No mediolateral differences in striatal autoreceptor-mediated modulation of dopamine release: in vivo voltammetric data

Medial and lateral neostriatum differ qualitatively in their sources of dopamine (DA) innervation and in their behavioural functions. The present study sought to ascertain whether these differences were reflected in their response to DA autoreceptor drugs. Fast cyclic voltammetry was used to measure stimulated DA release at medial and lateral carbon fibre microelectrodes. Metoclopramide and (+)-3-PPP were used as autoreceptor antagonist and agonist respectively. No differences were observed in the level of DA release evoked by stimulation or in the agonist and antagonist responses at medial or lateral sites. We therefore conclude that differences between medial and lateral striatal DA function are not evident at the autoreceptor level.     

Neurochemical correlates of sparing from motor deficits in rats depleted of striatal dopamine as weanlings

The behavioral and neurochemical effects of striatal DA depletions were investigated in rats lesioned as weanlings (Day 27) or as adults (250-300 g). Administration of 6-OHDA into the medial forebrain bundle resulted in comparably large (> or = 95%) depletions of tissue levels of DA in both age groups. As expected, rats depleted of DA as adults exhibited marked deficits in motoric behavior and body weight regulation that persisted for the 8 days of postsurgical observation. In contrast, rats depleted of DA as weanlings were spared from such deficits, and their behavior closely resembled that of age-matched controls. Microdialysis studies revealed dialysate levels of striatal DA that paralleled these age-dependent behavioral differences. At a time when age-related behavioral differences were still quite pronounced (5-6 days postsurgery), basal DA levels were reduced by 80% of control values in rats lesioned as adults whereas basal DA levels in rats lesioned as weanlings were unchanged relative to their controls. Finally, adults depleted of striatal DA as weanlings were no more sensitive to the movement-impairing effects of intrastriatal sulpiride (3.0 or 10.0 micrograms/hemisphere) infusions than were control rats. These data suggest that weanlings compensate for large, but incomplete, denervation of striatal DA with markedly enhanced release and turnover from residual terminals. This developmental plasticity may prevent the occurrence of behavioral deficits soon after the lesion and also the supersensitivity to the challenging effects of DA antagonists as animals grow into adulthood.     

Acetylcholine release from striatal slices of young adult and aged Fischer 344 rats

The release of endogenous and newly synthesized acetylcholine (ACh) was examined in neostriatal slices prepared from young adult (10-month) and aged (28-month) Fischer 344 rats. Both spontaneous and potassium-stimulated release were tested after various in vitro incubation times (1, 3 or 5 hr). The potassium-stimulated release of ACh from slices of 28-month rats was decreased by 53% when tested after incubating the slices 1 hr. The age-related differences in ACh release lessened if the slices were incubated for longer times (3 or 5 hr) before monitoring release. The spontaneous release of ACh was similar among the slices from both age-groups and at all times points monitored. When the neostriatal slices were incubated in medium supplemented with deuterated choline, the release of both the endogenous and newly synthesized ACh from slices of 28-month rats was decreased by 33% when tested after a 1-hr incubation, but was again similar to that released from slices of 10-month rats when tested after a 3-hr incubation. Choline release from slices of the 28-month rats was similar to that released from the slices of the 10-month rats when acetylcholinesterase (AChE) was inhibited during the release incubation. In slices with intact AChE activity, however, the age-related difference in choline release was similar to that observed for ACh release when AChE was inhibited. That is, when AChE activity was intact, the potassium-stimulated choline release from slices of 28-month rats was less than that released from slices of 10-month rats when release was tested after a 1-hr incubation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modeling functions of striatal dopamine modulation in learning and planning

The activity of midbrain dopamine neurons is strikingly similar to the reward prediction error of temporal difference reinforcement learning models. Experimental evidence and simulation studies suggest that dopamine neuron activity serves as an effective reinforcement signal for learning of sensorimotor associations in striatal matrisomes. In the current study, we simulate dopamine neuron activity with the extended temporal difference model of Pavlovian learning and examine the influences of this signal on medium spiny neurons in striatal matrisomes. The modeled influences include transient membrane effects of dopamine D(1) receptor activation, dopamine-dependent long-term adaptations of corticostriatal transmission, and effects of dopamine on rhythmic fluctuations of the membrane potential between an elevated "up-state" and a hyperpolarized "down-state". The most dominant activity in the striatal matrisomes is assumed to elicit behaviors via projections from the basal ganglia to the thalamus and the cortex. This "standard model" performs successfully when tested for sensorimotor learning and goal-directed behavior (planning). To investigate the contributions of our model assumptions to learning and planning, we test the performance of several model variants that lack one of these mechanisms. These simulations show that the adaptation of the dopamine-like signal is necessary for sensorimotor learning and planning. Sensorimotor learning requires dopamine-dependent long-term adaptation of corticostriatal transmission. Lack of dopamine-like novelty responses decreases the number of exploratory acts, which impairs planning capabilities. The model loses its planning capabilities if the dopamine-like signal is simulated with the original temporal difference model, because the original temporal difference model does not form novel associative chains. Transient membrane effects of the dopamine-like signal on striatal firing substantially shorten the reaction time in the planning task. The capability for planning is improved by influences of dopamine on the durations of membrane potential fluctuations and by manipulations that prolong the reaction time of the model. These results suggest that responses of dopamine neurons to conditioned stimuli contribute to sensorimotor reward learning, novelty responses of dopamine neurons stimulate exploration, and transient dopamine membrane effects are important for planning.     

GABAergic modulation of striatal peptide expression in rats and the alterations induced by dopamine antagonist treatment

GABAergic modulation of enkephalin, substance P and glutamic acid decarboxylase (GAD67) gene expression and the alterations induced by dopamine receptor blockade were studied in the rat striatum. Following subchronic treatment with the GABA-A agonist muscimol, the GABA-B agonist baclofen or the GABA transaminase inhibitor γ-vinyl GABA there were no significant changes in striatal peptide and GAD67 gene expression. Following repeated administration of the D-2 antagonists, eticlopride and haloperidol, there was an increase in enkephalin and GAD67 mRNA levels and parallel decrease in that of substance P. These were unaffected by co-administration of γ-vinyl GABA. The D-1 antagonist, SCH 23390 administered alone or together with γ-vinyl GABA did not alter peptide or GAD67 mRNA levels. It seems that pharmacological stimulation of GABA receptors has little effect on enkephalin, substance P or GAD67 mRNA expression in striatal output neurons.     

Modification of adenosine modulation of acetylcholine release in the hippocampus of aged rats

Adenosine is a neuromodulator acting through inhibitory A₁ receptors (A₁Rs) and facilitatory A_2ARs. Since A_2AR antagonists attenuate memory deficits in aged animals and memory deficits might involve a decreased cholinergic function, we investigated how aging affects the density and function of adenosine receptors in rat hippocampal cholinergic terminals. In young adult (2 months) rats, 64 and 36% of cholinergic terminals (immunopositive for vesicular ACh transporters) possessed A₁Rs and A_2ARs, respectively. In aged (24 months) rats, the percentage of cholinergic terminals with A₁Rs was preserved, whereas that with A_2ARs was larger (49%). In young adults adenosine only tonically inhibited ACh release through A₁Rs, whereas in aged rats there was a greater A₁R-mediated inhibition and a simultaneous A_2AR-mediated facilitation of ACh release. Thus, the enhanced A_2AR density and facilitation compensates for the greater tonic A₁R modulation, preserving the global adenosine modulation of ACh release in aged rats. Furthermore, since A_2AR antagonists inhibit ACh release, the beneficial effects of A_2AR antagonists on memory in aged rats might not result from ACh release modulation.     

Changes in striatal dopamine release and metabolism during and after subchronic haloperidol administration in rats.

The release and metabolism of dopamine (DA) in the striatum of rats during and after subchronic haloperidol (HAL) administration (3 weeks) was assessed using in vivo microdialysis. Basal extracellular levels of DA, DA metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) and the serotonin metabolite (5-hydroxyindoleacetic acid) were not significantly different from control values at 3 weeks of HAL administration and 3 days after drug withdrawal. The specific DA D2 receptor antagonist, raclopride (0.5 mg/kg, i.p.), significantly increased DA release and metabolism in control animals, but decreased DA release in the HAL-treated groups at 3 weeks of drug treatment. This effect was not significant following drug withdrawal. These results contrast with our previous finding that chronic HAL treatment (32 weeks) increases basal DA metabolism and further support the possibility that changes in DA function differ following short term vs. long term neuroleptic exposure.     

Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration

Compelling evidence has shown, that neurotrophins responsible for the regulation of neuronal growth, survival, and differentiation are involved in neurodegenerative diseases. Whereas lower serum levels of brain derived neurotrophic factor (BDNF) have been observed in patients with Parkinson's disease, no studies have directly related the degree of striatal neurodegeneration of dopaminergic neurons (DA) with serum BDNF levels. In this study we examined the relationship between striatal neurodegeneration as determined with ¹²³I-PE2I-single photon emission computer tomography (SPECT) and serum BDNF levels in patients with parkinsonism. Twenty-one patients with abnormal in vivo striatal dopamine transporter (DAT) binding as evidenced with [¹²³I]PE2I SPECT brain scanning were included. Samples for serum BDNF levels were collected at the time of the SPECT scanning, and BDNF was measured with enzyme-linked immunosorbent assay (ELISA). The striatal binding potential of non-displaceable [¹²³I]PE2I was calculated. We found a positive correlation between serum BDNF levels and striatal DAT availability (p < 0.01, R² = 0.36). We find that in patients with striatal dopaminergic neurodegeneration serum BDNF levels decrease along with loss in striatal DAT binding.     

Frequency-dependent modulation of dopamine release by nicotine

Although nicotine activation of dopamine release is implicated in addiction, it also desensitizes nicotinic acetylcholine receptors (nAChRs), leading to a prolonged depression of evoked dopamine release. Here we show that nicotine's effects depend on the firing pattern of dopamine neurons, so that while desensitization of nAChRs indeed curbs dopamine released by stimuli emulating tonic firing, it allows a rapid rise in dopamine from stimuli emulating phasic firing patterns associated with incentive/salience paradigms. Nicotine may thus enhance the contrast of dopamine signals associated with behavioral cues.     

In vivo brain microdialysis studies on the striatal dopamine and serotonin release in zitter mutant rats

In the present study, using in vivo brain microdialysis, we investigated the basal extracellular dopamine (DA) and serotonin (5-HT) release in the caudal striatum (cSTR) of young (4-6 months old) and aged (10-12 months old) zitter mutant rats. The basal extracellular levels of DA release in both young and aged zitter rats were significantly lower than that of age-matched Sprague-Dawley (SD) rats, whereas only aged zitter rats showed a significant difference in the basal 5-HT release. Dopaminergic neurons were more vulnerable than serotonergic neurons in the cSTR of zitter mutant rats during aging. Perfusion of 60 mM potassium (K+) enhanced the extracellular levels of cSTR DA in the young zitter rats and the extracellular levels of both DA and 5-HT in the cSTR of the aged zitter rats. The firing rate of K+-stimulated monoamine release in the cSTR was significantly higher in the zitter rats than in the age-matched SD rats. These findings suggest that there are innate quantitative differences in the releasable pool and the availability of monoamines in the cSTR of zitter mutant rats.     

Alteration of methamphetamine-induced striatal dopamine release in mint-1 knockout mice

Mint-1, which is also called as X11 or mammalian Lin10, protein has been implicated in the synaptic vesicle exocytosis and the targeting and localization of synaptic membrane proteins. Here, we established mint-1 gene knockout (mint-1 KO) mice and investigated vesicular and transporter-mediated dopamine (DA) release evoked by high K(+) and methamphetamine (METH), respectively. Compared with wild-type control, high K(+)-evoked striatal DA release was attenuated, but not significantly, in the KO mice as measured by microdialysis method. The METH-induced DA release was significantly attenuated in the KO mice. In addition, METH-induced stereotypy was also significantly attenuated in the KO mice. Mint-1 KO mice showed more sensitive and prominent behavioral response to an approaching object as compared with wild-type mice. These results suggest that mint-1 protein is involved in transporter-mediated DA release induced by METH.     

Tyrosine availability determines stimulus-evoked dopamine release from rat striatal slices

Direct evidence that precursor levels can affect catecholamine release from brain cells has not previously been presented. We observe a dose-dependent relationship between the tyrosine (Tyr) concentration of the superfusing medium and the amount of dopamine (DA) released from rat striatum by trains of electrical pulses. In the absence of exogenous tyrosine, tissue Tyr and DA levels are reduced following stimulation. These findings suggest that DA release from striatal neurons may not be sustained if fluctuations occur in the supply of Tyr to the brain.     

Alpha modulation in parietal and retrosplenial cortex correlates with navigation performance

The present study investigated the brain dynamics accompanying spatial navigation based on distinct reference frames. Participants preferentially using an allocentric or an egocentric reference frame navigated through virtual tunnels and reported their homing direction at the end of each trial based on their spatial representation of the passage. Task-related electroencephalographic (EEG) dynamics were analyzed based on independent component analysis (ICA) and subsequent clustering of independent components. Parietal alpha desynchronization during encoding of spatial information predicted homing performance for participants using an egocentric reference frame. In contrast, retrosplenial and occipital alpha desynchronization during retrieval covaried with homing performance of participants using an allocentric reference frame. These results support the assumption of distinct neural networks underlying the computation of distinct reference frames and reveal a direct relationship of alpha modulation in parietal and retrosplenial areas with encoding and retrieval of spatial information for homing behavior.     

Functional recovery of the striatal cholinergic system in aged rats by adenoviral vector-mediated gene transfer of dopamine D2 receptor

We previously reported that the striatal dopamine-acetylcholine (ACh) interaction was affected by the aging process, possibly via a decrease of the striatal D(2)R expression. In the current study, the ACh responses to the infusion of 0.1microM of the D(2)R agonist quinpirole were measured with microdialysis techniques after adenoviral vector-mediated gene transfer of D(2)R into the striatum of 25-month-old rats. The D(2)R gene-transferred rats showed significantly stronger responses of the striatal cholinergic neurons to the infusion of the D(2)R agonist than did control vector-transferred rats. The current study suggests that age-associated functional decline with decreased gene expression of the receptor may be restored by intervention.     

Intra-ischemic extracellular release of dopamine and glutamate is associated with striatal vulnerability to ischemia

We have previously described a marked attenuation of postischemic striatal neuronal death by prior substantia nigra (SN) lesion, and have shown that lowering the brain temperature by only a few degrees during ischemia also confers a marked protective effect. The present study was carried out to evaluate whether the protective effect of these manipulations involves changes in extracellular release of striatal dopamine (DA) and glutamate (Glu) during ischemia. Four animal subgroups were investigated, including unilateral SN-lesioned rats whose intra-ischemic brain temperature was maintained at 36 degrees C, and non-lesioned animals whose brain temperature was not regulated, or was maintained at 33 or 36 degrees C during ischemia. Striatal extracellular sampling was performed by a microdialysis probe in rats subjected to 20 min of ischemia by 4-vessel occlusion. In rats whose intra-ischemic brain temperature was 36 degrees C, both DA and Glu increased significantly. In SN-lesioned rats no changes were found in extracellular levels of DA. However, significant increases in Glu were measured. In animals whose brain temperature was not regulated (the intra-ischemic brain temperature fell to 30 degrees C) or maintained at 33 degrees C there was a significant increase of DA release, but no changes were found in extracellular levels of Glu. These results, taken together with the neuropathological findings, suggest that release of both DA and Glu during ischemia is necessary for the development of postischemic striatal damage.     

Somatostatin induces striatal dopamine release and contralateral turning behaviour in the mouse

Application of somatostatin to the striatum of the anaesthetized rat has previously been shown to elicit large increases in extracellular levels of dopamine and GABA via a glutamate-dependent mechanism. These actions have been ascribed to the SSTR2 receptor. Here we describe experiments designed to investigate whether these effects occur in C57Bl6 mice and if they elicit rotational behaviours associated with increased dopamine in the striatum. Application of somatostatin resulted in increased concentrations of dopamine in striatum, hippocampus and amygdala of anaesthetized mice. Unilateral striatal infusions of the peptide by retrodialysis increased locomotion. Application of N-methyl-D-aspartate and AMPA to the freely-moving mouse striatum resulted in increased dopamine release; however, only AMPA caused increased locomotion. These results further confirm that somatostatin can play a role in the control of locomotor function by modulating striatal dopamine release.     

Place cell rigidity correlates with impaired spatial learning in aged rats

In humans and in animals, some aged individuals are severely impaired in learning and memory capacity whereas others perform as well as young adults. In the present study, the spatial memory capacity of young and aged rats was characterized by the Morris water maze task, and then firing patterns of hippocampal "place cells" were assessed as the animals explored a familiar environment and a geometrically-altered version of the environment. Spatial representations of hippocampal cells in young and memory-intact aged rats changed upon exposure to the altered environment. In contrast, spatial representations of many cells in aged, memory-impaired rats were unaffected by the environmental alteration. Furthermore, combining all groups, the extent to which spatial representations distinguished the familiar and altered environments predicted learning capacity in the water maze. These findings suggest that a major component of memory impairment in aging may be the failure of the hippocampus to encode subtle differences in contextual information that differ across multiple experiences, such as the sequence of training trials in the water maze.     

Effect of aging on striatal dopamine receptor subtypes in Wistar rats

Both D1 and D2 dopamine receptor subtypes are lost from striata as Wistar rats age. The magnitude of loss differs slightly for the two subtypes (approximately 30% for D1, approximately 40% for D2) as does the temporal pattern (progressive loss from 3 to 24 months for D2, no decrease in D1 after 12 months) although most D2 loss also occurs in the first half of the lifespan. Dopamine stimulated adenylate cyclase activity also declines during striatal aging in a manner roughly proportioned to D1 receptor loss.