Brain serotonin depletion by lesions of the median raphe nucleus enhances the psychotomimetic action of phencyclidine, but not dizocilpine (MK-801), in rats

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138-2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague-Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine-but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.     

Phencyclidine-induced locomotor hyperactivity is enhanced in mice after stereotaxic brain serotonin depletion

The aim of this study was to investigate the role of forebrain serotonin projections in behavioural models with relevance to schizophrenia. Mice received stereotaxic micro-injections of the serotonin neurotoxin 5,7-dihydroxytryptamine into the median raphe nucleus (MRN). Two weeks later, MRN-lesioned mice were hyperactive at baseline and showed enhanced locomotor hyperactivity induced by phencyclidine. In contrast, no lesion effect was observed on the locomotor hyperactivity induced by amphetamine treatment or on prepulse inhibition. Lesioned mice showed a 68% depletion of serotonin in the hippocampus and 31% depletion in the striatum. These data confirm previous studies in rats that selective serotonin depletion in the brain enhances the effect of phencyclidine, but not amphetamine, on locomotor activity. This enhanced action of phencyclidine is likely to be mediated by the absence of serotonin-mediated behavioural inhibition in the hippocampus, leaving the psychostimulant effects of phencyclidine unopposed. Taken together with previous studies in rats, these studies in mice suggest that serotonin release in the dorsal hippocampus constitutes a behavioural inhibitory pathway normally involved in dampening excessive behavioural stimulation. Dysfunction of this pathway could be involved in psychosis and its stimulation could be a potential mechanism of action of antipsychotic drugs.     

Differential role of serotonin projections from the dorsal and median raphe nuclei in phencyclidine-induced hyperlocomotion and fos-like immunoreactivity in rats

Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine‐induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine‐induced hyperlocomotion by parallel assessment of Fos‐like immunoreactivity (FLI), a marker of neuronal activation in the brain. Male Sprague‐Dawley rats were anesthetized with pentobarbitone and stereotaxically microinjected with 5 μg of the serotonergic neurotoxin, 5,7‐dihydroxytryptamine (5,7‐DHT), into either the dorsal raphe (DRN) or median raphe nucleus (MRN). Two weeks after the surgery, rats with lesions of the MRN, but not those with lesions of the DRN, showed significant enhancement of the hyperlocomotion induced by injection of 2.5 mg/kg of phencyclidine. Rats with MRN lesions also showed significantly higher levels of FLI in the polymorphic layer of the dentate gyrus in the dorsal hippocampus (PoDG) when compared with sham‐operated controls. Rats with lesions of the DRN showed significantly higher levels of FLI in the nucleus accumbens (NAcc). These results indicate that FLI in the PoDG, but not the NAcc, correlates with enhanced phencyclidine‐induced locomotor hyperactivity in MRN‐lesioned rats. These results support our previous studies suggesting a role of serotonergic projections from the MRN to the dorsal hippocampus in some of the symptoms of schizophrenia. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Hippocampal mediation of raphe lesion- and PCPA-induced hyperactivity in the rat.

These experiments provide a direct test of the hypothesis that median raphe lesion- or PCPA-induced hyperactivity in the rat is mediated specifically by the hippocampus. Previous studies had shown that a marked depletion of hippocampal serotonin accompanied median lesion-induced hyperactivity. In the present studies, aspiration of the anterodorsal hippocampus of adult male rats prior to median raphe lesions or PCPA administration abolished the ability of both of these treatments to produce locomotor hyperactivity in animals chronically housed in tilt cages. Control lesions of the overlying dorsal cortex and corpus callosum were ineffective in blocking the hyperactivity produced by these two treatments. The possibility that serotonin depletion-induced hyperactivity was dependent on the pituitary was excluded by the fact that PCPA effectively elevated the activity of hypophysectomized rats. These data indicate that serotonin depletion-induced hyperactivity in the rat is mediated by the hippocampus.     

Differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not in psychotomimetic drug-induced hyperlocomotion

While there is abundant evidence for a role of 5-HT and the amygdala in anxiety and depression, the role of 5-HT in this brain region in schizophrenia is less well understood. We therefore examined the effects of local 5-HT depletion in the amygdala on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition, two animal model of aspects of schizophrenia. Pentobarbital-anaesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically micro-injected with 0.5 microl of a 5 microg/mul solution of the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the basolateral (BLA) or central nucleus of amygdala (CeN). Two weeks after the surgery, rats with BLA lesions did not show changes in either psychotomimetic drug-induced locomotor hyperactivity or prepulse inhibition. In contrast, rats with CeN lesions showed significant disruption of prepulse inhibition, but no changes in psychotomimetic drug-induced locomotor hyperactivity. Neurochemical analysis and autoradiographic labelling of 5-HT transporter sites showed that a good degree of anatomical selectivity was obtained. Following administration of 5,7-DHT into the amygdala, the concentration of 5-HT was significantly reduced. Similarly, 5-HT transporter autoradiographs showed differential and selective lesions of 5-HT innervation in targeted subregions of the amygdala. These results provide evidence for differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not locomotor hyperactivity. Thus, the present study supports the view that 5-HT in the amygdala may be involved in aspects of schizophrenia and a target for antipsychotic drug action.     

When injected into the fimbria-fornix/cingular bundle, not in the raphe, 5,7-dihydroxytryptamine prevents amphetamine-induced hyperlocomotion

The locomotor effects of acute amphetamine treatment (1 mg/kg, i.p.) were assessed in Long-Evans rats after 5,7-dihydroxytryptamine (5, 7-DHT) injections into the fimbria-fornix/cingular bundle (FiFx/CB; 4 microg/side), or the dorsal and median raphe (Raphe; 10 microg). In control rats, amphetamine induced a significant increase of home-cage activity for about 2 h. This effect was similar in Raphe rats, but was absent in FiFx/CB rats. The raphe lesions reduced serotonin concentrations by 50% in the dorsal hippocampus, 75% in the ventral hippocampus and 58% in the fronto-parietal cortex. After FiFx/CB lesions, the reduction amounted 50, 61 and only 25%, in each of these regions, respectively. In the fronto-partietal cortex, dopamine concentration was significantly decreased in Raphe (-27%) and FiFx/CB rats (-65%). The results suggest that a serotonergic denervation of the hippocampus by injections of 5,7-DHT into the FiFx/CB pathways hampers the stimulating effects of amphetamine on locomotor activity. This effect might be related to the reduced dopaminergic tone in the fronto-parietal cortex.     

Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat

We examined in the rat, the effects of neonatal (postnatal Day 7) and adult excitotoxic lesions of the mediodorsal thalamus (MDT), a brain area innervating the prefrontal cortex and implicated as a site of neuropathology in schizophrenia. Previous studies showed that rats with neonatal excitotoxic damage of the ventral hippocampus (VH), used as an animal model of this disorder, display in young adulthood a variety of abnormalities reminiscent of schizophrenia, including hyperactivity to stressful stimuli and amphetamine. It has been speculated that behavioral abnormalities of the neonatally VH lesioned animals are mediated through MDT projections to the prefrontal cortex. We tested if rats with ibotenic acid (1.5 microg per hemisphere in neonates, 2 microg in adults) lesions of MDT exhibited motor hyperactivity in the same experimental conditions (i.e. in response to novelty, saline injections and amphetamine administration) as rats with the VH lesions. We found that, in contrast to rats with VH lesions, neonatally lesioned MDT rats showed reduced vertical activity in response to amphetamine and no changes in locomotor activity to novelty, saline or amphetamine injections 7 weeks postlesion. Adult lesioned MDT rats exhibited no changes in motor activity as compared to controls at 7 weeks postlesion. These results indicate that neonatal or adult excitotoxic lesions of MDT do not produce behavioral changes analogous to those seen after neonatal VH lesions and do not appear to reproduce animal model-like features of schizophrenia.     

Lesion size and amphetamine hyperlocomotion after neonatal ventral hippocampal lesions: more is less

Neonatal hippocampal lesions in rats produce behavioral and neurochemical abnormalities post-puberty that are used in animal models for developmentally linked pathology in schizophrenia. In one model, adult rats exhibit enhanced sensitivity to the locomotor-activating effects of amphetamine, if they had sustained excitotoxic lesions of the ventral hippocampus on post-natal day 7. The hippocampal elements responsible for these lesion-induced developmental changes have not been fully characterized. The present study assessed the locomotor-activating effects of amphetamine in adult rats that on day 7 had sustained either sham or ibotenic acid lesions of the ventral hippocampus alone ("standard lesions"), or the ventral hippocampus plus surrounding portions of entorhinal cortex and dorsal hippocampus ("large lesions"). "Standard lesions" produced the expected "supersensitive" locomotor response to amphetamine, while "large lesions" did not. No differences between these lesion groups were observed in baseline levels of locomotor activity or habituation. These data suggest that models of enhanced behavioral sensitivity to dopamine agonists after neonatal hippocampal lesions require functionality in the entorhinal cortex and/or dorsal hippocampus. It is possible that the behavioral abnormalities in the "neonatal hippocampal lesion model" reflect, at least in part, aberrant function within spared elements of the hippocampal complex.     

Differential serotonergic innervation of individual hypothalamic nuclei and other forebrain regions by the dorsal and median midbrain raphe nuclei

Lesions in the midbrain median but not in the dorsal raphe nucleus significantly decreased the serotonin (5-HT) content of the hippocampus (61%), medial preoptic area (49%), suprachiasmatic nucleus (70%) and anterior hypothalamic area (60%). Electrolytic lesions restricted to either the median or dorsal raphe nucleus produced significant reductions in the 5-HT concentration of the caudate-putamen, anterolateral hypothalamic area (45%) and arcuate nucleus (48–58%). The fall in caudate-putamen 5-HT level was significantly greater after the dorsal (66%) than after the median (24%) raphe lesion. Neither lesion significantly affected the 5-HT content of the posterolateral hypothalamic area, the ventromedial hypothalamic nucleus or the dorsomedial hypothalamic nucleus. Thus, like their differential projections to the caudate-putamen and hippocampus, the mesencephalic dorsal and median raphe nuclei appear to innervate different preoptico-hypothalamic nuclei and areas. Whereas the median raphe nucleus seems to be the primary source of 5-HT fibers to the suprachiasmatic nucleus, anterior hypothalamic area and medial preoptic area, the 5-HT inputs to the anterolateral hypothalamic area and arcuate nucleus appear to derive from both the dorsal and median raphe nuclei.     

Neurotoxic effects of p-chloroamphetamine on the serotoninergic innervation of the trigeminal motor nucleus: a retrograde transport study

The rat forebrain receives projections from both dorsal and median raphe nuclei. It has recently been shown that serotoninergic axons arising from the dorsal raphe nucleus, but not those from the median raphe nucleus, degenerate following systemic administration of p-chloroamphetamine (PCA). The present study was conducted to determine (i) whether the motor nucleus of the trigeminal nerve is innervated by overlapping projections from multiple serotonin cell groups and (ii) whether a particular subset of serotoninergic axon terminals in the trigeminal motor nucleus are sensitive to the neurotoxic effects of PCA. Retrograde transport was used in combination with immunofluorescence to identify the serotonin-positive cells that project to the trigeminal motor nucleus both in control rats and in rats previously treated with PCA. In untreated rats, an average of 95 retrogradely labeled serotonin-positive neurons were found in the dorsal raphe nucleus, 135 in the nucleus raphe obscurus, 132 in the nucleus raphe pallidus and 63 in the ventrolateral medulla. After treatment with PCA, there was a marked decrease (-77%) in the number of retrogradely labeled serotoninergic neurons in the dorsal raphe nucleus, whereas the number of labeled neurons was unchanged in the raphe obscurus and raphe pallidus. These results demonstrate that PCA selectively lesions serotonin axon terminals arising from the dorsal raphe nucleus, while sparing projections from the raphe obscurus and raphe pallidus to the trigeminal motor nucleus. This conclusion is in agreement with previous findings that in the forebrain only axons from the dorsal raphe are vulnerable to PCA. The data provide further evidence that serotoninergic axons originating in the dorsal raphe nucleus differ from other serotoninergic axons in their pharmacological properties and that the dorsal raphe may contain a functionally unique subset of serotonin neurons.     

Behavioural alterations relevant to developmental brain disorders in mice with neonatally induced ventral hippocampal lesions

Neonatal lesioning of the ventral hippocampus (vHc) in rats has served as a useful heuristic animal model to elucidate neurodevelopmental mechanisms of schizophrenia (SCZ). In the current study we have established that this procedure can be applied to model SCZ symptomatology in mice. Neonatal mice (postnatal day 6) were anaesthetised by hypothermia and electrolytic lesions of the vHc were induced. We observed locomotor hyperactivity at prepubertal and adult age and hypersensitivity to amphetamine. Furthermore, working memory deficits were observed in Y-maze (spontaneous alternation) and T-maze (exploration of a novel arm) test protocols. Decreased anxious behaviour in the elevated plus maze and increased sociability were also observed. These changes were dependent on lesion size. No differences were observed in prepulse inhibition of the startle reflex, latent inhibition, spatial memory (Morris water maze), problem solving capacities (syringe puzzle) and ability to discriminate between different unfamiliar mice. The presented findings might further help to identify neurobiological mechanisms of neurodevelopmental disorders.     

Further studies on the activation of rat median raphe serotonergic neurons by inescapable sound stress

Previous studies, using a biochemical measure of serotonergic neuronal function, show that inescapable, randomly presented sound pulses activate serotonergic neurons in the rat median raphe but not dorsal raphe nucleus. The present study reveals that this activation also occurs in serotonin projection areas, in hippocampus, nucleus accumbens and cortex but not in caudate nucleus. The selectivity of this response is examined by comparing the response to sound stress with that produced by morphine, a treatment known to selectively activate dorsal raphe but not median raphe serotonergic neurons. Two approaches are used in Sprague-Dawley rat to measure the activation of serotonergic neurons: (1) determination ex vivo of accumulation of 5-hydroxytryptophan (5-HTP) in tissue from the dorsal and median raphe nuclei, hippocampus, cortex, caudate nucleus, and nucleus accumbens following in vivo inhibition of aromatic amino acid decarboxylase; and (2) measurement of extracellular serotonin levels in hippocampus, caudate nucleus, and nucleus accumbens. Sound stress increases 5-HTP accumulation in median raphe nucleus, hippocampus, cortex, and nucleus accumbens, but not dorsal raphe nucleus or caudate nucleus. Sound stress also enhances extracellular serotonin levels in hippocampus and nucleus accumbens, but not caudate nucleus. In contrast, the morphine treatment enhances 5-HTP accumulation in dorsal raphe nucleus, cortex and caudate nucleus, but not in median raphe nucleus, hippocampus or nucleus accumbens. Furthermore, it increases extracellular serotonin levels in only the caudate nucleus. The combined effects of sound stress and morphine on 5-HTP accumulation are identical to those obtained by each treatment individually. These findings provide further support for the presence of serotonergic neurons within the median raphe nucleus that have a unique response profile. These neurons may have an important role in responses or adaptations to stress.     

Serotonergic lesions alter cocaine-induced locomotor behavior and stress-activation of the mesocorticolimbic dopamine system

The aim of this study was to examine the effects of serotonergic lesions to the dorsal raphe on midbrain dopaminergic systems. 5,7-Dihydroxytryptamine lesions of the dorsal raphe resulted in a substantial loss of serotonin in the medial prefrontal cortex (about 75%) and the nucleus accumbens (about 50%), while no change in DA levels or DA metabolism were noted in either region at 12 days postlesion. A transient basal locomotor activation was noted in the lesioned animals compared to the sham controls 7 to 12 days after the lesions. The locomotor response to an acute dose of cocaine was also enhanced in 5,7-dihydroxytryptamine lesioned rats, however, no change in the time course or magnitude of the behavioral locomotor response to repeated cocaine administration was observed. Restraint for 30 min increased DA metabolism in both the NAS and mPFC of sham rats, as expected. However, in 5,7-dihydroxytryptamine lesioned rats, restraint stress enhanced the usual stress-induced increase in DA metabolism by about 50 and 150% in the medial prefrontal cortex and nucleus accumbens, respectively. Our results indicate the 5,7-dihydroxytryptamine lesions of the dorsal raphe lower serotonin in both the mPFC and NAS leading to an enhanced responsiveness of the DA projections in both regions. This effect may be explained by a loss of sensitivity of DA receptors in 5,7-dihydroxytryptamine denervated rats. This interpretation implies that the stimulated, but not basal, release of DA in the mPFC and NAS is dependent on serotonin tone. © 1996 Wiley-Liss, Inc.     

Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats

The substantia nigra pars reticulata (SNR) is one of the major output nuclei of the basal ganglia. It connects the dorsal and ventral striatum with the thalamus, superior colliculus and pontomedullary brainstem. The SNR is therefore in a strategic position to regulate sensorimotor behavior. We here assessed the effects of SNR lesions on prepulse inhibition (PPI) of the acoustic startle response (ASR), stereotypy and locomotion in drug-free rats, as well as after systemic administration of the dopamine agonist DL-amphetamine (2 mg/kg), and the NMDA receptor antagonists dizocilpine (0.16 mg/kg) and CGP 40116 (2 mg/kg). SNR lesions reduced PPI, enhanced spontaneous sniffing and potentiated the locomotor stimulation by dizocilpine and CGP 40116. PPI was impaired by dizocilpine and CGP 40116 in controls. The ASR was enhanced in controls by dizocilpine and amphetamine. SNR lesions prevented the enhancement of the ASR by amphetamine. A second experiment tested the hypothesis that the SNR mediates PPI via a GABAergic inhibition of the startle pathway. Infusion of the GABA(B) antagonist phaclofen but not the GABA(A) antagonist picrotoxin into the caudal pontine reticular nucleus reduced PPI. Hence, lesion of the SNR reduces sensorimotor gating possibly by elimination of a nigroreticular GABAergic projection interacting with GABA(B) receptors. Moreover, destruction of the SNR enhances the motor stimulatory effects of amphetamine and of the NMDA antagonists dizocilpine and CGP 40116. We conclude that the SNR exerts a tonic GABAergic inhibition on sensorimotor behavior that is regulated by the dorsal and the ventral striatum.     

Prepulse inhibition of acoustic startle in spontaneously hypertensive rats

Prepulse inhibition is modulated by dopaminergic drugs and is disrupted in attention-deficit hyperactivity disorder, as well as mental illnesses such as schizophrenia. Spontaneously hypertensive rats (SHR) have been proposed as an animal model of attention-deficit hyperactivity disorder and show marked alterations of dopaminergic regulation of behaviour. SHR showed significantly lower startle amplitude than Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats, but no difference in startle habituation. Baseline percentage prepulse inhibition was higher in SHR and WKY rats than in SD rats. Treatment with amphetamine caused significant disruption of prepulse inhibition in SHR and WKY rats, but not SD rats. In contrast, treatment with apomorphine caused prepulse-dependent disruption of prepulse inhibition in SD rats only. Both MK-801 and 8-OH-DPAT treatment caused disruption of prepulse inhibition in all three rat strains. This study shows differential changes in startle level and prepulse inhibition in SHR, however these rats are not uniformly different from either WKY rats or SD rats and WKY rats differ in a number of respects from SD rats. In conclusion, these data further reveal altered dopaminergic regulation of behaviour in SHR, but also shows that caution is needed about the control strain used to compare these animals with.     

Neuronal projections from the mesencephalic raphe nuclear complex to the suprachiasmatic nucleus and the deep pineal gland of the golden hamster (Mesocricetus auratus)

Neuronal projections from the mesencephalic raphe system to the suprachiasmatic nucleus and the pineal complex were mapped in this study of the golden hamster, by use of the anterograde tracer Phaseolus vulgaris-leucoagglutinin and the retrograde tracer cholera toxin subunit B. From the median raphe nucleus, a rostral projection ascended in the ventral part of the mesencephalon to continue in the medial forebrain bundle of the forebrain. Nerve fibres from this bundle innervated the ventral and medial parts of the suprachiasmatic nucleus. At the level of the interpeduncular nucleus of the mesencephalon, fibres of the ventral bundle bent dorsally to reach the epithalamic area and to continue in the forebrain in a periventricular position. Some of these fibres innervated the dorsal tip of the suprachiasmatic nucleus. The dorsal raphe nucleus was the origin of a nerve fibre bundle, located in the periaqueductal gray of the mesencephalon, innervating the deep pineal gland and pineal stalk. Injection of cholera toxin B into the suprachiasmatic nucleus labelled cells in the median raphe. Combination of the retrograde tracing from the suprachiasmatic nucleus and serotonin transmitter immunohistochemistry showed that some of the cholera toxin B–immunoreactive nerve cells also contained serotonin. Thus, this study of the golden hamster shows a serotonergic projection from the median raphe nucleus to the suprachiasmatic nucleus and a projection from the dorsal raphe nucleus to the deep pineal gland supporting physiological indications of an influence of serotonin on the photoreceptive circadian system of the brain. J. Comp. Neurol. 399:73–93, 1998. © 1998 Wiley-Liss, Inc.     

The efferent connections of the nucleus raphe centralis superior in the rat as revealed by radioautography.

By chronically implanting a glass micropipette filled with tritiated leucine in the raphe centralis superior of the rat, the projection of this nucleus was traced by radioautography. The majority of the ascending projections were located within the ventral tegmental area and, further rostrally, the median forebrain bundle. Along the course of this bundle numerous fibers branched successively into the mammillary peduncle, the fasciculus retroflexus, the stria medullaris, the fornix and the cingulum. The most significant projections included the ones to the interpeduncular nucleus, the mammillary bodies, the habenular nuclei and the hippocampus. No projections were detected in the striatum, the cortex piriformis or the amygdala. Descending projections diffused to the pontine reticular formation and central gray through the medial and the dorsal longitudinal bundles. In addition widespread projections were also seen in nuclei located near the raphe centralis superior: raphe nuclei, dorsal and ventral tegmental nuclei.     

Delayed onset of prepulse inhibition deficits following kainic acid treatment on postnatal day 7 in rats

Abnormal activity in corticolimbic circuits during development may be a predisposing factor for schizophrenia. Permanent or temporary lesions of limbic structures such as the ventral hippocampus and basolateral amygdala in rats on postnatal day (PND) 7 result in functional changes similar to some behavioural and cognitive signs of schizophrenia. The present experiments tested whether transient increases in the neural activity of corticolimbic circuits on PND 7 would result in similar behavioural changes. Long-Evans rats were treated with either kainic acid (KA, 1.5 mg/kg, i.p.) or saline on PND 7 and tested for prepulse inhibition (PPI) of the acoustic startle response and spontaneous locomotor activity both in a novel environment and following amphetamine treatment before puberty (PND 35) and in early adulthood (PND 56). In subgroups of animals PPI was also measured following apomorphine administration (0.2 mg/kg) and spatial learning and memory were tested in the water maze. Rats treated with KA were indistinguishable from saline-treated animals on PND 35. However, on PND 56, KA-treated animals showed a subtle consistent decrease in PPI relative to control animals, but did not show increased sensitivity to the disruptive effects of a low dose of apomorphine on PPI. Locomotor responses to novelty or amphetamine were not reliably altered in the KA-treated animals. KA- and saline-treated animals performed similarly in the water maze. These results support the hypothesis that neural hyperactivity on PND 7 in rats causes behavioural changes in early adulthood that resemble some symptoms of schizophrenia. These pharmacological data suggest that the changes are not mediated by postsynaptic alterations in mesolimbic dopamine transmission.     

Dopamine-rich transplants in rats with 6-OHDA lesions of the ventral tegmental area. I. Effects on spontaneous and drug-induced locomotor activity

In order to investigate the relative contribution of dopaminergic projections to the nucleus accumbens and prefrontal cortex in the regulation of spontaneous and drug-induced locomotor activity, separate groups of rats were prepared with 6-OHDA lesions of the ventral tegmental area alone, or additional grafts of dopamine-rich tissue reinnervating either the nucleus accumbens or medial prefrontal cortex. A fourth unoperated group served as normal controls. The lesions induced no change in spontaneous, daytime activity, but increased overnight activity. The lesioned rats were also hyperactive to apomorphine, while the activational effects of amphetamine were blocked. Grafts of dopamine-rich tissue, whether into the prefrontal cortex or nucleus accumbens, resulted in a significant normalization of both drug responses towards control levels. Neither graft influenced overnight hyperactivity, whereas spontaneous daytime activity was increased above both control and lesion levels by the accumbens grafts alone. The results are interpreted as suggesting that dopaminergic projections to prefrontal cortex and nucleus accumbens are similarly rather than antagonistically involved in the regulation of drug-induced locomotor activation.     

Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats

Locomotor activity and regional forebrain levels of serotonin (5-HT) were measured following the placement of electrolytic lesions in either the dorsal or median raphe nucleus of adult male rats. In the first two experiments, control lesions were placed in the brachium conjunctivum, and in the third experiment, a sham lesion group served as control. Median lesions significantly increased locomotor actiivity as measured in tilt cages, by 250–300% on the second day post-lesion, and this elevation stabilized at approximately 100% above control levels on day 9 post-lesion. There were no statistically significant differences in the amount of locomotor activity in the dorsal, brachium or sham lesioned groups on any post-lesion day. When the amount of 5-HT depletion was measured 5 days post-lesion, it was found that the dorsal (D) and median (M) lesions produced similar reductions in cerebral cortex (D — 40%; M — 31%); hypothalamus (D — 54%; M — 58%) and striatum (D — 50%; M — 29%). However, the effects of the two lesions were markedly different in the hippocampus. The dorsal lesion produced a non-significant 10% reduction in hippocampal 5-HT level, while the median lesion caused an 82% reduction. On the basis of these data it is hypothesized that a reduction in hippocampal 5-HT may account for the increased activity in the median lesioned group.