Neonatal Dopamine Depletion Research Articles

Behavioral responses to anxiogenic tasks in young adult rats with neonatal dopamine depletion

The dopaminergic neural system plays a crucial role in motor regulation as well as regulation of anxiety-related behaviors. Although rats with neonatal dopamine depletion exhibit motor hyperactivity and have been utilized as animal models of attention deficit hyperactivity disorder, characterization of their behavior under anxiogenic conditions is lacking. In the present study, we investigated behavioral responses to anxiogenic stimuli in young adult rats with neonatal dopamine depletion using the open field (OF), elevated plus maze (EPM), and light/dark (L/B) box tests. The OF and EPM tests were performed under low-light and bright-light conditions. The ameliorative effects of pretreatment with methamphetamine (MAP) or atomoxetine (ATX) on abnormal behaviors induced by neonatal dopamine depletion were also assessed. Rats that underwent 6-hydroxydopamine treatment 4 day after birth showed significant increases in motor activity and decreases in anxiety-related behaviors in OF tests under both conditions and in EPM tests under bright-light conditions. Furthermore, rats with neonatal dopamine depletion did not show normal behavioral responsiveness to changes in the intensity of anxiogenic stimuli. Pretreatment with MAP (4 mg/kg) and ATX (1.2 mg/kg/day) ameliorated motor hyperactivity but not abnormal anxiety-related behaviors. These results suggest that the dopaminergic system plays a crucial role in the development of neural networks involved in locomotion as well as in those involved in anxiety-related behavior. The results indicate that the mechanisms underlying the abnormal anxiolytic responses partially differ from those underlying motor hyperactivity.

Neonatal 6-OHDA lesion model in mouse induces Attention-Deficit/ Hyperactivity Disorder (ADHD)-like behaviour

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impaired attention, impulsivity and hyperactivity. The “neonatal 6-hydroxydopamine” (6-OHDA) lesion is a commonly used model of ADHD in rat. However, a comprehensive assessment of ADHD‐like symptoms is still missing, and data in mouse remain largely unavailable. Our aim was to analyse symptoms of ADHD in the mouse neonatal 6‐OHDA model. 6‐OHDA mice exhibited the major ADHD‐like symptoms, i.e. hyperactivity (open field), attention deficit and impulsivity (five‐choice serial reaction time task). Further, the model revealed discrete co‐existing symptoms, i.e. anxiety‐like (elevated plus maze test) and antisocial (social interaction) behaviours and decreased cognitive functioning (novel object recognition). The efficacy of methylphenidate, a classical psychostimulant used in the treatment of ADHD, was also evaluated. A histological analysis further supports the model validity by indicating dopamine depletion, changes in cortical thickness and abnormalities in anterior cingulate cortex neurons. A principal component analysis of the behaviour profile confirms that the 6‐OHDA mouse model displayed good face and predictive validity. We conclude that neonatal dopamine depletion results in behavioural and morphological changes similar to those seen in patients and therefore could be used as a model for studying ADHD pathophysiological mechanisms and identifying therapeutic targets.

Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion

Rats with dopamine depletion caused by 6-hydroxydopamine (6-OHDA) treatment during adulthood and the neonatal period exhibit akinetic motor activity and spontaneous motor hyperactivity during adolescence, respectively, indicating that the behavioral effects of dopamine depletion depend on the period of lesion development. Dopamine depletion during adulthood induces hyperalgesic response to mechanical, thermal, and/or chemical stimuli, whereas the effects of neonatal dopamine depletion on nociceptive response in adolescent rats are yet to be examined. The latter aspect was addressed in this study, and behavioral responses were examined using von-Frey, tail flick, and formalin tests. The formalin test revealed that rats with neonatal dopamine depletion exhibited a significant increase in nociceptive response during interphase (6–15min post formalin injection) and phase 2 (16–75min post formalin injection). This increase in nociceptive response to the formalin injection was not reversed by pretreatment with methamphetamine, which ameliorates motor hyperactivity observed in adolescent rats with neonatal 6-OHDA treatment. The von-Frey filament and tail flick tests failed to reveal significant differences in withdrawal thresholds between neonatal 6-OHDA-treated and vehicle-treated rats. The spinal neuronal response to the formalin injection into the rat hind paw was also examined through immunohistochemical analysis of c-Fos protein. Significantly increased numbers of c-Fos-immunoreactive cells were observed in laminae I–II and V–VI of the ipsilateral spinal cord to the site of the formalin injection in rats with neonatal dopamine depletion compared with vehicle-treated rats. These results suggest that the dopaminergic neural system plays a crucial role in the development of a neural network for tonic pain, including the spinal neural circuit for nociceptive transmission, and that the mechanism underlying hyperalgesia to tonic pain is not always consistent with that of spontaneous motor hyperactivity induced by neonatal dopamine depletion.

Neonatal dopamine depletion induces changes in morphogenesis and gene expression in the developing cortex

The mesocorticolimbic dopamine (DA) system is implicated in mental health disorders affecting attention, impulse inhibition and other cognitive functions. It has also been involved in the regulation of cortical morphogenesis. The present study uses focal injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of BALB/c mice to examine morphological, behavioral and transcriptional responses to selective DA deficit in the fronto-parietal cortex. Mice that received injections of 6-OHDA on postnatal day 1 (PND1) showed reduction in DA levels in their cortices at PND7. Histological analysis at PND120 revealed increased fronto-cortical width, but decreased width of somatosensory parietal cortex. Open field object recognition suggested impaired response inhibition in adult mice after 6-OHDA treatment. Transcriptional analyses using 17K mouse microarrays showed that such lesions caused up-regulation of 100 genes in the cortex at PND7. Notably, among these genes are Sema3A which plays a repulsive role in axonal guidance, RhoD which inhibits dendritic growth and tubulin beta-5 microtubule subunit. In contrast, 127 genes were down-regulated, including CCT-epsilon and CCT-zeta that play roles in actin and tubulin folding. Thus, neonatal DA depletion affects transcripts involved in control of cytoskeletal formation and pathway finding, instrumental for normal differentiation and synaptogenesis. The observed gene expression changes are consistent with histological cortical and behavioral impairments in the adult mice treated with 6-OHDA on PND1. Our results point towards specific molecular targets that might be involved in disease process mediated by altered developmental DA regulation.

Plasticity within striatal direct pathway neurons after neonatal dopamine depletion is mediated through a novel functional coupling of serotonin 5‐HT2 receptors to the ERK 1/2 map kinase pathway

Dysfunction within the striatal direct and indirect projecting systems arises after 6-hydroxydopamine (6-OHDA)-induced dopamine depletion, highlighting the central regulatory function of dopamine in motor systems. However, the striatal 5-hydroxytryptamine (5-HT) innervation remains intact after 6-OHDA lesions, suggesting that the 5-HT system may contribute to the lesion-induced dysfunction, or alternatively, it may adapt and compensate for the dopamine deficit. Neonatal 6-OHDA lesions actually give rise to a 5-HT axonal hyperinnervation within the dorsal striatum, further reinforcing the idea that the 5-HT system plays a central role in striatal function after dopamine depletion. Here we show that neonatal but not adult 6-OHDA lesions result in a novel coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase pathway, a signaling cascade known to regulate neuronal plasticity. Chloroamphetamine-induced 5-HT release or direct stimulation of striatal 5-HT2 receptors via the 5-HT2 agonist DOI, produced robust ERK1/2 phosphorylation throughout the dorsal striatum of neonatal lesioned animals, a response not observed within the intact striatum. Pretreatment with the select 5-HT2 receptor antagonist Ketanserin blocked DOI-induced ERK1/2 phosphorylation. This drug-induced ERK1/2 phosphorylation was subsequently shown to be restricted to direct pathway striatal neurons. Our data show that adaptation of direct pathway neurons after neonatal 6-OHDA lesions involves coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase cascade, a pathway not typically active in these neurons. Because dopamine-mediated signaling is redundant after 6-OHDA lesions, 5-HT-mediated stimulation of the ERK1/2/MAP Kinase pathway may provide an alternative signaling route allowing the regulation of neuronal gene expression and neuronal plasticity in the absence of dopamine.

Diminished serotonergic innervation of adult medial prefrontal cortex after 6-OHDA lesions in the newborn rat

The development of the serotonergic (5HT) and dopaminergic (DA) systems may contribute to the onset of psychotic disorders during late adolescence and early adulthood. Previous studies in our laboratory have suggested that these systems may compete for functional territory on neurons during development, as lesions of the serotonergic system at postnatal day 5 (P5) result in an increase in the density of dopaminergic fibers in rat medial prefrontal cortex (mPFC). In the present study, the dopaminergic system of P5 rats was lesioned with intracisternal injections of 6-hydroxydopamine (6-OHDA). Quantification of serotonin-immunoreactivity (5HT-IR) in mPFC at adulthood (P70) revealed a significant decrease in fiber density within layers II and III of the Cg3 subdivision of mPFC in lesioned rats compared to sham controls. We propose that the decrease in serotonergic fibers in mPFC in response to a neonatal depletion of dopamine may be due to the loss of a trophic effect of this system on 5HT neurons and/or fibers during development. Taken together with previous findings, our data suggest that there may be an “inverse trophic” relationship between the cortical DA and 5HT systems whereby dopamine facilitates the ingrowth of 5HT fibers, while serotonin suppresses the ingrowth of DA fibers. We present a model based on neurotrophic interactions at the cortical and brainstem levels that could potentially explain these unexpected results.

Neonatal depletion of cortical dopamine: Effects on dopamine turnover and motor behavior in juvenile and adult rats

Abnormal development of mesoprefrontal dopamine (DA) neurons may contribute to the pathophysiology of schizophrenia. Consistent with this hypothesis, DA nerve terminal density is decreased in the cortex of schizophrenic subjects [M. Akil, J.N. Pierri, R.E. Whitehead, C.L. Edgar, C. Mohila, A.R. Sampson, and D.A. Lewis, Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects, Am. J. Psychiatry, 156 (1999) 1580–1589]. This abnormality may be present early in development, giving rise to dysfunction as an individual matures. The present studies examined the effects of early partial loss of medial prefrontal cortex (mPFC) DA on DA turnover and locomotor behavior in juvenile, pubertal, and adult rats (30, 45, and 60 days of age, respectively). Local infusions of 6-hydroxydopamine on postnatal day (PN) 12–14 produced persistent decreases in basal tissue DA concentrations and increases in 3,4-dihydroxyphenylacetic acid (DOPAC):DA ratios in the mPFC. In the nucleus accumbens of lesioned rats, basal DA concentrations were decreased and DOPAC:DA ratios were increased on PN30, but not PN45 or 60. Footshock (30 min at 0.6 mA) increased DOPAC and DOPAC:DA ratios in the mPFC of PN30 and 60 control rats. These effects were attenuated in age-matched rats previously sustaining ∼50% loss of mPFC DA on PN12–14. Footshock did not affect DOPAC:DA ratios in the nucleus accumbens of control or lesioned rats. The lesion also failed to alter basal or stress-evoked motor activity. The present data suggest that a decreased density of mPFC DA nerve terminals occurring early in development results in persistent alterations in basal and stress-evoked activity of mesoprefrontal DA neurons, but not mesoaccumbens DA neurons.

Functional deficits following neonatal dopamine depletion and isolation housing: circular water maze acquisition under pre-exposure conditions and motor activity.

Seven experiments and several behavioural tests were performed to study the effects of housing condition and experimental test conditions upon the behavioural responses and performance of adult rats neonatally treated with 6-hydroxydopamine (6-OHDA, 100 ug intracisternally, i.c.) or with vehicle. Postnatal 6-OHDA induced locomotor and total activity hyperactivity and deficits in navigational learning in a circular swim maze that were blocked by pretreatment with a dopamine (DA) reuptake inhibitor but not a noradrenaline (NA) reuptake inhibitor. Isolation-housing induced deficits in maze learning performance. Grouped housing improved the maze learning performance of 6-OHDA treated rats whereas vehicle treated rats that were isolation housed performed better following latent learning (LL) pre-exposure trials. 6-OHDA treated rats that received both Grouped housing and latent learning trials performed better on the spatial navigation task than those that received Grouped housing but no latent learning or Isolation housing and latent learning. Analysis of habituation quotients indicated marked deficits by 6-OHDA-treated rats suggesting inability to acquire this simple, nonassociative form of learning. Methylphenidate increased all three parameters of motor activity: locomotion, rearing and total activity, in both Isolation-housed and Group-housed rats from 60- to 90- or 120-min post-injection. NDO 008 induced variable and parameter-dependent effects: locomotion was elevated initially in both Isolated and Grouped rats by the compound and then reduced in the Isolated rats only whereas total activity was only elevated initially in the Isolated rats and unaffected in the Grouped rats. Rearing behaviour was reduced markedly, directly post-injection, in the Isolation-housed rats. DA, DOPAC and HVA concentrations in the striatum, nucleus accumbens, olfactory tubercle and midbrain were reduced but most markedly in the striatum. 5-Hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations were elevated in the striatum, nucleus accumbens (not 5-HIAA) and olfactory tubercle.

NMDA receptor antagonism modifies the synergistic regulation of striatal tachykinin gene expression induced by dopamine D 1 and serotonin 2 receptor stimulation following neonatal dopamine depletion

Co-application of SKF-38393 (dopamine D 1 agonist; 1 mg/kg) and DOI (serotonin 2 agonist; 1 mg/kg) induced a synergistic increase in striatal preprotachykinin (PPT) mRNA levels in adult rats 60 days after neonatal intracerebroventricular injection of 6-hydroxydopamine. This magnitude of response was not observed in intact (vehicle-injected) rats and was restricted to the dorsomedial (DM, 333±25% of lesion) subregion of the anterior striatum, with smaller increases observed in the dorsolateral striatum (DL, 206±26% of lesion). A single i.p. injection of MK-801 (NMDA antagonist; 0.1 mg/kg) administered prior to dopamine D 1 (D 1) and serotonin 2 (5-HT 2) receptor co-stimulation suppressed the synergistic regulation of PPT mRNA expression in the DM striatum, but also produced a large increase in PPT message levels within the DL striatum (321±17% of lesion). These data suggest that the synergistic regulation of PPT mRNA within the DM striatum induced by D 1/5-HT 2 receptor co-stimulation in the dopamine lesioned rat is dependent on NMDA receptor activity. However, MK-801 may simultaneously potentiate striatal PPT mRNA expression by a separate mechanism due to the changed environment of the dopamine-depleted basal ganglia.

Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamine D1 and serotonin 2 receptors and is targeted to tachykinin neurons of the dorsomedial striatum

It has been hypothesized that dopamine D1 and serotonin 2 receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine D1 and serotonin 2 receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine D1 and serotonin 2 receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine D1 partial agonist) or (±)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, serotonin 2 agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine D1 and serotonin 2 receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine D1 antagonist) or ritanserin (1 mg/kg, serotonin 2 antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine D1 receptor stimulation, but was slightly elevated by DOI or both agonists together (42–58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone. Dopamine depletion appears to promote a synergistic interaction between dopamine D1 and serotonin 2 receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.

Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression

Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague–Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 μg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine ( PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60–66% across three subregions of the A-STR and 52–59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50–62%) and P-STR (55–82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.

Suppression of serotonin hyperinnervation does not alter the dysregulatory influences of dopamine depletion on striatal neuropeptide gene expression in rodent neonates

Sixty days following neonatal dopamine depletion (>98%) with 6-hydroxydopamine, preprotachykinin and preprodynorphin mRNA levels were significantly reduced (67 and 78% of vehicle controls, respectively) in the anterior striatum as determined by in situ hybridization while preproenkephalin mRNA expression was elevated (133% of vehicle controls). Suppression of the serotonin hyperinnervation phenomenon in the dopamine-depleted rat with 5,7-dihydroxytryptamine yielded no significant alterations in reduced striatal preprotachykinin (66%) or preprodynorphin (64%) mRNA levels, while preproenkephalin mRNA expression remained significantly elevated (140%). These data suggest that striatal serotonin hyperinnervation does not contribute to the development of dysregulated striatal neuropeptide transmission in either direct or indirect striatal output pathways following neonatal dopamine depletion.

Effects of neonatal dopamine depletion on sensory inhibition in the rat

Central dopamine systems appear to play an important role in sensory information processing. In particular, the filtering (or gating) of repetitive auditory stimuli is modulated by pharmacological manipulations that affect dopaminergic neurotransmission. The present study further addressed the role of dopamine in auditory gating. Three-day-old male Sprague-Dawley rats, pretreated with desipramine, received intracisternal injections of 6-hydroxydopamine (6-OHDA; 75 μg in 10 μl) or the vehicle. At 4 months of age the rats were implanted for evoked potential recording and auditory gating was assessed using a paired click paradigm. Neonatally administered 6-OHDA did not alter gating in the adult rats. However, unlike for the control group, systemic amphetamine (1.83 mg/kg, IP) failed to disrupt gating in the treated rats. Apomorphine (1.0 mg/kg, SC) disrupted gating in both groups. Neonatal 6-OHDA treatment caused significant reductions in dopamine levels in the striatum, nucleus accumbens, and substantia nigra/ventral tegmental regions. There was an inverse relationship between substantia nigra/ ventral tegmental area dopamine levels and auditory gating. Overall, the results suggest that amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency occurs through postsynaptic dopamine receptor activation.

Impaired acquisition and operant responding after neonatal dopamine depletion in rats

The effect of neonatal dopamine depletion in rats was examined using operant conditioning. Rat pups were given 6-hydroxydopamine (6-OHDA) or sham lesions at 3 days of age. When tested as adults, 6-OHDA treated subjects were impaired in the acquisition of lever pressing for reward and displayed stereotyped sniffing patterns not observed in the control subjects. In addition, significantly lower rates of responding were measured for the lesion group during continuous reinforcement (CRF), dilution of reinforcer efficacy, and with progressively increasing fixed ratio requirements. Alpha-methyl-p-tyrosine (AMPT), given before one CRF session, attenuated responding in over half the lesion animals and in none of the controls. Dopamine content in caudate nucleus was found to significantly correlate with number of trials to acquisition and rates of responding following AMPT in the lesion group, but not in the control group. Overall, the results of this experiment showed that neonatal dopamine depletion does not lead to severe motor impairment or the inability to learn, but does disrupt the normal patterns of behavior associated with operant conditioning.

Altered activity patterns following neonatal 6-hydroxydopamine lesions to dopaminergic neurons: effect of SKF-38393

The effects of neonatal dopamine depletion on activity levels and locomotor patterns were tested in rats at 4 months of age. Measurements were taken using an activity pattern monitor. The lesioned group was significantly hypoactive in comparison to the control animals during the initial exposures to the monitor. Examination of locomotor paths indicated that the lesioned animals failed to develop the increasingly organized spatial behavior observed in control animals. In a second study, changes in motility and locomotor patterns before, during, and after the repeated administration of a D 1-dopamine agonist, SKF-38393 (3.0 mg/kg) were investigated. A priming effect, leading to increases in ambulations and fine movements, was observed only in the lesioned animals after repeated administration of SKF-38393. The D 1-dopamine agonist did not change the activity of the unlesioned animals and did not lead to persistent effects in lesioned animals tested 2 and 4 days following the final drug administration. Across the duration of the second study, the lesioned group did not demonstrate hypoactivity. Overall, the experiments showed that neonatal dopamine depletion disrupts the normal patterns of behavior associated with habituation to a novel environment, and repeated administration of SKF-38393 can further alter these abnormal activity patterns.

D1 and D2 dopamine receptors do not up-regulate in response to neonatal intrastriatal 6-hydroxydopamine lesions

The extent of dopamine (DA) depletion appears to exert important influences on the plasticity of the DA system following lesions made in adulthood. The aim of this study was to determine if the extent of DA depletion has long-term effects on DA receptor regulation after early neonatal lesions. Early intrastriatal injections of 6-hydroxydopamine (6-OHDA) caused a dose-dependent loss of high-affinity DA uptake sites and μ-opioid receptor patches evident in adulthood. DA receptors did not up-regulate in response to any degree of neonatal DA depletion. A patchy loss of D1 binding was evident following the neonatal lesions, although the loss was somewhat more severe and uniform with the highest dose of 6-OHDA (20 μg per striatum). There was also a slight decrease in D2 binding which was not dose-dependent. These results suggest that the consequences of early neonatal DA lesions are not dependent upon the degree of DA depletion, as the effects on DA receptor expression were similar regardless of the extent of the lesions.

Effects of intracerebral dopaminergic grafts on behavioural deficits induced by neonatal 6-hydroxydopamine lesions of the mesotelencephalic dopaminergic pathway

The functional capabilities of dopamine neuron-rich grafts implanted into the accumbens and striatal regions in neonatal rats were evaluated in a series of behavioural tests. The ascending mesotelencephalic dopaminergic system of three-day-old rat pups was bilaterally lesioned by injecting 6-hydroxydopamine at the level of the lateral hypothalamus. Five days later a suspension containing dopaminergic neurons obtained from embryonic day 14 mesencephali was injected bilaterally into the striatal complex. The functional effects of such grafts were evaluated using behavioural tests for which it was known that the performance of the animals is changed following the lesion of the mesotelencephalic pathway and for which the influence of dopaminergic grafts implanted into adult hosts have previously been described. The dopamine-rich grafts compensated for the modifications of the locomotor responsiveness to amphetamine and apomorphine induced by neonatal dopamine depletion. However, the grafts were unable to restore more complex behaviours such as hoarding for food pellets, schedule-induced polydipsia and learning behaviours. Moreover, the neonatal transplants induced additional deficits such as catalepsia, nocturnal hyperactivity and day-time hyperactivity during food deprivation. It was concluded that, at least in the present paradigm, the implantation into neonatal brain does not lead to any greater functional recovery than that observed after implantation during adulthood.

Neonatal brain dopamine depletion and the cortical and behavioral consequences of enriched postweaning environment

This study investigated the effects of neonatal intraventricular administration of 6-hydroxydopamine (6-OHDA, 15 μg total with and without desmethylimipramine pretreatment) on the cortical thickening and behavioral effects of 35 days of enriched postweaning housing (ENR) in the rat. The 6-OHDA treatment depleted cortical dopamine (DA) to about 40% of control. It did not affect the thickness of the cerebral cortex nor did it affect the capacity for the cortex to be thickened by ENR. In addition, it did not alter the superior performance on two spatial water maze tasks that was caused by ENR. Thus, The potential for neurobehavioral plasticity was not change by neonatal DA depletion. ENR eliminated the spatial learning/memory deficits that were caused by neonatal DA depletion and that were manifested when the rat was raised in standard (impoverished) laboratory conditions. Hence, environmental factors can modulate the cognitive effects of neonatal DA depletion. ENR did not attenuate the hyperactivity of the neonatal DA-depleted rat. This may reflect the subcortical mediation of this behavioral abnormality.

Latent learning in a radial arm maze following neonatal dopamine depletion

Animals neonatally depleted of dopamine show decreases in exploratory behaviour. As latent learning may depend on exploratory behaviour the present study was undertaken to examine the effects of neonatal dopamine depletion on latent learning. In two experiments dopamine was depleted neonatally, using 6-hydroxydopamine injected intracisternally on day 1 after birth. In both experiments, exploratory behaviour, measured as rearing and head-dip responses in a modified openfield/holeboard, was reduced in the dopamine depleted rats whereas ambulatory behaviour was elevated. In a modified radial arm maze also, rearing responses were decreased while ambulation was increased for the 6-hydroxydopamine treated rats. Latent learning was tested in each experiment following preexposure to the maze for either a single trial or four trials. 6-Hydroxydopamine treated rats demonstrated a comparable latent learning effect to vehicle treated rats after four maze exposures but showed a greatly attenuated latent learning effect following only a single exposure. It is suggested that the effects of neonatal dopamine upon maze and latent learning are secondary to the effects on hyperactivity, reduced exploration and/or increased neophobia shown by these rats.

Dopamine depletion in neonatal rats: effects on behavior and striatal dopamine release assessed by intracerebral microdialysis during adulthood

Rats depleted of dopamine (DA) by intraventricular 6-hydroxydopamine (6-OHDA) in infancy show behavioral impairments as adults, but their basic sensory-motor functions and feeding abilities are intact; at least relative to the pronounced deficits seen in rats given similar v treatment in adulthood. Here we investigate whether presynaptic changes culminating in enhanced DA release are present in adult rats that received neonatal damage, and whether these are of a sufficient magnitude to contribute to the sparing of function. We used microdialysis in rats during the resting state, walking on a treadmill, and after a systemic injection of amphetamine. It was found that neonatal 6-OHDA produced a nearly complete (<1% of control) depletion of DA in postmortem tissue, but this was not accompanied by a comparable decline in the basal extracellular concentrations of DA, which were only reduced by 12–54% of control values. In contrast, the extracellular concentrations of DA metabolites were greatly reduced, reflecting the post-mortem tissue concentrations of DA. Nevertheless, neonatally depleted animals were markedly deficient in their ability to respond to an amphetamine challenge, both behaviorally and in their ability to further increase DA release. Thus, following neonatal DA depletion there appear to be extensive changes in the few remaining DA terminals that are sufficient to maintain relatively high extracellular (and presumably synaptic) concentrations of DA during the resting state, but the capacity of the remaining DA neurons to respond to increased demand is very limited. This presynaptic compensatory response may play a role in the sparing of behavioral function seen following neonatal damage.