Similarities in the physiological bases of an abnormal grooming behavior in thyroidectomized cats and in cats with lesions of the central nervous system.

Thyroidectomized cats display a dissociation of the appetitive and consummatory components of grooming behavior when the body surface is tactually stimulated, an abnormal behavior that also occurs in cats with pontile or frontal neocortical lesions. Systemic administration of 5-hydroxytryptophan (5-HTP) abolishes the abnormal behavior, whereas dihydroxyphenylalanine administration does not, and p-chlorophenylalanine (PCPA) administration induces the abnormal grooming behavior in thyroidectomized cats that are not displaying the abnormal behavior because of spontaneous seasonal reversions. Microinjections of 5-HTP or serotonin into the superior colliculi also abolish the abnormal grooming behavior in thyroidectomized cats. Lesions of the superior colliculi prevent the development of the abnormal behavior after thyroidectomy, even with PCPA treatment. These pharmacological results in thyroidectomized cats parallel the behavioral effects observed in cats with pontile or frontal neocortical lesions.     

Role of glucocorticoids in an abnormal grooming behavior in cats with pontile or frontal neocortical lesions.

Cats with pontile or frontal neocortical lesions display a tactually elicited dissociation of appetitive and consummatory grooming behaviors. Systemic administration of glucocorticoids abolished the abnormal grooming behavior in cats with lesions, even when the stimulatory effect of glucocorticoids on serotonin metabolism was blocked by administration of p-chlorophenylalanine (PCPA). Microinjections of glucocorticoids into the superior colliculi also significantly decreased the abnormal grooming behavior. Adrenalectomized cats did not display the abnormal grooming behavior, but the abnormal behavior did occur in PCPA-treated adrenalectomized cats. Administration of either glucorticoids or 5-hydroxytryptophan abolished the abnormal behavior in PCPA-treated adrenalectomized cats. Thus, it appears that the pontile and frontal neocortical lesions produce deficits in both glucocorticoids and serotonin, and these deficits are necessary and sufficient conditions for inducing the abnormal grooming behavior.     

Behavior of the rat after removal of the neocortex and hippocampal formation

After surgical removal of the neocortex and hippocampal formation, rats retained most of the movement patterns of locomotion, climbing, grooming, feeding, and fighting. However, forepaw immobility during swimming was abolished. Feeding behavior was suppressed temporarily but recovered partially. The distinctive postures of sleep and walking and a circadian rhythm of motor activity were retained. However, behaviors were often not performed at the appropriate time and place. The normal sequence of grooming behavior was disrupted; food hoarding and social behavior were essentially abolished. Removal of the neocortex alone had much the same effect as removal of neocortex and hippocampus together. Removal of hippocampus alone produced only a mild disruption of behavior. It is suggested that ascending nonspecific projections to the cerebral cortex play an important role in the moment-to-moment control of behavior but are not essential for the sleep-waking cycle.     

Serotonin's influence on predatory behavior of highly aggressive cba and weakly aggressive DD strains of mice

The effects of serotonin were studied on locust-killing behavior of mice from low (DD) and high (CBA) predatory aggressive strains. 5-HTP injected intraperitoneally (50 and 100 mg/kg) or 5-HT administered into the lateral ventricle (10 μg) significantly reduced locust-killing behavior in highly aggressive CBA mice. Imipramine (20, 30, and 40 mg/kg) elicited a dose-dependent inhibitory effect on predatory behavior. Fluoxetine (10 and 20 mg/kg) alone had a slight influence on locust-killing behavior but potentiated the action of the subthreshold dose of 5-HTP (25 mg/kg). Pretreatment with the blocker of 5-HT₂ type receptors methysergide (2 mg/kg) abolished the inhibitory effect of 5-HTP. These finding indicate that serotonin of the brain exerts an inhibitory effect on predatory behavior in mice. In contrast, neither lesion of the dorsal raphe nucleus (although significantly depleting the brain serotonin) nor treatment with methysergide (2 mg/kg) induced locust-killing behavior in weakly aggressive DD mice. Low predatory aggressiveness in DD mice is suggested to be related to the low tonus of the mechanisms activating killing behavior rather than to excessive serotonergic inhibitory influences.     

Evidence for neocortical involvement in reference memory

Rats were trained on an eight-arm radial maze task using a procedure that provides for an assessment of both working and reference memory. Following training, rats received parietal cortex, medial prefrontal cortex, visual cortex, or nucleus basalis magnocellularis lesions. Rats with visual cortex lesions showed no change in performance on either working or reference memory. Rats with parietal cortex lesions displayed a temporary deficit in reference, but no deficit on working memory. Animals with medial prefrontal cortex lesions showed a temporary deficit on both working and reference memory. Rats with extensive lateral frontal and parietal cortex depletion of acetylcholinesterase following nucleus basalis magnocellularis lesions had a marked disruption only of reference but not of working memory. It is concluded that neocortex and possibly the cholinergic projections to neocortex play an important role in mediating reference memory.     

Antagonism of behavioral effects of bromocriptine by prolactin in female cats

The effects of the dopaminergic agonist bromocriptine (BC) and exogenously administered prolactin (PRL) on the spontaneous behavior of female cats were investigated. The objective was to test whether BC-induced behavioral effects may be antagonized by PRL. BC (6 mg/kg ip) administration induced abnormal behaviors such as limb flicks, abortive grooms, head/body shakes, and hallucinatory-like behavior/escape as well as excessive grooming. PRL (5 mg/kg ip) administration induced biphasic changes in grooming. The first change was an increase in grooming frequency averaging 256% of baseline control values and lasting for 1 h. This change was followed by reductions in grooming of 75 and 82.5% below baseline during Hours 2 and 3 postinjection, respectively. Combined BC and PRL treatment antagonized the frequency of BC-induced motor effects such as limb flicks, abortive grooms, and head/body shakes. Limb flicks occurred nine times more often 2 h after BC alone than after BC and PRL. The combined treatment also antagonized the excessive grooming observed after separate administrations of BC and PRL. The observed interactions between PRL and BC behavioral effects support the notion that PRL may be an important modulator of dopamine-dependent motor behavior in female cats.     

Beware of frontal lobe deficits in hippocampal clothing

The Wisconsin card-sorting test (WCST) is a commonly used clinical tool for the detection of frontal lobe dysfunction, specifically executive dysfunction. Patients with lesions outside the frontal lobes sometimes show deficits on the WCST, however, and some researchers have implicated hippocampal dysfunction as the cause of the deficit. But a critical role for the hippocampus seems to be untenable because amnesic patients with bilateral medial temporal lobe (MTL) lesions perform the WCST normally. In the case of epileptic patients, an alternative explanation of the card-sorting impairment is the propagation of abnormal discharges from MTL to frontal lobe structures, causing remote interference with executive circuits.     

Deficient passive and one-way active avoidance acquisition following medial forebrain bundle lesions in rats.

Cathodal electrolytic lesions of the medial forebrain bundle (MFB) at posterior hypothalamic levels in male hooded rats produced a mild, transient hypodipsia and lowered jump thresholds to footshock. The lesions produced marked deficits in passive avoidance performance in a paradigm that paired discrete, linearly incrementing footshock intensities with contact of a water spout following 48 hr of water deprivation. Intraperitoneal injections of DL-5-hydroxytryptophan (75 mg/kg), the immediate metabolic precursor of serotonin, had no effect on the passive avoidance performance of either experimental or operated control subjects. Lesions of the MFB also resulted in deficient acquisition in a one-trial step-through passive avoidance paradigm not using motivation to drink and caused a severe acquisition deficit in a one-way active avoidance task. Lesions of the septal nuclei produced lowered jump thresholds but did not affect acquisition in the first passive avoidance task. The results are interpreted as indicating a lesion-induced deficiency in fear learning, independent of the serotonergic functions of the MFB.     

Cortical substrates of taste aversion learning: dorsal prepiriform (insular) lesions disrupt taste aversion learning

The functional relation between restricted damage to ventral primary somatosensory neocortex and the ability of rats to acquire conditioned taste aversion (CTA( was examined by a combination of behavioral and neurohistological techniques. Lesions confined exclusively to the established gustatory neocortex (GN) did not disrupt CTA acquisition, nor did lesions confined to suprarhinal cortical areas ventral to the GN. Lesions that encroached on dorsal prepiriform and insular cortices produced CTA acquisition deficits and damaged a large proportion of efferent projections to the prefrontal and precentral neocortex. In a second experiment, lesions of dorsal prepiriform and insular cortices did not modify taste preference-aversion threshold to any of the four taste modalities. It is concluded tha ventral somatosensory neocortical fields, including the established GN, do not mediate CTA acquisition and that rhinal cortices ventral and posterior to the GN are preferentially involved in associative learning for tastes and illness.     

Sentence processing in Lewy body spectrum disorder: the role of working memory

Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson's disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferior prefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease.     

Peripheral 8-OH-DPAT and scopolamine infused into the frontal cortex produce passive avoidance retention impairments in rats

The present study determined whether peripheral injections of the 5HT(1A) agonist (8-OH-DPAT), scopolamine infusions into the frontal cortex, or a combination of both drug treatments would produce impairments in rats trained on passive avoidance. Using a 2x2 design, rats were infused with either bacteriostatic water or 30 microg/1 microl of scopolamine HCl into the frontal cortex 30 min before being trained on passive avoidance. This was followed by injections (ip) of either 0.1% ascorbic acid/bacteriostatic water or 30 microg/kg of 8-OH-DPAT 15 min later. All subjects were tested for retention 72h later. At test, the initial latency to enter into the black shocked compartment and the total time spent in the white safe compartment (TTW) were recorded. Analysis of the latency data indicated that scopolamine and 8-OH-DPAT, when administered singly or in combination, produced amnesia for the task. Assessment of TTW scores, however, revealed that of the three drug-treated groups, only animals treated with 8-OH-DPAT alone tended to avoid the previously shocked black compartment and spend more time in the white safe compartment. These data indicate that either stimulating 5-HT(1A) or blocking frontal cortical muscarinic receptors at training impairs passive avoidance performance and that the deficit following the latter treatment is somewhat more extensive. Implications for the role frontal cortical muscarinic and 5HT(1A) receptors play in learning and memory are discussed.     

Spinal and locus coeruleus noradrenergic lesions abolish the analgesic effects of 5-methoxy-N,N-dimethyltryptamine

Two experiments were performed on Sprague-Dawley rats to study the effects of noradrenaline and 5-hydroxytryptamine depletion upon the antinociceptive effects of acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) administration. 6-Hydroxydopamine-induced lesions following microinjections to either the locus coeruleus or the spinal cord (lumbar) abolished completely 5-MeODMT-induced analgesia in the tail-flick, hot-plate, and shock titration tests whereas 5,7-dihydroxytryptamine-induced lesions of the nucleus raphe magnus and the lumbar spinal cord attenuated 5-MeODMT analgesia in the tail-flick and shock titration tests. Thus, the experiments serve to demonstrate an important interaction between descending noradrenergic and serotonergic pathways, possibly at a spinal locus.     

Maternal behavior of mice with cingulate cortical, amygdala, or septal lesions.

Nest building, pup retrieving, and pup survival and growth were evaluated in primiparous control mice and those with cingulate cortical, neocortical, amygdala, or septal lesions. Mice with neocortical or amygdala lesions showed little or no deficits in maternal behavior. Mice with septal lesions were severely impaired in all aspects of maternal care. These mice did not build nests, showed a variety of aberrant behaviors during pup retrieving, and their pups died or gained significantly less weight than those of controls. Mice with cingulate cortical lesions retrieved pups more slowly than controls, and retrieving deficits were correlated with the extent of retrograde degeneration found in the anterior thalamic nuclei.     

Decreased locomotor and investigatory exploration after denervation of catecholamine terminal fields in the forebrain of rats.

Exploratory behaviors were examined after bilateral microinjections of 6-hydroxydopamine into two hypothalamic sites that produced different patterns of denervation of forebrain catecholamine terminal fields. After anterolateral injections rats locomoted and reared less in a novel open field, responded abnormally to changes in the degree of novelty of the open field, and investigated a novel object less. These are deficits in exploratory behavior because they were not secondary to the inhibition of open-field behavior by hyperemotionality, by general motor disability, or by the failure to detect novel spaces or objects. Such anterolateral injections produced loss of catecholamine fibers, determined histochemically, in neocortical, hippocampal, anterolateral hypothalamic, mesolimbic, mesocortical, and anteromedioventral striatal terminal fields and loss of dopaminergic perikarya in the A10 and anteromedial A9 cell groups. No deficits in exploratory behaviors occurred, however, after bilateral anteromedial 6-hydroxydopamine injections that denervated neocortical, hippocampal, and anteromedial hypothalamic catecholamine terminal fields. A critical forebrain catecholaminergic innervation for exploratory responses to novel stimuli may be within areas that were denervated by anterolateral but not by anteromedial hypothalamic 6-nydroxydopamine injections. These areas are mesolimbic, mesocortical, anteromedioventral, and anterolateral hypothalamic terminal fields.     

Deficits in visual learning produced by posterior temporal lesions in cats

Eight cats with lesions in the posterior temporal (PT) cortex, seven cats with lesions in the basolateral amygdala (BLA), and eight intact controls were observed on eight tests of visual discrimination learning and of spontaneous responses to salient visual stimuli. The effects of the two lesions were somewhat dissociable. The PT lesions were accompanied by a severe deficit in pattern discrimination learning but no loss in visual tracking or orientation to the silhouette of a threatening cat. The BLA lesions produced a milder and less consistent loss in pattern discrimination but serious defects in tracking and reponse to the cat silhouette. Both operated groups performed well on the visual cliff. The deficit from PT lesions appeared independent of damage to the geniculocortical system. The parallel of symptoms from PT lesions in cats and inferotemporal lesions in monkeys is discussed.     

Amino Acid Effects on Post-Stress Ulcers: Relationship to Brain Serotonin, 5-HIAA and Norepinephrine

To replicate and extend results of earlier studies on amino acid effects on post-stress ulcers, rats were subjected to i.p. injections of (a) saline, (b) tryptophan, (c) tyrosine + valine or(d) tryptophan + tyrosine + valine, either 30 minutes before or immediately after one hour of water restraint stress. Gastric lesions, brain norepinephrine, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) were examined after one hour of poststress rest. We hypothesised that post-stress lesions could be aggravated by central noradrenergic hypoactivity and serotonergic hyperactivity during the post-stress period. Other studies have indicated that tyrosine + valine reduces central serotonergic activity, while additional tryptophan blocks this effect. We therefore expected post-stress lesions to be reduced in tyrosine + valine but not in tryptophan + tyrosine + valine treated animals. Although these expectations were met tentatively in animals injected prior to stress, thus replicating tyrosine + valine effects we had observed earlier, opposite results were found in animals treated post-stress. The brain analyses indicate that the data cannot be explained by a norepinephrine/serotonin imbalance hypothesis. The time dependency of the effects underlines the need for caution in clinical applications of these amino acid treatments.     

The effects of p-chloroamphetamine, a depletor of brain serotonin, on the performance of rats in two types of positively reinforced complex spatial discrimination tasks

Learning in male Sprague-Dawley rats was assessed in two types of positively reinforced complex spatial discrimination tasks (Stone 14-unit T-maze and eight-arm radial-arm maze) following cytotoxic lesions of central serotonergic terminal projection fields with p-chloroamphetamine (PCA). Learning, as expressed as mean number of errors per day and mean number of trails required to reach criterion, was significantly enhanced in the PCA-lesioned animals trained in the Stone maze. On the other hand, the performance of the PCA-lesioned animals trained in the eight-arm radial-arm maze was not found to differ significantly from that of saline-injected animals. The improved acquisition of the PCA-lesioned rats trained in the Stone maze was completely abolished following pretreatment with the selective serotonergic reuptake inhibitor norzimeldine. Neurochemical analyses of the brains of representative animals revealed that the levels of serotonin and its major metabolite, 5-hydroxy-3-indoleacetic acid, were both significantly reduced by PCA in all regions examined. While it is clear from these and other studies that the serotonergic nervous system plays an important role in the processes underlying learning and memory, these results further underscore the selective role of this neurotransmitter system in the way information is processed by the brain.     

Processing of temporal duration information in working memory after frontodorsal tumour excisions

This study aimed to test the hypothesis that impairments of temporal duration processing after frontal lobe lesions reflect deficits in executive monitoring functions rather than a domain-specific deficit in the maintenance of duration information in working memory. Patients with frontodorsal lesions, clinical controls with post-central lesions, and healthy controls performed recognition and classification tasks, which should allow for testing maintenance and monitoring functions, respectively. Results showed mild non-selective impairments of the frontal patients on both temporal and spatial recognition tasks, but a marked selective degradation on temporal classification while performance on spatial classification was unimpaired. This suggests that maintenance of duration information in working memory after frontal lesions is basically preserved but that, depending on executive task characteristics, there is a specific deficit in the strategic organization of this type of information.     

Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology

There is evidence that disturbances in central serotonin (5-HT) function have a role in impulsive aggression, violence, and criminality. A deletion/insertion polymorphism within the 5-HT transporter (5-HTT) promoter gene (5-HTT gene-linked polymorphic region, 5-HTTLPR) is thought to be associated with several psychopathological phenotypes related to disturbed impulse control, anxiety and depression. This study examined the association of the 5-HTTLPR with violent behavior in a sample of 153 male Caucasians referred for a forensic psychiatric examination. We found a significant excess of the short (s) allele and the s/s genotype in patients characterized by recurrent and overt physical violent behavior. This genetic variance explained 5% of the variance of violent behavior. When controlled for the impact of several psychopathologies related to violent behavior, this association was observed in individuals with a history of childhood attention deficit/hyperactivity disorder (ADHD)-related symptoms, but not presenting with personality disorder or increased impulsiveness. In conclusion, the results (i). suggest an association between serotonergic dysfunction and violent behavior, (ii). provide evidence for an-at least partial-genetic regulation of violent behavior in a subgroup of male offenders, and (iii). suggest a significant role for 5-HT transporter functionality for violent behavior.