Mesotelencephalic Dopamine Research Articles

Early cellular and synaptic changes in dopaminoceptive forebrain regions of juvenile mice following gestational exposure to valproate.

Gestational exposure of mice to valproic acid (VPA) is one currently used experimental model for the investigation of typical failure symptoms associated with autism spectrum disorder (ASD). In the present study we hypothesized that the reduction of dopaminergic source neurons of the VTA, followed by perturbed growth of the mesotelencephalic dopamine pathway (MT), should also modify pattern formation in the dopaminoceptive target regions (particularly its mesoaccumbens/mesolimbic portion). Here, we investigated VPA-evoked cellular morphological (apoptosis-frequency detected by Caspase-3, abundance of Ca-binding proteins, CaBP), as well as synaptic proteomic (western blotting) changes, in selected dopaminoceptive subpallial, as compared to pallial, regions of mice, born to mothers treated with 500 mg/kg VPA on day 13.5 of pregnancy. We observed a surge of apoptosis on VPA treatment in nearly all investigated subpallial and pallial regions; with a non-significant trend of similar increase the nucleus accumbens (NAc) at P7, the age at which the MT pathway reduction has been reported (also supplemented by current findings). Of the CaBPs, calretinin (CR) expression was decreased in pallial regions, most prominently in retrosplenial cortex, but not in the subpallium of P7 mice. Calbindin-D 28K (CB) was selectively reduced in the caudate-putamen (CPu) of VPA exposed animals at P7 but no longer at P60, pointing to a potency of repairment. The VPA-associated overall increase in apoptosis at P7 did not correlate with the abundance and distribution of CaBPs, except in CPu, in which the marked drop of CB was negatively correlated with increased apoptosis. Abundance of parvalbumin (PV) at P60 showed no significant response to VPA treatment in any of the observed regions we did not find colocalization of apoptotic (Casp3+) cells with CaBP-immunoreactive neurons. The proteomic findings suggest reduction of tyrosine hydroxylase in the crude synaptosome fraction of NAc, but not in the CPu, without simultaneous decrease of the synaptic protein, synaptophysin, indicating selective impairment of dopaminergic synapses. The morpho-functional changes found in forebrain regions of VPA-exposed mice may signify dendritic and synaptic reorganization in dopaminergic target regions, with potential translational value to similar impairments in the pathogenesis of human ASD.

The push and pull of dopamine in cue-reward learning.

A recent study by Saunders, Richard, Margolis, and Janak (2018) shows that there is a great deal left to learn about what different mesotelencephalic dopamine circuits contribute to learning about the motivational significance of reward-related cues. Their findings suggest that nigrostriatal and mesolimbic dopamine pathways support distinct reinforcement processes that independently push and pull animals toward their goals.

Simultaneous Detection of c-Fos Activation from Mesolimbic and Mesocortical Dopamine Reward Sites Following Naive Sugar and Fat Ingestion in Rats.

This study uses cellular c-fos activation to assess effects of novel ingestion of fat and sugar on brain dopamine (DA) pathways in rats. Intakes of sugars and fats are mediated by their innate attractions as well as learned preferences. Brain dopamine, especially meso-limbic and meso-cortical projections from the ventral tegmental area (VTA), has been implicated in both of these unlearned and learned responses. The concept of distributed brain networks, wherein several sites and transmitter/peptide systems interact, has been proposed to mediate palatable food intake, but there is limited evidence empirically demonstrating such actions. Thus, sugar intake elicits DA release and increases c-fos-like immunoreactivity (FLI) from individual VTA DA projection zones including the nucleus accumbens (NAC), amygdala (AMY) and medial prefrontal cortex (mPFC) as well as the dorsal striatum. Further, central administration of selective DA receptor antagonists into these sites differentially reduce acquisition and expression of conditioned flavor preferences elicited by sugars or fats. One approach by which to determine whether these sites interacted as a distributed brain network in response to sugar or fat intake would be to simultaneous evaluate whether the VTA and its major mesotelencephalic DA projection zones (prelimbic and infralimbic mPFC, core and shell of the NAc, basolateral and central-cortico-medial AMY) as well as the dorsal striatum would display coordinated and simultaneous FLI activation after oral, unconditioned intake of corn oil (3.5%), glucose (8%), fructose (8%) and saccharin (0.2%) solutions. This approach is a successful first step in identifying the feasibility of using cellular c-fos activation simultaneously across relevant brain sites to study reward-related learning in ingestion of palatable food in rodents.

The role of the neural reward system in attention selection.

The prefrontal cortex may play a role in attention selection using motivational information from the mesotelencephalic dopamine system, a neural system that responds to reward prediction violations. If so, neural indices of attention selection and reward prediction violation should have overlapping spatiotemporal distributions. Attention selection elicits a frontal event-related potential component around 200-300 ms, the frontal selection positivity. A component with similar spatiotemporal characteristics, the reward positivity is elicited in reward prediction designs to outcomes that are better than expected. The current study used dense sensor array recording in a sample of 41 participants performing visual oddball (attention) and a reward prediction 'slot machine-like' design to compare the spatiotemporal distributions of the frontal selection positivity and the reward positivity. The components did not differ in their peak latencies and had overlapping scalp topographies, supporting the hypothesis that these positivities represent attachment of incentive salience to perceptual representations in the prefrontal cortex.

Estradiol, dopamine and motivation.

The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol's adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors.

C-Fos induction in mesotelencephalic dopamine pathway projection targets and dorsal striatum following oral intake of sugars and fats in rats.

Overconsumption of nutrients high in fats and sugars can lead to obesity. Previous studies indicate that sugar or fat consumption activate individual brain sites using Fos-like immunoreactivity (FLI). Sugars and fats also elicit conditioned flavor preferences (CFP) that are differentially mediated by flavor-flavor (orosensory: f/f) and flavor-nutrient (post-ingestive: f/n) processes. Dopamine (DA) signaling in the medial prefrontal cortex (mPFC), the amygdala (AMY) and the nucleus accumbens (NAc), has been implicated in acquisition and expression of fat- and sugar-CFP. The present study examined the effects of acute consumption of fat (corn oil: f/f and f/n), glucose (f/f and f/n), fructose, (f/f only), saccharin, xanthan gum or water upon simultaneous FLI activation of DA mesotelencephalic nuclei (ventral tegmental area (VTA)) and projections (infralimbic and prelimbic mPFC, basolateral and central-cortico-medial AMY, core and shell of NAc as well as the dorsal striatum). Consumption of corn oil solutions, isocaloric to glucose and fructose, significantly increased FLI in all sites except for the NAc shell. Glucose intake significantly increased FLI in both AMY areas, dorsal striatum and NAc core, but not in either mPFC area, VTA or Nac shell. Correspondingly, fructose intake significantly increased FLI in the both AMY areas, the infralimbic mPFC and dorsal striatum, but not the prelimbic mPFC, VTA or either NAc area. Saccharin and xanthan gum intake failed to activate FLI relative to water. When significant FLI activation occurred, highly positive relationships were observed among sites, supporting the idea of activation of a distributed brain network mediating sugar and fat intake.

6-Hydroxydopamine lesions of the ventral tegmental area suppress ghrelin's ability to elicit food-reinforced behavior

While past research suggests that ghrelin stimulates appetite through an action on hypothalamic signaling, recent evidence indicates that the peptide acts via mesotelencephalic dopamine neurons to alter appetitive motivation. In the present study, rats were trained to operantly respond for food on a progressive ratio PR5 schedule until stable breakpoints were established. Ghrelin (30–300pmol) was then injected directly into the ventral tegmental area (VTA) and the 300pmol dose was observed to increase breakpoint. The dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA, 6μg) was subsequently administered into the VTA resulting in a significant depletion of striatal dopamine. Stable breakpoints were then re-established. When ghrelin's effects were reassessed, the peptide's ability to alter operant responding for food was reliably reduced. Our findings demonstrate that ghrelin induces food-reinforced behavior in the mesotelencephalic reward pathway and that this effect is dependent on intact dopaminergic signaling. We conclude that the metabolic peptide ghrelin interacts with dopamine, within reward circuitry, to modulate appetitive behavior.

Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice

Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1(-/-)) or NTS2 (NTS2(-/-)). Basal and amphetamine-stimulated locomotor activity was determined. In vivo microdialysis in freely moving mice, coupled with HPLC-ECD, was used to detect basal and d-amphetamine-stimulated striatal extracellular dopamine levels. In vitro radioligand binding and synaptosomal uptake assays for the dopamine transporters were conducted to test for the expression and function of the striatal pre-synaptic dopamine transporter. NTS1(-/-) and NTS2(-/-) mice had higher baseline locomotor activity and higher basal extracellular dopamine levels in striatum. NTS1(-/-) mice showed higher locomotor activity and exaggerated dopamine release in response to d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice exhibited lower dopamine D(1) receptor mRNA expression in the striatum relative to wild type mice. Dopamine transporter binding and dopamine reuptake in striatum were not altered. Therefore, lack of either NTS1 or NTS2 alters the dopaminergic system. The possibility that the dysregulation of dopamine transmission might stem from a deficiency in glutamate neurotransmission is discussed. The data strengthen the hypothesis that NT receptors are involved in the pathogenesis of schizophrenia and provide a potential model for the biochemical changes of the disease.

The Lateral Habenula:No Longer Neglected

In this contribution to theCNS Spectrumsneuroanatomy series, Stefanie Geisler, MD, discusses the lateral habenula (LHb). This nuclear complex is one of the areas of the brain that forms part of the cross-talk between limbic fore-brain and some important ascending modulatory pathways. Situated at the caudal end of the dorsal diencephalon and classically regarded as projecting largely to the brainstem, including the serotoninergic raphe nuclei, the LHb receives afferents from widespread forebrain areas. Therefore, the LHb is able to influence serotonin tone in the brain, and has long interested neuroanatomists as a potential limbic-motor interface. Nonetheless, the LHb was not much discussed outside neuroanatomical circles until recently, when it was discovered that its impact on the mesotelencephalic dopamine system is probably much greater than had been assumed. The LHb has become a hot topic. This article-addresses these developments and emphasizes the clinical relevance of this interesting brain structure.

Mesencephalic dopamine neuron number and tyrosine hydroxylase content: Genetic control and candidate genes

The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra–ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ ( P<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ ( P<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic TH protein content in C4A6/B in comparison to C4A6/N ( P=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the single nucleotide polymorphism (SNP) genotype data of the whole-genome scan, and detected two small differential chromosome segments on chr. 13 and chr. 14. Microarray gene expression studies and bioinformatic analysis of the two differential regions implicated two cis-regulated genes ( Spock1 and Cxcl14, chr. 13), and two growth factor genes [bone morphogenetic protein 6 ( Bmp6) (chr. 13), and fibroblast growth factor 14 ( Fgf14) (chr. 14)]. Taken together, the results suggest that (1) nigral dopamine neuron number and TH protein content may be genetically associated but further studies are needed to establish unequivocally this linkage, and (2) Spock1, Cxcl14, Bmp6, and Fgf14 are novel candidates for modulating the expression and maintenance of TH content in mesencephalic dopamine neurons in vivo.

When Things Are Better or Worse than Expected: The Medial Frontal Cortex and the Allocation of Processing Resources

Access to limited-capacity neural systems of cognitive control must be restricted to the most relevant information. How the brain identifies and selects items for preferential processing is not fully understood. Anatomical models often place the selection mechanism in the medial frontal cortex (MFC), and one computational model proposes that the mesotelencephalic dopamine (DA) system, via its reward prediction properties, provides a "gate" through which information gains access to limited-capacity systems. There is a medial frontal event-related potential (ERP) index of attention selection, the anterior positivity (P2a), associated with DA reward system input to the MFC for the identification of task-relevant perceptual representations. The P2a has a similar spatio-temporal distribution as the medial frontal negativity (MFN), elicited to error responses or choices resulting in monetary loss. The MFN has also been linked to DA projections to the MFC but for action monitoring rather than attention selection. This study proposes that the P2a and the MFN reflect the same MFC evaluation function and use a passive reward prediction design containing neither instructed attention nor response to demonstrate that the ERP over medial frontal leads at the P2a/MFN latency is consistent with activity of midbrain DA neurons, positive to unpredicted rewards and negative when a predicted reward is withheld. This result suggests that MFC activity is regulated by DA reward system input and may function to identify items or actions that exceed or fail to meet motivational prediction.

The Molecular Pages of the mesotelencephalic dopamine consortium (DopaNet)

BackgroundDopaNet is a Systems Biology initiative that aims to investigate precisely and quantitatively all the aspects of neurotransmission in a specific neuronal system, the mesotelencephalic dopamine system. The project should lead to large-scale models of molecular and cellular processes involved in neuronal signaling. A prerequisite is the proper storage of knowledge coming from the literature.MethodsDopaNet Molecular Pages are highly structured descriptions of quantitative parameters related to a specific molecular complex involved in neuronal signal processing. A Molecular Page is built by maintainers who are experts in the field, and responsible for the quality of the page content. Each piece of data is identified by a specific ontology code, annotated (method of acquisition, species, etc.) and linked to the relevant bibliography. The Molecular Pages are stored as XML files, and processed through the DopaNet Web Service, which provides functionalities to edit the Molecular Pages, to cross-link the Pages and generate the public display, and to search them.ConclusionsDopaNet Molecular Pages are one of the core resources of the DopaNet project but should be of widespread utility in the field of Systems Neurobiology.

Role of the mesotelencephalic dopamine system in learning and memory processes in the rat

The effects of lesioning the ventral tegmental area or substantia nigra pars reticulata by means of bilateral microinjections of two doses of kainic acid (50 ng/250 nl and 100 ng/500 nl) or 6-hydroxydopamine (8 μg/4 μl) were investigated to clarify the role of the mesotelencephalic dopamine system in learning and memory processes. Our findings suggest that ventral tegmental area and substantia nigra dopaminergic neurons play an important role in retention of both short-term memory, tested in the Y-maze task and long-term memory evaluated with the multi-trial passive avoidance test, without affecting memory acquisition. As compared to short-term memory, long-term memory is more susceptible to the decreased dopamine level in nervous structures involved in processing and storage of information.

Inhibition of NMDA-induced striatal dopamine release and behavioral activation by the neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate.

Our laboratory has previously shown that the synthetic neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate (3alpha5betaHS) is a negative modulator of NMDA receptors in vitro. Similarly, 3alpha5betaHS exhibits rapid sedative, analgesic, anticonvulsive, and neuroprotective effects in vivo. Here we report a study designed to investigate whether a negatively charged neuroactive steroid, 3alpha5betaHS, modulates the action of NMDA receptors in vivo. Our results indicate that peripherally administered 3alpha5betaHS enters the CNS and inhibits NMDA-mediated motor activity and dopamine release in the rat striatum. The increase in motor activity induced by intrastriatal microinjection of NMDA was blocked by the systemic administration of 3alpha5betaHS and the NMDA-induced increase in extracellular dopamine in the striatum was also attenuated by both systemically administered and intrastriatally administered (by in vivo microdialysis) 3alpha5betaHS. These data indicate that 3alpha5betaHS acts through striatal NMDA receptors in vivo. When taken together, these results suggest that neuroactive steroids may prove to be effective in the treatment of neurological and psychiatric disorders involving over-stimulation of NMDA receptors in the mesotelencephalic dopamine system.

Immunohistochemical assessment of mesotelencephalic dopamine activity during the acquisition and expression of Pavlovian versus instrumental behaviours

Dopaminergic activity during Pavlovian or instrumental learning in key target regions of the mesotelencephalic dopamine system was investigated immunohistochemically using antibodies raised against glutaraldehyde-conjugated dopamine. Experiment 1 examined dopamine immunoreactivity during acquisition of a Pavlovian conditioned-approach response. Observations were taken at three stages of learning: initial, intermediate and asymptotic; each with a conditioned stimulus+ (CS+) group for whom visual or auditory stimuli immediately preceded an unconditioned stimulus (sucrose), and a conditioned stimulus− (CS−) group for whom stimuli and the unconditioned stimulus were unpaired. Animals learned to approach the alcove during CS+ presentations, whilst approach behaviour of the CS− group remained low. In general, target regions exhibiting a dopaminergic reaction responded maximally during the intermediate stage of acquisition, and were less responsive initially, and not responsive at all at asymptote. Specifically, the pattern of dopaminergic response was: shell more than core of the nucleus accumbens; prefrontal cortex, central and basolateral nuclei of the amygdala also significantly responsive. Mediodorsal and laterodorsal striatal regions were reactive only very early in training. Experiment 2 examined dopaminergic reaction following acquisition of a novel conditioned instrumental response. The conditioned response+ (CR+) group responded at a much higher rate on the lever for which unconditioned stimulus-associated stimuli were presented, than on the control lever. The conditioned response− (CR−) group responded at a low rate on both levers. In contrast with experiment 1, the most responsive regions were the core of the nucleus accumbens, medial prefrontal cortex and basolateral area of the amygdala. Thus, the acquisition, but not expression of Pavlovian associations activated dopamine within several key target regions of the mesotelencephalic dopamine system, and preferentially within the shell rather than core of the nucleus accumbens. By contrast, acquisition of a novel instrumental response preferentially activated the core of the nucleus accumbens, and basolateral area of the amygdala. These data carry significant implications for the potential role of these regions in learning and memory.

An immunohistochemical examination of the effects of sensitisation on the mesotelencephalic dopaminergic response to d-amphetamine

The dopaminergic response to d-amphetamine with or without prior repeated experience with the drug was investigated immunohistochemically in key target regions of the mesotelencephalic dopamine system using antibodies raised against glutaraldehyde-conjugated dopamine. This methodology permitted the unambiguous determination of dopaminergic activity within specific subregions of structures implicated in the behavioural effects of psychomotor stimulants drugs, and in the expression of behavioural sensitisation. Experiment 1 examined dopamine immunoreactivity in central or basolateral amygdala, shell or core of the nucleus accumbens, medial and lateral caudate-putamen and medial prefrontal cortex following the administration of various doses of d-amphetamine to drug-naïve rats. Whilst dose-related increases in dopaminergic activity were detected in all regions examined, a regional heterogeneity was clearly evident. For example, d-amphetamine enhanced dopaminergic activity preferentially within the shell subregion of the nucleus accumbens both with respect to the core subregion and to other striatal and non-striatal areas. Experiment 2 examined changes in dopaminergic activity following the administration of a low dose of d-amphetamine to d-amphetamine-sensitised rats and saline-pretreated control animals. Regional heterogeneity both between and within terminal areas was again detected. Thus, there was evidence of a preferential increase in dopaminergic activity within the shell of the nucleus accumbens of sensitised rats. Moreover, sensitisation to d-amphetamine increased the dopaminergic response to acute administration of d-amphetamine within all striatal and non-striatal areas examined. Comparison of this effect across subterritories of the areas under investigation revealed that in sensitised rats, acute administration of d-amphetamine elevated dopaminergic activity within the shell of the nucleus accumbens to a greater extent than within the core. These data therefore indicate that systemic administration of d-amphetamine is associated with regionally heterogeneous changes in dopaminergic activity within terminal regions of the mesotelencephalic dopamine system in both sensitised and unsensitised rats. Moreover, the present methodology permitted resolution of these changes at an anatomical level beyond that of conventional approaches.

Mesotelencephalic dopamine neurochemical responses to glucocorticoid administration and adrenalectomy in Fischer 344 and Lewis rats

The effects of alterations in peripheral corticosterone levels on multiple dopamine neurochemical estimates were examined in inbred Fischer and Lewis inbred rat strains. 2×2 ANOVA’s (treatment×strain) showed a main effect for treatment (1 week CORT versus placebo) on the concentrations of the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid in the medial prefrontal cortex, with lower levels after treatment, but no significant treatment versus strain interaction. There was no effect of CORT treatment on DA metabolites in the nucleus accumbens shell or dorsal striatum. DOPA accumulation in any terminal region examined and tyrosine hydroxylase protein content in the ventral tegmental area were also not affected by 1 week of corticosterone in either strain. One week after adrenalectomy, homovanillic acid but not dihydroxyphenylacetic acid concentrations were significantly increased in the medial prefrontal cortex, dorsal striatum, and nucleus accumbens shell in the Lewis but not the Fischer strain, with a significant treatment×strain interaction only in the dorsal striatum. Based on these findings, the effect of adrenalectomy on DOPA accumulation and extracellular DA concentrations was examined in the Lewis strain only. Adrenalectomy produced a decrease in DOPA accumulation in the dorsal striatum with no significant change in the other regions. Adrenalectomy did not alter estimates of extracellular dopamine concentrations determined by in vivo no net flux microdialysis but did significantly increase in vivo dopamine recovery in the dorsal striatum. The findings indicate a pattern of changes in neurochemical measurements consistent with a small magnitude inhibition of basal dopamine metabolism, but not with a change neuronal activity, release or reuptake.

Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning.

Mesotelencephalic dopamine (DA) pathways are exquisitely vulnerable to ischemic-anoxic insult. These insults are known to produce long-term derangements in DA signaling and have been hypothesized to contribute, at least in part, to pathologic behaviors such as cerebral palsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Whether modest intermittent hypoxia, such as that encountered with repetitive apneas in premature infants, contributes to clinically significant impairments in DA signaling, and how these impairments manifest at a systems level, is unknown. To address these voids there is a need to develop animal models emulating features of a common disorder of prematurity, namely, apnea with hypoxia. Behavioral traits exhibited by such models include disturbed sleep-wake architecture, excessive locomotion, and impaired working memory persisting 1 to 2 months post-insult. Western-blot analysis of expression patterns of proteins involved in DA signaling (e.g., DA and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptors) are consistent with that which might be expected from hyper- or hypodopaminergic functioning in DA-responsive prefrontal cortex and striatal circuits, respectively. These novel observations suggest that intermittent hypoxia occurring during a period of critical brain development disrupts development of those mesotelencephalic pathways modulating the expression of sleep and wakefulness, locomotion, and executive functioning.

Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia.

Based on a number of neuroanatomical and behavioural similarities, recent evidence suggests that heterozygous reeler mice, haploinsufficient for reelin expression, represent a useful model of psychosis vulnerability. As brain mesolimbic dopamine pathways have been proposed to be associated with the pathophysiology of psychotic disorders, we thought it would be of interest to examine whether these animals present disturbances in the mesolimbic dopamine system. To this end we studied by immunocytochemical, in situ hybridization procedures and receptor autoradiography, several markers of the mesotelencephalic dopamine pathway in heterozygous reeler mice and controls. We report that heterozygous reeler mice exhibit a reduction in the number of tyrosine hydroxylase-immunoreactive cell bodies and tyrosine hydroxylase mRNA levels in the ventral tegmental area, as well as a reduction of tyrosine hydroxylase and dopamine transporter immunoreactivity in the dopamine terminal fields of the limbic striatum. In these areas we also observed a reduction of dopamine D2 receptor mRNA. Finally, a marked increase in D3 receptor mRNA levels was observed concomitant with a significant increase in D3 binding sites. On the contrary, the nigrostriatal pathway did not show any significant alteration in heterozygous reeler mice with regards to the dopaminergic markers examined in substantia nigra cell bodies and dorsal striatum dopamine terminal fields. These results suggest a specific link between reelin-related neuronal pathology and dopamine involvement in the pathophysiology of psychotic disorders.

Neurons of origin of the neurotensinergic plexus enmeshing the ventral tegmental area in rat: retrograde labeling and in situ hybridization combined

The morphological and physiological substrates that underlie the mutual regulatory interactions of neurotensin and dopamine in the rat mesotelencephalic projections and related structures remain to be fully described. A salient candidate for neurotensinergic effects on the mesotelencephalic dopamine projection is the dense plexus of neurotensin immunoreactive axons that enmeshes the ventral tegmental area and substantia nigra, but the locations of the neurons that give rise to this plexus have not been identified and its systemic context remains obscure. To address this, Fluoro-Gold and the cholera toxin beta subunit, retrogradely transported axonal tracers, were injected into the ventral tegmental area of rats and the brains were processed to demonstrate neurons that contained both retrograde tracer immunoreactivity and a probe against neurotensin/neuromedin N messenger RNA. Substantial numbers of double-labeled neurons were observed in the rostral part of the lateral septum, and in a region centered on the shared boundaries of the bed nucleus of stria terminalis, ventromedial ventral pallidum, diagonal band of Broca, lateral preoptic area and rostral lateral hypothalamus. A few double-labeled neurons were also observed in the dorsal raphe nucleus and adjacent periaqueductal gray. Despite the administration of haloperidol and D-amphetamine to elicit and enhance neurotensin/neuromedin N messenger RNA expression in striatum, including the nucleus accumbens and olfactory tubercle, no double-labeled neurons were observed there. These results identify a novel brain substrate for control of midbrain dopamine levels, which affect reward mechanisms and motivation.