Endogenous Striatal Dopamine Research Articles

Combination of In Vivo [123I]FP-CIT SPECT and Microdialysis Reveals an Antipsychotic Drug Haloperidol-induced Synaptic Dopamine Availability in the Rat Midbrain and Striatum.

Synaptic dopamine (DA) is mainly regulated by the presynaptic DA transporter (DAT). Single-photon emission computerized tomography (SPECT) with the DAT radiotracer [123I]FP-CIT assesses changes in synaptic DA availability when endogenous DA displaces [123I]FP-CIT or competes for DAT. Here, we investigated the effects of haloperidol (HAL) and clozapine (CLZ) on [123I]FP-CIT binding in the rat striatum and midbrain to assess the utility of [123I]FP-CIT SPECT to quantify changes in synaptic DA availability. Rats underwent [123I]FP-CIT SPECT after intraperitoneal administration of normal saline (vehicle), HAL (1 and 7 mg/kg), CLZ (10 and 54 mg/kg) and bupropion (BUP, a DAT blocker, 20 and 100 mg/kg). In the striatum and midbrain, percent differences in the nondisplaceable binding potential (BPND) of [123I]FP-CIT compared to the vehicle were calculated for the various drugs and doses. In another experiment, changes in endogenous striatal DA concentration were measured by in vivo microdialysis under the conditions used in the SPECT study. BUP dose-dependently occupied DAT at considerable levels. Compared to the vehicle, HAL decreased [123I]FP-CIT BPND in the striatum (−25.29% and −2.27% for 1 and 7 mg/kg, respectively) and to a greater degree in the midbrain (−58.74% and −49.64% for 1 and 7 mg/kg, respectively), whereas the CLZ-treated group showed a decrease in the midbrain (−38.60% and −40.38% for 10 and 54 mg/kg, respectively) but an increase in the striatum (18.85% and 38.64% for 10 and 54 mg/kg, respectively). Antipsychotic-induced changes in endogenous striatal DA concentrations varied across drugs and doses. The data demonstrate that [123I]FP-CIT SPECT may be a useful preclinical technique for detecting increases in synaptic DA availability in the midbrain and striatum in response to HAL, with results comparable to those of in vivo microdialysis.

DAT1 Polymorphism Determines L-DOPA Effects on Learning about Others’ Prosociality

Despite that a wealth of evidence links striatal dopamine to individualś reward learning performance in non-social environments, the neurochemical underpinnings of such learning during social interaction are unknown. Here, we show that the administration of 300 mg of the dopamine precursor L-DOPA to 200 healthy male subjects influences learning about a partners’ prosocial preferences in a novel social interaction task, which is akin to a repeated trust game. We found learning to be modulated by a well-established genetic marker of striatal dopamine levels, the 40-bp variable number tandem repeats polymorphism of the dopamine transporter (DAT1 polymorphism). In particular, we found that L-DOPA improves learning in 10/10R genoype subjects, who are assumed to have lower endogenous striatal dopamine levels and impairs learning in 9/10R genotype subjects, who are assumed to have higher endogenous dopamine levels. These findings provide first evidence for a critical role of dopamine in learning whether an interaction partner has a prosocial or a selfish personality. The applied pharmacogenetic approach may open doors to new ways of studying psychiatric disorders such as psychosis, which is characterized by distorted perceptions of others’ prosocial attitudes.

Effect of Pre- and Postnatal Manganese Exposure on Brain Histamine Content in a Rodent Model of Parkinson’s Disease

Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats, and to determine effects on histamine content in the brain of these rats in adulthood. Manganese (MnCl₂·4H₂O; 10,000 ppm) was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (60 or 134 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 60 or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 92 and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of histamine content in frontal cortex, hippocampus, hypothalamus, and medulla oblongata of adult rat brain after 6-OHDA (60 and 134 μg) injection on the day 3rd postnatal day. These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that manganese enhances effects of 6-OHDA on histamine in brain.

Ontogenetic Exposure of Rats to Pre- and Post-Natal Manganese Enhances Behavioral Impairments Produced by Perinatal 6-Hydroxydopamine

Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats. Manganese (MnCl(2)·4H(2)O) 10,000ppm was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20mg/kg ip 1h) prior to bilateral icv administration of 6-OHDA (30, 60, or 137μg) or its vehicle saline-ascorbic (0.1%) (control). At 2months after birth, in rats lesioned with 30, 60, or 134μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 66, 92, and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of DA D(1) agonist (i.e., SKF 38393)-induced oral activity in the group of rats exposed perinatally to manganese and also treated neonatally with the 30mg/kg dose of 6-OHDA. The 30mg/kg 6-OHDA group, demonstrating cataleptogenic responses to SCH 23390 (0.5mg/kg) and haloperidol (0.5mg/kg ip), developed resistance if co-exposed to perinatal manganese. In the group exposed to manganese and lesioned with the 60mg/kg dose of 6-OHDA, there was a reduction in D(2) agonist (i.e., quinpirole, 0.1mg/kg)-induced yawning. The series of findings demonstrate that ontogenetic exposure to manganese results in an enhancement of behavioral toxicity to a moderate dose of 6-OHDA, despite the fact that there is no enhanced depletion of striatal DA depletion by the manganese treatment.

Pre‐synaptic dopaminergic compensation after moderate nigrostriatal damage in non‐human primates

Despite a dramatic loss of nigrostriatal dopaminergic neurons in Parkinson's disease, clinical symptoms only arise with 70-80% reduction of striatal dopamine. The mechanisms responsible for this functional compensation are currently under debate. Although initial studies showed an enhanced pre-synaptic dopaminergic function with nigrostriatal degeneration, more recent work suggests that functional compensation is not dopamine-mediated. To address this issue, we used cyclic voltammetry to directly measure endogenous dopamine release from striatal slices of control monkeys and animals with a moderate or severe MPTP-induced dopaminergic lesion. The moderately lesioned monkeys were asymptomatic, while the severely lesioned animals were parkinsonian. In monkeys with a moderate lesion, a 300% increase was obtained in endogenous striatal dopamine release. In contrast, in striatal slices from severely lesioned animals, a small % of evoked dopamine signals were similar in amplitude to control while the greater majority were undetectable. These findings suggest that pre-synaptic dopaminergic compensation develops in residual dopaminergic terminals with moderate lesioning, but that this response is lost with severe nigrostriatal damage. Such an interpretation is supported by the results of dopamine turnover studies. This enhanced pre-synaptic dopaminergic activity may be important in maintaining normal motor function during the initial stages of Parkinson's disease.

Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine

Prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to increase striatal dopaminergic activity. Here we investigated dopaminergic neurotransmission using single photon emission computed tomography (SPECT) and [ 123I]IBZM to indirectly assess the change in endogenous striatal dopamine concentration upon rTMS as compared with d-amphetamine challenge. SPECT imaging was performed twice each in five patients during rTMS, and in two patients who received 0.3 mg/kg d-amphetamine. Administration of rTMS led to a mean relative decrease in striatal IBZM binding by 9.6 ± 6.2%, and d-amphetamine challenge ( n = 4) induced a mean relative reduction by 8 ± 2.95% (difference not statistically significant). Acute rTMS challenge showed similar striatal dopaminergic effects to those associated with the administration of d-amphetamine, a substance known to increase synaptic dopamine.

Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine

Prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to increase striatal dopaminergic activity; however, the magnitude of these effects compared with other dopaminergic stimuli is unknown. We have investigated dopaminergic neurotransmission in patients with major depressive episodes using single photon emission computed tomography (SPECT) and [123I] iodobenzamide (IBZM) under a bolus and constant infusion paradigm to indirectly assess the change in endogenous striatal dopamine concentration upon rTMS and d-amphetamine challenge. SPECT imaging was performed twice each in five patients during rTMS, and in two patients who received 0.3mg/kg d-amphetamine. The change in striatal IBZM binding upon challenge was assessed with a region of interest technique. Data sets of 13 SPECT imaging sessions were available for analysis. TMS (9 SPECT assessments) led to a mean relative decrease in striatal IBZM binding by 9.6±6.2%, d-amphetamine challenge (n=4) induced a mean relative reduction by 8±2.95% (difference not statistically significant). The decrease of IBZM binding upon challenge is suggestive of an increase in endogenous dopaminergic stimulation. Acute rTMS challenge showed similar striatal dopaminergic effects as compared to administration of d-amphetamine, a substance known to increase synaptic dopamine.

Understanding the Placebo Effect: Contributions from Neuroimaging

Neuroimaging studies have provided a major contribution to our understanding of the mechanisms of the placebo effect in neurological and psychiatric disorders. Expectation of symptom improvement has long been believed to play a critical role in the placebo effect, and is associated with increased endogenous striatal dopamine release in Parkinson's disease and increased endogenous opioid transmission in placebo analgesia. Evidence from positron emission tomography and functional magnetic resonance imaging studies suggests that expectations of symptom improvement are driven by frontal cortical areas, particularly the dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortices. The ventral striatum is involved in the expectation of rewarding stimuli and, together with the prefrontal cortex, has also been shown to play an important role in the placebo-induced expectation of therapeutic benefit. Understanding the mechanisms of the placebo effect has important implications for treatment of several medical conditions, including depression, pain, and Parkinson's disease.

Mitochondrial Stress-Induced Dopamine Efflux and Neuronal Damage by Malonate Involves the Dopamine Transporter

Endogenous striatal dopamine (DA) overflow has been associated with neuropathological conditions resulting from ischemia, psychostimulants, and metabolic inhibition. Malonate, a reversible inhibitor of succinate dehydrogenase, models the effects of energy impairment in neurodegenerative disorders. We have previously reported that the striatal DA efflux and damage to DA nerve terminals resulting from intrastriatal malonate infusions is prevented by prior DA depletion, suggesting that DA plays a role in the neuronal damage. We presently report that the malonate-induced DA efflux is partially mediated by reverse transport of DA from the cytosol to the extracellular space via the DA transporter (DAT). Pharmacological blockade of the DAT with a series of structurally different inhibitors [cocaine, mazindol, 1-(2-(bis(4-fluophenyl methoxy) ethyl)-4-(3-(4-fluorophenyl)-propyl)piperazine) dimethane sulfonate (GBR 13098) and methyl(-)-3beta-(p-fluorophenyl)-1alphaH,5alphaH-tropane-2beta-carboxylate1,5-naphthalene (Win 35,428)] attenuated malonate-induced DA overflow in vivo and protected mice against subsequent damage to DA nerve terminals. Consistent with these findings, the DAT inhibitors prevented malonate-induced damage to DA neurons in mesencephalic cultures and also protected against the loss of GABA neurons in this system. The DAT inhibitors did not modify malonate-induced formation of reactive oxygen species or lactate production, indicating that the DAT inhibitors neither exert antioxidant effects nor interfere with the actions of malonate. Taken together, these findings provide direct evidence that mitochondrial impairment and metabolic stress cause striatal DA efflux via the DAT and suggest that disruptions in DA homeostasis resulting from energy impairment may contribute to the pathogenesis of neurodegenerative diseases.

Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: Preliminary results of a dynamic [ 123I] IBZM SPECT study

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [ 123I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10 Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [ 123I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D 2 receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6 ± 6.2% in IBZM binding to striatal dopamine D 2 receptors after rTMS challenge compared to baseline ( p = 0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.

Striatal glutamate release evoked in vivo by NMDA is dependent upon ongoing neuronal activity in the substantia nigra, endogenous striatal substance P and dopamine

The aim of the present microdialysis study was to investigate whether the increase in striatal glutamate levels induced by intrastriatal perfusion with NMDA was dependent on the activation of extrastriatal loops and/or endogenous striatal substance P and dopamine. The NMDA-evoked striatal glutamate release was mediated by selective activation of the NMDA receptor-channel complex and action potential propagation, as it was prevented by local perfusion with dizocilpine and tetrodotoxin, respectively. Tetrodotoxin and bicuculline, perfused distally in the substantia nigra reticulata, prevented the NMDA-evoked striatal glutamate release, suggesting its dependence on ongoing neuronal activity and GABA(A) receptor activation, respectively, in the substantia nigra. The NMDA-evoked glutamate release was also dependent on striatal substance P and dopamine, as it was antagonized by intrastriatal perfusion with selective NK(1) (SR140333), D(1)-like (SCH23390) and D(2)-like (raclopride) receptor antagonists, as well as by striatal dopamine depletion. Furthermore, impairment of dopaminergic transmission unmasked a glutamatergic stimulation by submicromolar NMDA concentrations. We conclude that in vivo the NMDA-evoked striatal glutamate release is mediated by activation of striatofugal GABAergic neurons and requires activation of striatal NK(1) and dopamine receptors. Endogenous striatal dopamine inhibits or potentiates the NMDA action depending on the strength of the excitatory stimulus (i.e. the NMDA concentration).

Clozapine prolongs hypotonic immobility in rats with bilateral 6-hydroxydopamine lesions of the striatum

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.

Clozapine prolongs hypotonic immobility in rats with bilateral 6-hydroxydopamine lesions of the striatum

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.

Stimulation of the subthalamic nucleus in Parkinson's disease does not produce striatal dopamine release.

The subthalamic nucleus (STN) is a target in the surgical treatment of Parkinson's disease (PD). The mechanism by which electrical stimulation of the STN ameliorates symptoms of PD remains unknown. One consistent aspect of STN stimulation is the ability to reduce the dosage of dopaminergic medications; sometimes they can be eliminated altogether. Furthermore, nigrostriatal projection axons are apposed to the dorsal surface of the STN and are likely affected by the application of current in this region. We sought to determine whether STN stimulation could release endogenous striatal dopamine. Five patients with PD, who had previously undergone surgical implantation of bilateral STN stimulators, underwent [(11)C]raclopride positron emission tomographic scanning. l-dopa was withheld for 12 hours, and both stimulators were turned off 9 hours before scanning. We assayed for striatal dopamine release by measuring radioligand displacement as a consequence of turning on the right STN stimulator after 45 minutes of a 90-minute [(11)C]raclopride infusion. Patients were evaluated with the motor section of the Unified Parkinson's Disease Rating Scale before and after the studies. Comparisons between the right and left striata, before and after right STN stimulation, demonstrated no significant differences in [(11)C]raclopride binding, despite significant improvements in Unified Parkinson's Disease Rating Scale motor scores with unilateral stimulation (mean improvement, 26.0 +/- 16.4%; P < 0.05). This finding was also noted when the striatum was partitioned into dorsal and ventral caudate and putamen and the four regions were analyzed separately. Our results suggest that STN stimulation does not mediate its anti-PD effects via the release of dopamine, as assessed with [(11)C]raclopride displacement.

Ontogenetic quinpirole treatments fail to prime for D2 agonist-enhancement of locomotor activity in 6-hydroxydopamine-lesioned rats.

Repeated treatments with a dopamine (DA) D2 receptor agonist results in the induction of DA D2 receptor supersensitivity, as evidenced by enhanced behavioral responses to subsequent D2 agonist treatments - a phenomenon known as priming of receptors. Priming of D2 receptors has been well-studied in otherwise intact (non-lesioned) rats. In contrast to D2 priming, repeated treatments with a DA D1 agonist are unable to prime D1 receptors unless nigrostriatal DA fibers are largely destroyed in early postnatal ontogeny. In order to determine if D2 receptors could be primed in rats in which nigrostriatal DA fibers were largely destroyed in early postnatal ontogeny, rats were (a) lesioned at 3 days after birth with 6-hydroxydopamine (67 micrograms in each lateral ventricle; desipramine, 20 mg/kg IP, 1 h; 6-OHDA), (b) treated daily for the first 28 days after birth with the D2 agonist quinpirole HCl (3.0 mg/kg IP), and (c) observed in adulthood for both quinpirole-induced and SKF 38393- (D1 agonist-) induced locomotor activity and stereotyped activities. In 6-OHDA-lesioned rats in which endogenous striatal DA was reduced by 99%, quinpirole did not produce enhanced locomotor or stereotyped activities. However, SKF 38393 produced increased locomotor and stereotyped activities even after the first dose of SKF 38393. These findings demonstrate that D2 receptors are not primed by ontogenetic quinpirole treatments of neonatally 6-OHDA-lesioned rats, although D2 agonist treatments do at least partially prime D1 receptors in the 6-OHDA-lesioned rats.

Striatal dopamine-NMDA receptor interactions in the modulation of glutamate release in the substantia nigra pars reticulata in vivo: opposite role for D1 and D2 receptors.

Dual probe microdialysis was employed in conscious rats to investigate whether endogenous dopamine is involved in the stimulation of glutamate release in the substantia nigra pars reticulata following striatal NMDA receptor activation. Intrastriatal perfusion with NMDA (1 and 10 microm) facilitated nigral glutamate release (dizocilpine- and tetrodotoxin-sensitive). The D2 dopamine receptor antagonist raclopride increased spontaneous nigral glutamate release and caused a leftward shift in the NMDA sensitivity, lowering NMDA effective concentrations to submicromolar levels. Conversely, the D1 antagonist SCH23390 prevented the effect of NMDA (1 microm) and caused a rightward shift in the NMDA sensitivity. It was tested whether the antagonist effects were due to dopamine receptor blockade or increased tone on D1/D2 receptors. SCH23390 prevented the raclopride-induced enhancement of spontaneous but not NMDA-evoked glutamate release while raclopride left unchanged the SCH23390-induced inhibition. The physiopathological relevance of the dopaminergic modulation was strengthened by perfusing NMDA in the dopamine-depleted striatum of hemiparkinsonian rats. Nigral glutamate responsiveness to NMDA was enhanced as with raclopride. We conclude that endogenous striatal dopamine regulates both spontaneous and NMDA-induced nigral glutamate release via an opposite control mediated by D1 facilitatory and D2 inhibitory receptors. Alterations of this control may subserve the motor symptoms of Parkinson's disease.

Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo.

The authors investigated whether striatal dopamine D2 receptor binding characteristics in vivo are similar in men and women and whether there are sex-related differences in the decline in D2 receptor density due to aging. Striatal D2 receptor density (Bmax), affinity (Kd), and binding potential (Bmax/Kd) were measured with positron emission tomography and [11C]raclopride in 54 healthy subjects (33 men and 21 women). Women had generally lower D2 receptor affinity than men, and this difference was statistically significant in the left striatum. Bmax and Bmax/Kd tended to decline with age twice as fast in men as in women, but the difference did not reach statistical significance. These results confirm the age-related reduction of D2 receptor density and binding potential in both sexes in vivo. The lower D2 receptor affinity suggests an increased endogenous striatal dopamine concentration in women. This may have implications for the differential vulnerability of men and women to psychiatric disorders like schizophrenia and alcohol and substance dependence.

Differential Control by N‐Methyl‐D‐Aspartate and Kainate of Striatal Dopamine Release In Vivo: A Trans‐Striatal Dialysis Study

Using the technique of trans-striatal dialysis in halothane-anesthetized rats, we have studied the effects of intrastriatally infused N-methyl-D-aspartate (NMDA), kainate, and quisqualate on the liberation of endogenous striatal dopamine. The striatal infusion of NMDA (10(-3)-10(-2) M) or kainate (10(-4)-10(-2) M) but not of quisqualate (up to 10(-2) M) for one 20-min fraction provoked a dramatic increase in striatal dopamine efflux up to a maximum of 1,200 and 3,400% of basal levels for NMDA and kainate, respectively. NMDA (10(-3) M) evoked liberation of striatal dopamine was totally blocked by coinfusion of 2-amino-5-phosphonovalerate (2-APV; 5 X 10(-4) M) and by the systemic injection of phencyclidine (3 mg/kg i.p.). The effects of NMDA (10(-3) M) were also totally antagonized in a dose-dependent manner by the striatal coinfusion of atropine (10(-7)-10(-4) M), and abolished in rats that had received bilateral striatal ibotenate lesions (10 micrograms/1 microliter) 1 week prior to implantation of the dialysis fiber. The striatal infusion of tetrodotoxin (10(-6) M) reduced basal dopamine efflux by 60-70% and abolished the NMDA (10(-3) M)-evoked liberation of striatal dopamine. The effects of kainate (10(-3) M) on striatal dopamine efflux were only partially reduced by doses of 2-APV or atropine that totally blocked the NMDA response, and were also partially resistant to tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related decrements in the muscarinic enhancement of K +-evoked release of endogenous striatal dopamine: an indicator of altered cholinergic-dopaminergic reciprocal inhibitory control in senescence

Previous experiments have indicated that the release of striatal dopamine (DA) is controlled by inhibitory DA autoreceptors which are mediated by inhibitory cholinergic heteroreceptors (HTRs). Activation of the HTRs by muscarinic or nicotinic agonists potentiates the K +-evoked release of DA from the striatum. Present experiments were carried out to determine if this relationship is altered as a function of aging. Cross-cut striatal tissue slices obtained from 3 age-groups (6,12–18 and 24 months) Wistar rats were superfused with a modified Krebs-Ringer basal release medium containing 2.5 mM KCl. After a 30-min equilibration period, a 5-min baseline fraction was collected from each chamber. The medium was then switched to one containing 30 mM KCl, and depending upon the experiment, 1 of 4 concentrations of a particular muscarinic (oxotremorine, pilocarpine, carbachol or bethanecol) or nicotinic (nicotine) agonist. In some experiments DA autoreceptor function was assessed directly with haloperidol. Six 5-min fractions were taken during depolarization. DA release was assessed using high performance liquid chromatography coupled to electrochemical detection. Results indicated that the efficacy of the muscarinic agonists was reduced in an age-dependent manner with the oldest age groups showing the smallest enhancement. The age at which the decline was seen was dependent on the muscarinic agonist that was applied. Deficits were seen as early as 12 months when full agonists (e.g. carbachol) were applied, but did not appear until 18 months when partial agonists (e.g. oxotremorine) were applied. These age-related alterations were not seen when haloperidol or nicotine were used to enhance the K +-evoked release of DA. Results are discussed in terms of specific deficits in the muscarinic control of striatal DA autoreceptors in senescence. These decrements occur as result of age-related alterations in the conformational/orientational state of the muscarinic receptors regulating striatal DA release.

Effects of hypoxia-ischemia on monoamine metabolism in the immature brain.

We measured acute changes in monoamine metabolites in corpus striatum of immature rat pups exposed to hypoxia-ischemia, hypoxia alone, or total global ischemia. Carotid ligations and two hours of 8% oxygen environment in 7-day-old pups led to asymmetrical turning behavior, a 70% decrease in endogenous striatal dopamine levels, and a 125% increase in homovanillic acid (HVA) concentrations on the side of ligation. In contrast, hypoxia alone and total global ischemia alone were not associated with HVA level elevation. Elevation of HVA level with hypoxia-ischemia showed a threshold effect between 1 and 1.5 hours, and this time course paralleled that for production of gross morphological changes in rats raised to maturity. The data suggest that dopamine release from striatal nerve terminals is associated with events causing brain injury during perinatal hypoxia-ischemia. Tissue HVA in the animal model appears to be a quantitative marker for the effects of the insult on a population of nerve terminals.