization normally studied. To examine whether intrinsic and extrinsic sensitization are mediated by different physiological processes, the effects of 5,7-dihydroxytryptamine-induced serotonin (5-HT) depletion on intrinsic sensitization of the leech whole-body shortening response were observed. Previous experiments have shown that 5-HT depletion disrupts dishabituation and extrinsic sensitization of this behavior in the leech. Intrinsic sensitization was observed in preparations from both control and 5-HT-depleted animals, indicating that this form of behavioral facilitation was not affected by 5-HT depletion. The differences in the effects of 5-HT depletion on intrinsic versus extrinsic sensitization suggest that there are distinct neurophysiological processes mediating these two forms of behavioral facilitation. In addition, 5-HT depletion appeared to disrupt a putative extrinsic form of habituation of the shortening reflex. These data support the hypothesis that both intrinsic and extrinsic processes of neuromodulation mediate habituation and sensitization.     

Central noradrenergic neurons: differential effects on body weight of electrolytic and 6-hydroxydopamine lesions in rats.

The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for the hyperphagia and obesity produced by ventromedial hypothalamic lesions. To determine the relationship between body weight and damage to the VB, the effects of bilateral electrolytic and 6-hydroxy-dopamine (6-OHDA) lesions of the VB were compared. When rats were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. A second study in which both types of lesions were placed at a rostral ventromedial hypothalamic site yielded the same pattern of results. Diet-dependent increases in body weight were attributed to the destruction of a non-noradrenergic system, which was spared by the relatively selective 6-OHDA lesion but damaged by the nonselective electrolytic lesion.     

Species-typical taxic behavior and event-reinforcer interactions in conditioning

The role of species-typical taxic behavior in conditioning was studied using thigmotaxis (wall hugging) in rats. Running toward or staying near walls in an open-field apparatus was assumed to be compatible with the rat's defensive behavior, and running to or staying in open spaces was assumed to be incompatible. With large food rewards no differences between the center and side responses were found in acquisition under continuous or intermittent reward, but the center response showed greater suppression after contingent punishment was applied on nonreward trials. Two additional experiments showed that differences between center and side responses occur during extinction when avoidance of shock but not when food is the reinforcer. The results suggest that instances of response-reinforcer interactions may be predicted by knowledge of species-typical defensive behavior and that reactions elicited by shock are not always identical to those elicited by frustration in their consequences for the performance of conditioned behavior.     

Behaviors of Swiss-Webster and C57/BL/6N sin mice in a fear/defense test battery

When confronted by an approaching threat stimulus (experimenter or laboratory rat), Swiss-Webster mice show initial flight, followed by freezing and defensive vocalization and biting, the latter only when escape is blocked. These defense patterns resemble those of the wild rat, suggesting that mice of this strain do not show the reductions in flight and defensive threat/attack that are typical of laboratory rats. C57/BL/6N Sin strain mice showed fewer avoidances to an approaching predator, as well as reduced vocalization and defensive biting, a pattern more similar to that of laboratory rats. As with rats, female mice appeared to be more defensive to a predator. They showed greater reactivity to dorsal contact and more frequent defensive biting and jump attacks than males of the same strains. These patterns of defensive behaviors suggest that, although strain differences in defense are substantial, laboratory mice are suitable for, and may offer several advantages in, the study of the genetic, endocrine, and pharmacological basis of antipredator defense. © 1995 Wiley-Liss, Inc.     

The behavioral effects of depletions of brain serotonin induced by 5,7-dihydroxytryptamine vary with time after administration

Ether-anesthetized Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 micrograms 5,7-dihydroxtryptamine (57DHT). Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 57DHT. Liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 92% and striatal 5HT by 45%. Three or eleven days after lesioning, locomotor and exploratory behavior was characterized in separate groups of animals with a behavioral pattern monitor (BPM). On Days 4 and 12, the animals were retested following saline or 1.0 mg/kg amphetamine. Three days after depletion, lesioned rats exhibited a decrease rate of habituation of locomotor activity relative to controls. When challenged with amphetamine (1.0 mg/kg), 5HT-depleted rats exhibited increased corner and decreased center activity, as well as stereotyped patterns of locomotion. Eleven days following lesion, 5HT-depleted rats exhibited habituation rates greater than controls; amphetamine challenge yielded patterns of activity similar to those of control animals. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats, and that compensatory mechanisms operate over time to alter the behavioral effects of 57DHT-induced depletions of brain 5HT.     

The role of nucleus accumbens dopamine in outcome encoding in instrumental and Pavlovian conditioning

Considerable evidence suggests that dopamine in the core subregion of the nucleus accumbens is not only involved in Pavlovian conditioning but also supports instrumental performance. However, it is largely unknown whether NAc dopamine is required for outcome encoding which plays an important role both in Pavlovian stimulus-outcome learning and instrumental action-outcome learning. Therefore, we tested rats with 6-hydroxydopamine (6-OHDA) induced dopamine depletion of the NAc core for their sensitivity to outcome devaluation in a Pavlovian and an instrumental task. Results indicate that 6-OHDA-lesioned animals were sensitive to outcome devaluation in an instrumental task. This finding provides support to the notion that NAc core dopamine may not be crucial in encoding action-outcome associations. However, during instrumental conditioning lever pressing rates in 6-OHDA-lesioned animals were markedly lower which could reflect an impaired behavioral activation. By contrast, after outcome-specific devaluation in a Pavlovian task, performance in 6-OHDA-lesioned animals was impaired, i.e. their magazine-directed responding was non-selectively reduced. One possibility to explain non-selective responding is that NAc core DA depletion impaired the ability of conditioned stimuli to activate the memory of the current value of the reinforcer.     

Selection for reduced aggressiveness towards man and dopaminergic activity in Norway rats

The brain dopaminergic system is involved in the process of long-term selection for reduced aggressive reaction towards man in Norway rats. The dopamine levels in the striatum as well as the nucleus accumbens with the tuberculum olfactorium were significantly lower in domesticated rats than in their wild counterparts. A substantial decrease was found in homovanillic acid level in the n. accumbens and tuberculum olfactorium. Specific binding of [³H]spiperone which labels D-2 dopamine receptors was higher in the mesolimbic structure of tame rats, whereas binding of [³H]SCH 23390 (D-1 receptors) was unchanged in this area. No substantial differences were detected in D-1 and D-2 binding in striatum. Apomorphine (0.3 mg/kg) elicited less locomotion in tame animals, reflecting a decrease of sensitivity of postsynaptic dopamine receptors. Tame rats showed fewer aggressive contacts in a foot-shock test than wild rats and the D-2 receptor antagonist sulpiride (25 mg/kg) significantly decreased the foot-shock aggression only in wild rats. Therefore, domestication, which diminishes defensive behavior and emotional reactivity of animals, is associated with decreases of dopamine level in the striatum, changed metabolism of dopamine in mesolimbic system, and an alteration in density and senstivity of D-2 receptors.     

The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats

This study assessed whether dopamine in the dorsomedial striatum is necessary for flexible adaptation to changes in stimulus-response contingencies. As KW-6002 (Istradefylline), an adenosine A(2A) antagonist, improves motor deficits resulting from striatal dopamine depletion, we also tested for potential ameliorative effects of KW-6002 on dopamine depletion-induced cognitive deficits. Male Lister hooded rats were presented with two bowls, discriminable by either a textured covering on the outer surface, their scent or the bowl contents (digging media) in which bait was buried. Once they had learned in which bowl food was buried, the stimulus-response contingencies were reversed. In both phases (acquisition and reversal), the criterion for learning was defined a priori as six consecutive correct trials. Following depletion of dopamine in the dorsomedial striatum, acquisition of the discriminations was intact but there was an increase in the number of trials to attain criterion performance in the reversal phases, indicating an impairment in reversal learning. KW-6002 (1mg/kg bidaily for 10 days) non-specifically increased the number of trials to criterion at all stages of the test and in both controls (sham-operated) and dopamine-depleted rats. Chronic KW-6002 treatment did not improve the reversal deficits in dopamine-depleted rats. These findings suggest that dopamine transmission in the dorsomedial striatum is critical for the flexible shifting of response patterns and the ameliorative effects of KW-6002 following depletion of dopamine in the striatum may be restricted to motor functions without relieving deficits in response-shifting flexibility.     

Depletion of brain serotonin differently affects behaviors induced by 5HT1A, 5HT1C, and 5HT2 receptor activation in rats.

5-hydroxytryptamine (5HT)-depleted rats were subjected to behavioral experiments in which the response to activation of 5HT1A, 5HT1c, and 5HT2 receptor subtypes was measured. Depletion of 5HT was produced by unilateral intracerebroventricular injection of 5,7-dihydroxytryptamine (100 micrograms/rat) or by systemic injection of p-chlorophenylalanine (150 mg/kg injected intraperitoneally 72, 48, and 24 h before the test). The dose-response curve of the 5HT1A-mediated, 8-hydroxy-2-(di-n-propylamino)tetralin (0.022-0.46 mg/kg)-induced lower lip retraction was not changed after depletion, nor was the dose-response curve of the 5HT2 receptor-mediated (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (0.046-1.0 mg/kg)-induced head shake response. The dose-response curve for penile erections, a 5HT1c receptor-mediated response after mCPP (0.1-1.0 mg/kg), a direct 5HT1c agonist, is shifted to the left after 5HT depletion, whereas the response to indirect activation of the 5HT1c receptor with the 5HT reuptake inhibitors citalopram (2.2-4.6 mg/kg) and paroxetine (0.22-2.2 mg/kg) was inhibited after 5HT depletion. These results suggest that 5HT1c receptors are more subject to denervation supersensitivity than 5HT1A and 5HT2 receptors. This lesion model may be useful to discriminate behaviorally between direct and indirect activation of the 5HT1c receptor.     

Self-regulatory depletion and attachment avoidance: Increasing the accessibility of negative attachment-related memories

Bowlby (1980) theorized that insecurely attached people use defensive memory suppression to cope with adverse events involving childhood attachment figures. In this study, defensive memory suppression was conceptualized as a form of self-regulation that, like other types of self-regulation, requires limited resources and may be undermined by the prior exercise of self-regulation. The findings of the study showed that, in the absence of self-regulatory depletion, memories of negative experiences with attachment figures were less accessible among persons who reported more dismissing avoidance. Under self-regulatory depletion, however, accessibility increased among persons high in dismissing avoidance. Depletion of self-regulatory capacity did not moderate memory accessibility for secure, preoccupied, or fearful avoidant attachment. The results imply that dismissing avoidant persons devote their limited self-regulatory resources to suppressing negative memories and keeping their attachment systems deactivated.     

Nitric oxide is involved in appetitive but not aversive olfactory learning in the land mollusk Limax valentianus

The land slug Limax performs both aversive and appetitive olfactory learning, and we investigated neurotransmitters involved in each type of learning. Slugs were conditioned by presenting a vegetable juice (appetitive conditioning) or a mixture of vegetable juice and quinidine (aversive conditioning), and the latency to reach the juice became shorter (appetitive conditioning) or longer (aversive conditioning) after conditioning. L-NAME injected either before conditioning or testing blocked the reduction in latency in appetitive conditioning but had no significant effects in aversive conditioning. 5,7-dihydroxytryptamine had no significant effects in appetitive conditioning. These results suggest different mechanisms for appetitive and aversive learning.     

Defensive behavior of laboratory and wild Rattus norvegicus

Analysis of the defensive behaviors of wild rats to an inescapable approaching threat stimulus (the experimenter) indicated a pattern of freezing to distant stimuli, giving way to vocalization, jumps, and jump-attacks at shorter defensive distances. Comparisons of the defensive reactions of wild-trapped and laboratory-bred wild rats to a variety of threatening stimuli, in escapable as well as inescapable situations, indicated that the two wild strains were similar and consistently more defensive than laboratory rats to both human and conspecific threat stimuli. These results thus suggest that the defensive behaviors of rats have been substantially reduced during the process of domestication, with relatively little of this reduction being attributable to housing in standard laboratory conditions.     

Neuropsychological disorders indicative of postresuscitation encephalopaty in rats

The aim of this research was to study the effect of 12-minute clinical death on innate and acquired behavior, biogenic amine concentration, and the composition and quantity of neural populations in specific brain regions of white rats. The study shows that in animals during the postresuscitation period with formal restoration of neurological status, there are changes in emotional reactivity, orientation-exploration reactions, impairment of learning and memory, decrease in exercise tolerance and pain sensitivity. These processes are accompanied by alterations in serotonin and norepinephrine levels in the frontal cerebral cortex, dopamine and serotonin levels in the striatum, certain biochemical indices in blood plasma and neural loss in the CA1 sector of the hippocampus and lateral portions of the cerebellum.