Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.     

Reduced basal and ethanol stimulation of striatal extracellular dopamine concentrations in dopamine D2 receptor knockout mice

The present study was undertaken to examine the role of the dopamine (DA) D2 receptor in the ethanol-evoked DA response in the ventral striatum. We performed microdialysis experiments using the D2 null mutant and wild-type controls and measured the effect of an intraperitoneal (i.p.) injection of either saline or ethanol (2 g/kg) on dialysate DA concentrations in the ventral striatum. Dialysate ethanol concentrations were also determined in the samples from the ventral striatum. In addition, the effects of quinpirole, a D2/D3 agonist, were examined in both the ventral and dorsal striatum. Basal dialysate concentrations of DA were significantly reduced in both the ventral and dorsal striatum of the D2 knockouts compared with wild-type controls. Ethanol administration significantly enhanced ventral striatal DA in both groups, but the increase in dialysate DA concentration was 3.5-fold higher in the wild-type controls. The time course of dialysate ethanol concentrations was similar in the two groups. Saline injection did not alter DA concentrations in either the ventral or dorsal striatum. However, quinpirole (0.3 mg/kg) administration significantly depressed striatal dialysate DA concentrations in the wild-type mice, but not in the D2 knockouts. The results suggest that the D2 receptor is necessary for normal development and regulation of striatal extracellular DA concentrations, but the mechanism for this alteration is unclear. In addition, the blunted ethanol-evoked DA response in the D2 knockouts may contribute, in part, to some of the behavioral deficits previously observed in response to ethanol.     

Dopaminergic modulation of the updating of stimulus-response episodes in Parkinson's disease

Increasing evidence suggests that the control of retrieval of episodic feature bindings is modulated by the striatal dopaminergic pathway. The present study investigated whether this may reflect a contribution from the ventral or the dorsal part of the striatum. Along the lines of the overdose hypothesis in Parkinson's disease (PD), functions known to rely on the dorsal striatum are enhanced with dopaminergic medication, while operations relying on the ventral circuitry are impaired. We found that partial mismatches between present and previous stimulus-response relations are, compared to control participants, abnormally low OFF DA medication and normalized ON DA medication. The results suggest that the dorsal striatum, but not (or not so much) the ventral striatum, is driving the flexible control of retrieval of stimulus-response episodes.     

Limbic-striatal interactions in reward-related processes

Stimuli with formerly motivationally neutral properties gain incentive properties from their predictive association with primary reinforcement, and are termed conditioned reinforcers. Infusions of the indirect dopamine (DA) agonist d-amphetamine into the ventral striatum selectively enhanced responding for a light that was positively correlated with water. These selective stimulatory effects were blocked by 6-OHDA lesions of the ventral, but not dorsal striatum, and resembled those produced by DA itself when infused into the ventral striatum. However, the choice of the lever producing the conditioned reinforcer was not affected by ventral striatal DA depletion. This choice was, however, attenuated by excitotoxic lesions of the basolateral nucleus of the amygdala, suggesting an interaction between this structure and DA-dependent processes of the ventral striatum in the processes by which reward-related stimuli come to affect action. Parallel findings were obtained using a second order schedule of sexual reinforcement. Other observations indicated that the amygdala lesion did not impair the discriminative property of the reward-related stimuli, or affect primary motivation. Experiments using explicit conditional visuo-spatial discrimination tasks suggest that similar discriminative properties are preserved following DA depletion from the ventral, but not the dorsal, striatum. These results possibly represent a dissociation between stimulus-response (or habit) and stimulus-reward associative mechanisms, modulated respectively by the dorsal and ventral striatum.     

Striatal dopamine innervation and receptor density: regional effects of the weaver mutation

Mice homozygous for the autosomal recesive gene weaver (wv) exhibit a regionally specific depletion of forebrain dopamine (DA). DA is reduced approximately 70% in the dorsal striatum of homozygotes (wv/wv) relative to heterozygous (+/wv) controls while DA content in ventral striatum is relatively unchanged. The goal of the present study was to determine the regional effects of the weaver mutation on striatal DA receptors and DA uptake sites using quantitative autoradiography. Catecholamine histofluorescence was used to examine midbrain DA-containing cell bodies. Compared to behaviorally normal (+/-) littermates, the binding of [³H]spiroperidol to D₂ sites was significantly increased in the dorsal but not ventral striatum of wv/wv mice. Binding of the D₁ ligand, [³H]SCH23390, was significantly decreased throughout the striatum of wv/wv mice. The binding of [³H]mazindol to DA uptake sites was dramatically reduced in all wv/wv striatal regions except the ventrolateral portion. Compared to +/-littermates, wv/wv mice had far fewer fluorescent cell bodies in the substantia nigra and a less pronounced reduction of ventral tegmental area fluorescent somata. These findings support the hypothesis that heterogeneities exist in the genetic control of the mesotelencephalic DA system. The results underscore the usefulness of the weaver mouse in the study of mesostriatal sub-systems, receptor regulation, and potentially as a model of human neuropathologies that affect distinct populations of cells in the mesotelecephalic system.     

The distribution of dopamine immunoreactivity in the forebrain and midbrain of the lizard Gekko gecko: an immunohistochemical study with antibodies against dopamine

The distribution of dopamine (DA) immunoreactivity in the forebrain and the midbrain of the lizard Gekko gecko was studied by using recently developed antibodies against DA. Dopamine-containing cells were found around the glomeruli of the olfactory bulb, in several parts of the periventricular hypothalamic nucleus, in the periventricular organ, the ependymal wall of the infundibular recess, the lateral hypothalamic area and the pretectal posterodorsal nucleus of the diencephalon, and in the ventral tegmental area, the substantia nigra, and the presumed reptilian equivalent of the mammalian A8 cell group of the mesencephalon. Dopaminergic fibers and terminals were observed throughout the whole brain, but particularly in the diencephalon and the telencephalon. The nucleus accumbens appears to have the most dense innervation, but also the striatum, amygdaloid complex, olfactory tubercle, septum, and dorsal ventricular ridge (especially its superficial zone) show numerous DA-containing fibers and terminals. Except for the lateral cortex, cortical areas are not densely innervated by DA fibers. In several respects DA distribution in the gekkonid brain differs from that in other reptiles studied. For instance, in the Gekko the dorsal ventricular ridge is densely innervated by DA fibers, whereas in turtles and crocodiles the same structure shows only weak catecholaminergic histofluorescence. When compared to the distribution of DA immunoreactivity in mammals, it appears that the DA system in the gekkonid telencephalon resembles the distribution of DA in the limbic forebrain and striatum of mammals. Whether these similarities in distribution of DA also imply similarities in function will be discussed.     

Distribution of dopamine immunoreactivity in the forebrain and midbrain of the snake Python regius: a study with antibodies against dopamine

The distribution of dopamine (DA) immunoreactivity in the forebrain and midbrain of the ball python, Python regius, was studied by using recently developed antibodies against DA. In order to determine general and species-specific features of the DA system in reptiles, we have selected the ball python as a representative of a reptilian radiation that hitherto has not been the subject of (immuno)histochemical studies. Dopamine-containing cell bodies were found around the glomeruli and in the external plexiform layer of both the main and accessory olfactory bulb, but not in the telencephalon proper. In the diencephalon, DA cells were observed in several parts of the periventricular hypothalamic nucleus, in the periventricular organ, the ependymal wall of the infundibular recess, the lateral hypothalamic area, the magnocellular ventrolateral thalamic nucleus, and the pretectal posterodorsal nucleus. In the midbrain, DA cells were found in the ventral tegmental area, the substantia nigra, and the presumed reptilian homologue of the mammalian A8 cell group. Dopaminergic fibers and varicosities were observed throughout the whole brain, particularly in the telencephalon and diencephalon. The nucleus accumbens, striatum, olfactory tubercle, and nucleus of the accessory olfactory tract appear to have the most dense innervation, but the lateral septal nucleus, the dorsal ventricular ridge, and the nucleus sphericus also show numerous DA-containing fibers and varicosities. Except for the lateral cortex, cortical areas are not densely innervated by DA fibers. The DA system of the snake Python regius shares many features with that of lizards and turtles as determined with the same antibodies. The taxonomically close relationship between lizards and snakes, which together constitute the Squamata, is reflected in a similar distribution of DA fibers and varicosities to the dorsal ventricular ridge and the lateral cortex, and in the limited number of CSF-contacting DA neurons in the hypothalamus.     

Topographic organization of the ventral striatal efferent projections in the rhesus monkey: An anterograde tracing study

The ventral striatum is considered to be that portion of the striatum associated with the limbic system by virtue of its afferent connections from allocortical and mesolimbic areas as well as from the amygdala. The efferent projections from this striatal region in the primate were traced by using 3H aminoacids and Phaseolus vulgaris-leucoagglutinin (PHA-L). Particular attention was paid to the topographic organization of terminal fields in the globus pallidus and substantia nigra, the projections to non-extrapyramidal areas, the relationship between projections from the nucleus accumbens and the other parts of the ventral striatum, and the comparison between ventral and dorsal striatal projections. This study demonstrates that in monkeys a circumscribed region of the globus pallidus receives topographically organized efferent fibers from the ventral striatum. The ventral striatal fibers terminate in the ventral pallidum, the subcommissural part of the globus pallidus, the rostral pole of the external segment, and the rostromedial portion of the internal segment. The more central and caudal portions of the globus pallidus do not receive this input. This striatal output appears to remain segregated from the dorsal striatal efferent projections to pallidal structures. Fibers from the ventral striatum projecting to the substantia nigra are not as confined to a specific region as those projecting to the globus pallidus. Although the densest terminal fields occur in the medial portion, numerous fibers also extend laterally to innervate the dorsal stratum of dopaminergic neurons of the substantia nigra and the retrorubral area. Furthermore, they project throughout the rostral-caudal extent of the substantia nigra. Projections from the medial part of the ventral striatum reach the more caudally located pedunculopontine tegmental nucleus. Thus unlike the above described terminals in the globus pallidus, the ventral striatum project widely throughout the substantia nigra, a fact that indicates that they may contribute to the integration between limbic and other output systems of the striatum. Finally, the ventral striatum projects to non-extrapyramidal regions including the bed nucleus of the stria terminals, the nucleus basalis magnocellularis, the lateral hypothalamus, and the medial thalamus.     

Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice

Abnormal iron accumulations are frequently observed in the brains of patients with Parkinson's disease and in normal aging. Iron metabolism is regulated in the CNS by iron regulatory proteins (IRP-1 and IRP-2). Mice engineered to lack IRP-2 develop abnormal motoric behaviors including tremors at rest, abnormal gait, and bradykinesia at middle to late age (18 to 24 months). To further characterize the dopamine (DA) systems of IRP-2 -/- mice, we harvested CNS tissue from age-matched wild type and IRP-2 -/- (16-19 months) and analyzed the protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and DA levels in dorsal striatum, ventral striatum (including the core and shell of nucleus accumbens), and midbrain. We further analyzed the phosphorylation of TH in striatum at serine 40, serine 31, and serine 19. In both dorsal and ventral striatum of IRP-2 knockout mice, there was a 20-25% loss of TH protein and accompanied by a approximately 50% increase in serine 40 phosphorylation above wild-type levels. No change in serine 31 phosphorylation was observed. In the ventral striatum, there was also a significant loss (approximately 40%) of DAT and VMAT2. Levels of DA were decreased (approximately 20%) in dorsal striatum, but turnover of DA was also elevated ( approximately 30%) in dorsal striatum of IRP-2 -/- mice. We conclude that iron misregulation associated with the loss of IRP-2 protein affects DA regulation in the striatum. However, the modest loss of DA and DA-regulating proteins does not reflect the pathology of PD or animal models of PD. Instead, these observations support that the IRP-2 -/- genotype may enable neurobiological events associated with aging.     

Amphetamine-Induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: A microdialysis study in behaving rats

The purpose of this study was to compare the effects of amphetamine exposure on subsequent amphetamine-induced changes in behavior and dopamine (DA) release in the dorsal and ventral striatum, as a function of time following the discontinuation of repeated amphetamine treatment. Rats were pretreated with either saline or an escalating-dose amphetamine regimen, and then received a 0.5 mg/kg amphetamine “challenge” after either 3, 7, or 28 days of withdrawal. Animals tested after 28 days of withdrawal were hypersensitive (sensitized) to the locomotor-activating effects of amphetamine, and relative to control animals showed a significant enhancement in amphetamine-stimulated DA release in both the dorsal and ventral striatum, as revealed by in vivo microdialysis. Animals tested after only 3 or 7 days of withdrawal showed neither behavioral sensitization nor enhanced amphetamine-stimulated DA release. These results establish that time-dependent changes in behavioral sensitization to amphetamine are associated with time-dependent changes in amphetamine-stimulated DA release, and support the hypothesis that persistent sensitization-related changes in striatal DA neurotransmission contribute to the expression of behavioral sensitization. © 1995 Wiley-Liss, Inc.     

Topographical distribution of amines and major amine metabolites in the rat striatum

The topographical distribution of the proposed amine transmitters dopamine (DA), serotonin (5-HT), noradrenaline (NA), adrenaline and histamine (HA) and of the metabolites of DA and 5-HT has been investigated in the neostriatum of the rat. DA and, less pronounced, its metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine exhibited gradients with highest levels in dorso-rostral areas and the lowest content in the ventro-caudal part of the striatum. In contrast to this 5-HT, 5-hydroxyindole-acetic acid, and NA exhibited levels which increased from frontal and dorsal areas to the ventro-caudal part of the striatum. The rostral nucleus accumbens and the pallidum were low in DA and high in 5-HT and NA when compared with the dorsal striatum. The turnover rates of DA and 5-HT as judged by the metabolite/amine ratios followed a distribution which was opposite to the respective amine levels. Adrenaline was evenly low in the striatum and only slightly higher in the n. accumbens and pallidum. The levels of HA were considerably lower than those of the other amines. Although HA was also unevenly distributed within the striatum, no clear pattern was found. The topographical distribution of the amines suggests a preferential role of DA in the dorsal striatum and of 5-HT and NA in the ventral part of the striatum including the n. accumbens and the pallidum.     

Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [¹¹C]raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine‐addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine‐addicted individuals. Synapse 64:397–402, 2010. © 2009 Wiley‐Liss, Inc.     

Different effect of age on dopamine transporters in the dorsal and ventral striatum of controls and alcoholics

It is generally agreed that there is a deterioration in brain dopamine (DA) system with aging. The role of the mesolimbic DA in brain ethanol reinforcement is well established, with nucleus accumbens (NAC) serving as a major terminal area of this system, whereas dorsal striatum is more associated with motor control. The aim of this study was to compare putative age-related alterations of dopamine transporters (DAT) in dorsal and ventral striatum of healthy controls and alcoholics. We studied the effect of age on DAT in caudate (NC), putamen (Pu), and nucleus accumbens (NAC) of eight type 1 and 2 alcoholics and 10 healthy controls by using [(125)I]PE2I as a radioligand for postmortem human whole hemisphere autoradiography. In the type 1 alcoholic group age and DAT density did not correlate significantly with any of the structures studied. The mean densities of DAT declined significantly with age in controls and type 2 alcoholics in dorsal striatum (NC, Pu) (range of correlation coefficient from -0.49 to -0.94), but not statistically significantly in NAC. In type 1 alcoholics the lack of correlation between DAT density and age may indicate a preexisting dopaminergic deficit in this patient group, whereas age-related decline among type 2 alcoholics resembled that of healthy controls. Furthermore, dorsal striatal DAT may be more vulnerable to age-related decline than DAT in NAC. This is supported by the notion that DAT in NAC and dorsal striatum have different molecular weights.     

Limited recovery of striatal dopaminergic fibers by adrenal medullary grafts in MPTP-treated aging mice

Systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the dopaminergic (DA) nigrostriatal system in C57BL/6 mice. We have investigated the effect of MPTP neurotoxicity and subsequent adrenal medullary grafts into the striatum of young (2-3 months) and aging (12 months) mice. MPTP treatment (4 X 20 mg/kg ip given 3 or 12 h apart in young mice and 12 h apart in aging mice) resulted in 80-90% depletion of striatal DA and virtual disappearance of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in both young and aging mice 1 week following treatment. Only partial recovery of TH-IR fibers was seen 5 weeks after MPTP treatment in young mice, while virtually no recovery was seen in aging mice. Adrenal medullary minced pieces were grafted into the striatum of young and aging mice 1 week after MPTP treatment. In young mice, dense TH-IR fibers were observed in the striatum on the grafted side 4 weeks later, far denser than those in sham-operated striatum. Although this staining was most prominent around the grafts, many TH-IR fibers also were found in the ventral striatum close to the nucleus accumbens. No such increase in TH-IR fibers was found on the nongrafted side. DA concentration on the grafted side recovered to 45% of the control level. In aging mice receiving similar grafts, TH-IR fibers also were observed in the grafted striatum, but were less dense and more restricted around the site of the graft compared with young mice. DA concentration on the grafted side was 29% of the control level. We conclude that the MPTP-depleted nigrostriatal DA system in aging mouse brain can recover partially following adrenal medullary grafts, but the degree of recovery is more limited compared with that in young brain.     

Afferent connections of the striatum and the nucleus accumbens in the lizard Gekko gecko

The afferent connections of the striatum and the nucleus accumbens of the lizard Gekko gecko were studied with retrograde tracing by means of horseradish peroxidase and Fluoro-Gold and with anterograde tracing by means of Phaseolus vulgaris leukoagglutinin. The striatum receives projections from the cortex, the dorsal ventricular ridge, the lateral amygdaloid nucleus, the globus pallidus, the anterior peduncular nucleus, the ventral tegmental area and substantia nigra, the area ventral to the substantia nigra, and the dorsal thalamus. The nucleus accumbens is projected upon by the cortex, the diagonal band, the ventral pallidum, the lateral preoptic area, the ventral tegmental area, and the dorsal thalamus. The source of the cortical projection to the striatum and the nucleus accumbens is a longitudinal zone in the dorsal cortex that, rostrally in the hemisphere, is located medially and, more caudally, in its middle one third. The medial and rostrolateral areas of the dorsal ventricular ridge each project to the striatum in a vertical zone. The fibers from the caudolateral area of the ridge end in two oblique bands located parallel to the border between the dorsal ventricular ridge and the striatum. The pathways from the mesencephalic tegmentum to the striatum and the nucleus accumbens show a medial to lateral topography. This is similar to the situation in birds, but contrary to that in mammals in which these pathways are extensively interconnected. The specific sensory nuclei of the dorsal thalamus were found to project not only to the dorsal ventricular ridge, but also, and in a topographical fashion, to the striatum. The dorsomedial thalamic nucleus, which innervates the dorsal ventricular ridge, has additional projections to the striatum and the nucleus accumbens. This projection pattern is similar to that of the intralaminar thalamic nuclei of birds and mammals.     

Evidence for topographic guidance of dopaminergic axons by differential Netrin-1 expression in the striatum

There are two main subgroups of midbrain dopaminergic (DA) neurons: the more medially located ventral tegmental area (VTA) DA neurons, which have axons that innervate the ventral–lateral (VL) striatum, and the more laterally located substantia nigra (SN) DA neurons, which preferentially degenerate in Parkinson's disease (PD) and have axons that project to the dorsal–medial (DM) striatum. DA axonal projections in the striatum are not discretely localized and they arborize widely, however they do not stray from one zone to the other so that VTA axons remain in the VL zone and SN axons in the DM zone. Here we provide evidence that Netrin-1 acts in a novel fashion to topographically pattern midbrain DA axons into these two striatal zones by means of a gradient of Netrin-1 in the striatum and by differential attraction of the axons to Netrin-1. Midbrain DA neurons are attracted to the striatum in culture and this attraction is blocked by an anti-DCC (Netrin receptor) antibody. Mechanistically, outgrowth of both VTA and SN DA axons is stimulated by Netrin-1, but the two populations of DA axons respond optimally to overlapping but distinct concentrations of Netrin-1, with SN axons preferring lower concentrations and VTA axons preferring higher concentrations. In vivo this differential preference is closely mirrored by differences in Netrin-1 expression in their respective striatal target fields. In vivo in mice lacking Netrin-1, DA axons that reach the striatum fail to segregate into two terminal zones and to fully innervate the striatum. Our results reveal novel actions for Netrin-1 and provide evidence for a mechanism through which DA axons can selectively innervate one of two terminal zones in the striatum but have free reign to arborize widely within a terminal zone.     

Mesencephalic dopamine neurons interfacing the shell of nucleus accumbens and the dorsolateral striatum in the rat

Parallel corticostriatonigral circuits have been proposed that separately process motor, cognitive, and emotional‐motivational information. Functional integration requires that interactions exist between neurons participating in these circuits. This makes it imperative to study the complex anatomical substrate underlying corticostriatonigral circuits. It has previously been proposed that dopaminergic neurons in the ventral mesencephalon may play a role in this circuit interaction. Therefore, we studied in rats convergence of basal ganglia circuits by depositing an anterograde neuroanatomical tracer into the ventral striatum together with a retrograde fluorescent tracer ipsilaterally in the dorsolateral striatum. In the mesencephalon, using confocal microscopy, we looked for possible appositions of anterogradely labeled fibers and retrogradely labeled neurons, “enhancing” the latter via intracellular injection of Lucifer Yellow. Tyrosine hydroxylase (TH) immunofluorescence served to identify dopaminergic neurons. In neurophysiological experiments, we combined orthodromic stimulation in the medial ventral striatum with recording from ventral mesencephalic neurons characterized by antidromic stimulation from the dorsal striatum. We observed terminal fields of anterogradely labeled fibers that overlap populations of retrogradely labeled nigrostriatal cell bodies in the substantia nigra pars compacta and lateral ventral tegmental area (VTA), with numerous close appositions between boutons of anterogradely labeled fibers and nigrostriatal, TH‐immunopositive neurons. Neurophysiological stimulation in the medial ventral striatum caused inhibition of dopaminergic nigrostriatal neurons projecting to the ventrolateral striatal territory. Responding nigrostriatal neurons were located in the medial substantia nigra and adjacent VTA. Our results strongly suggest a functional link between ventromedial, emotional‐motivational striatum, and the sensorimotor dorsal striatum via dopaminergic nigrostriatal neurons.     

Long-term effect of MPTP in the mouse brain in relation to aging: neurochemical and immunocytochemical analysis

The long-term effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central monoaminergic neurons in young (2-3 months) and aging (12 months) C57BL/6 mice has been studied using neurochemical and immunocytochemical techniques. MPTP treatment (4 x 20 mg/kg i.p. given 12 h apart) resulted in significant depletion of dopamine (DA) concentration in the striatum, substantia nigra, nucleus accumbens, and olfactory tubercle 1 week after treatment in both young and aging mice. Although a decreased DA concentration in the ventral tegmental area was not seen in young mice, aging mice did show a significant decrease. The extent of decrease of DA concentration was greater in aging mice than in young mice in all areas investigated except in dorsal striatum. The long-term effect of MPTP on DA neurons in young mice included considerable recovery of DA concentration in both nigrostriatal and mesolimbic DA systems following the initial profound depletion; such recovery was minimal in aging mice, even 3 months after MPTP treatment. In young mice treated with MPTP, no significant change of norepinephrine (NE) or serotonin (5-HT) concentration was observed in any area investigated while a significant decrease of NE and 5-HT concentration was seen in several brain areas investigated in aging mice. Immunocytochemical analysis revealed that the MPTP injection resulted in marked disappearance of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in striatum of both young and aging mice 1 week following treatment. Partial recovery of TH-IR fibers was seen 5 weeks or 3 months after MPTP treatment in young mice, while no such apparent recovery was seen in aging mice. Aging mice also showed significant decrease in the number of TH-positive cell bodies in the substantia nigra and ventral tegmental area through all periods investigated, while such a significant decrease was only seen in the substantia nigra of young mice 1 week after treatment. We conclude that aging mice are more sensitive to MPTP and show more widespread damage to the monoaminergic systems than young mice, suggesting that MPTP-treated aging mice provide a more useful model for studying anatomical and neurochemical characteristics of Parkinson's disease than young mice.     

Histochemical mapping of dopamine neurons and fiber pathways in dog mesencephalon

A topographic mapping of dopamine (DA)-containing neurons and fibers was done mainly in the mesencephalon of the dog using the fluorescent histochemical technique of Falck and Hillarp. The extensive DA neuron system was found to be located in the ventral and medial regions of the mesencephalon; the pars compacta of the substantia nigra, the area almost corresponding to the ventral tegmental area of Tsai (hich consists of three groups, a caudal, the nucleus parabrachialis pigmentosus, a ventral, the nucleus paranigralis and a rostral, the caudal part of the nucleus tegmentalis gventralis of Tsai), the nucleus linearis of the raphe, and the mesencephalic reticular formation. The nigro-neostriatal projection can be traced in the non-treated or nialamide plus L-dopa treated puppies without the lesion-degeneration technique. Most fibers arising from these DA cell groups assemble at the prerubral area and ascend just dorsal to the medial forebrain bundle. Most fibers turn laterally at the lateral hypothalamus and enter the neostriatum via the dorsal part of the subthalamic nucleus, the zona incerta and the capsula interna. These findings show that the distribution of DA neurons and the nigro-neostriatal pathway are fundamentally similar to those in other mammals. In this study, the processes of the nigral and paranigral DA neurons have been demonstrated to project into the pars reticulata in the dog.