Local Dopamine Research Articles

Ovarian hormone influences on the density of immunoreactivity for tyrosine hydroxylase and serotonin in the primate corpus striatum

The serotonergic and dopaminergic inputs to the corpus striatum in human and non-human primates participate in diverse sensorimotor, cognitive, and affective functions, are implicated in dysfunction in diseases such as Parkinson's disease and schizophrenia, and are targets for many of the drugs used to treat these disorders. Sex differences in the incidence and/or clinical course of these disorders and in the effectiveness of related dopaminergic and serotonergic drug therapies suggest that primate striatal indolamines and catecholamines are also influenced by gonadal hormones. However, while well studied in rats, relatively little is known about precisely how gonadal steroids modulate stratial dopamine and serotonin systems in primates. To begin to address this issue, the present studies explored the effects of ovarian steroids on the serotonergic and dopaminergic innervation densities of the caudate, putamen, and the nucleus accumbens in young adult rhesus monkeys. Using densitometry to quantify immunoreactivity for serotonin and for the catecholamine-synthesizing enzyme tyrosine hydroxylase, innervation densities were compared in identified, functionally specialized striatal subdomains across animals that were either ovariectomized or ovariectomized and supplemented with estradiol and/or progesterone, i.e. in a primate model of surgical menopause, with and without hormone replacement therapy. These analyses revealed clear examples of structure-, hemisphere-, and replacement regimen-specific effects of changes in circulating steroids on the densities of each afferent system examined. Further, the predominantly stimulatory effects observed occurred in striatal areas analogous to those suspected as sites of localized dopamine and/or serotonin compromise in Parkinson's disease and schizophrenia. Thus, the hormone actions identified in this study could hold relevance for some of the sex differences identified in relation to these disorders, including the findings of decreased incidence and/or symptom severity in women that have led to hypotheses of protective effects for estrogen.

Evidence for Dysfunction of the Nigrostriatal Pathway in the R6/1 Line of Transgenic Huntington's Disease Mice

The present multidisciplinary study examined nigrostriatal dopamine and striatal amino acid transmission in the R6/1 line of transgenic Huntington's disease (HD) mice expressing exon 1 of the HD gene with 115 CAG repeats. Although the number of tyrosine hydroxylase-positive neurons was not reduced and nigrostriatal connectivity remained intact in 16-week-old R6/1 mice, the size of tyrosine hydroxylase-positive neurons in the substantia nigra was reduced by 15%, and approximately 30% of these cells exhibited aggregated huntingtin. In addition, using in vivo microdialysis, we found that basal extracellular striatal dopamine levels were reduced by 70% in R6/1 mice compared to their wild-type littermates. Intrastriatal perfusion with malonate in R6/1 mice resulted in a short-lasting, attenuated increase in local dopamine release compared to wild-type mice. Furthermore, the size of the malonate-induced striatal lesion was 80% smaller in these animals. Taken together, these findings suggest that a functional deficit in nigrostriatal dopamine transmission may contribute to the behavioral phenotype and the resistance to malonate-induced neurotoxicity characteristic of R6/1 HD mice.

Chronic Hypercortisolemia Inhibits Dopamine Synthesis and Turnover in the Nucleus accumbens: An in vivo Microdialysis Study

Over 60% of patients with Cushing’s syndrome suffer from major depression, which frequently abates after correction of the hypercortisolism. The mesolimbic and mesocortical dopaminergic (DAergic) systems are thought to participate in psychiatric disorders. In this study, we investigated whether hypercortisolemia affects indices of DAergic activity in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) of freely moving rats. Cortisol (CORT, 25 mg/kg/day) was infused subcutaneously for 7 days via an osmotic minipump. Microdialysate collection (30-min periods, 2 µl/min) began 24 h after probe placement. Concentrations of dihydroxyphenylalanine (DOPA) in interstitial fluid in the nucleus accumbens (NAc) and perifrontal cortex (PFC) were measured before and after local perfusion with NSD-1015, an irreversible inhibitor of L-aromatic amino acid decarboxylase, to assess local dopamine (DA) biosynthesis. The sum of microdialysate DA, dihydroxyphenylacetic acid, and homovanillic acid was used as an index of local DA turnover. DOPA accumulation after NSD-1015 was markedly attenuated in CORT-treated compared with saline-treated animals (5,703 ± 1,849 vs. 10,902 ± 2,454 pg/ml; p < 0.01). In contrast, the two groups did not differ in DOPA accumulation in the PFC. Values for the turnover index of DA were also significantly lower in CORT-treated animals in the NAc but not in the PFC. The results indicate that CORT inhibits DA synthesis and turnover in the NAc but not in the PFC. Region-specific CORT-induced inhibition of DAergic activity may help to explain depressive symptoms in patients with chronic hypercortisolemia and normalization after medical or surgical correction of hypercortisolism.

Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning.

Pavlovian conditioning results when an innocuous stimulus, such as an odour, is paired with a behaviourally relevant stimulus, such as a foot-shock, so that eventually the former stimulus alone will elicit the behavioural response of the latter. The lateral nucleus of the amygdala (LAT) is necessary for the emotional memory formation in this paradigm. Enhanced neuronal firing in LAT to conditioned stimuli emerge in parallel with the behavioural changes and are dependent on local dopamine. To study the changes in neuronal excitability and synaptic drive that contribute to the pavlovian conditioning process, here we used in vivo intracellular recordings to examine LAT neurons during pavlovian conditioning in rats. We found that repeated pairings of an odour with a foot-shock resulted in enhanced post-synaptic potential (PSP) responses to the odour and increased neuronal excitability. However, a non-paired odour displayed PSP decrement. The dopamine antagonist haloperidol blocked the PSP enhancement and associated increased neuronal excitability, without reversing previous conditioning. These results demonstrate that conditioning and habituation processes produce opposite effects on LAT neurons and that dopamine is important in these events, consistent with its role in emotional memory formation.

Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppresses growth of estrogen-induced pituitary prolactinomas.

Prolactin-secreting adenomas are one of the most common types of intracranial neoplasm found in humans. The modalities of clinical treatment currently in use include D(2)-dopamine receptor agonists, surgery, and radiotherapy, and the success rates for treatment are good. However, there are prolactinomas that are difficult to treat. As an alternative, we have developed a gene therapy strategy in which the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is overexpressed in the anterior pituitary (AP) gland. Because dopamine is known to have an inhibitory effect on lactotroph growth and prolactin secretion, we developed a system that would enable its local synthesis from freely available precursor amino acids. A dual adenovirus tetracycline-regulatable expression system was generated to control the production of TH. In the absence but not presence of the tetracycline analog doxycycline, TH expression was observed in AP tumor cell lines AtT20, GH3, and MMQ. In both primary AP cell cultures and the AP gland, in situ expression of TH was seen in lactotrophs, somatotrophs, corticotrophs, thyrotrophs, and gonadotrophs in the absence but not presence of doxycycline. The ability of this system to inhibit hyperprolactinemia and pituitary lactotroph hyperplasia was then assessed in a model of estrogen- or estrogen/sulpiride-induced pituitary tumors. In the absence but not presence of doxycycline, a 49% reduction in pituitary growth and 58% reduction in the increase of circulating prolactin levels were observed in estrogen, but not estrogen/sulpiride, treated rats. These results indicate that in situ dopamine enhancement gene therapy can be a useful tool for the treatment of prolactinoma. Dopamine synthesis can be tightly regulated and the therapeutic benefit of the system is only inhibited when local dopamine signaling is impaired.

Activation of 5-HT 1B/1D receptors in the mesolimbic dopamine system increases dopamine release from the nucleus accumbens: a microdialysis study

This study was designed to investigate the role of 5-hydroxytryptamine (5-HT) 1B receptors located in the ventral tegmental area and nucleus accumbens in the modulation of accumbal dopaminergic transmission. The selective 5-HT 1B receptor agonist CP 93129 {3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2- b]pyrid-5-one} was administered into the ventral tegmental area or nucleus accumbens of freely moving Sprague–Dawley rats via retrograde microdialysis. The effects of intra-accumbal and intra-tegmental CP 93129 on extracellular dopamine levels in the nucleus accumbens were measured using one- and dual-probe microdialysis, respectively. For dual-probe microdialysis, one probe was in the ventral tegmental area for drug administration and the other in the ipsilateral nucleus accumbens for dopamine measurement. The results show that infusion of CP 93129 (2, 5 and 10 μM) into the nucleus accumbens increased local dopamine levels in a concentration-related manner. Infusion of CP 93129 (10 and 20 μM) into the ventral tegmental area also increased dopamine levels in the ipsilateral nucleus accumbens. The increased dopamine release in the nucleus accumbens produced by intra-accumbal or intra-tegmental CP 93129 was antagonized by co-infusion of cyanopindolol (5 μM), a 5-HT 1B/1A receptor antagonist, but not by WAY-100635 { N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)- N-2-pyridinyl-cyclohexanecarboxamide} (5 μM), a highly selective 5-HT 1A receptor antagonist. In addition, augmentations of dopamine release in the nucleus accumbens induced by intra-accumbal CP 93129 were sensitive to Na + channel blockade with tetrodotoxin. These results are not in opposition to the concept that 5-HT 1B receptors within the ventral tegmental area and nucleus accumbens are all involved in the modulation of dopamine release in the terminal area of the mesolimbic dopamine system.

Cortically driven Fos induction in the striatum is amplified by local dopamine D2-class receptor blockade.

Dopamine D2-class receptors have been shown to control the excitability of striatal neurons in response to cortical activation. It has been unclear, however, whether such receptors could regulate the number of striatal neurons activated by cortical stimulation, and thus affect the population response of the striatum to its cortical inputs. We used Fos induction as a readout to measure the ensemble response of striatal neurons to localized stimulation of the frontal cortex and tested for the effects of D2-class dopamine receptor blockade on this response. In freely moving rats, we stimulated the frontal cortex by local epidural application of a dose of a GABAA receptor antagonist (picrotoxin) just threshold for inducing Fos in the striatum. We combined this treatment with D2-class dopamine receptor antagonist treatments at dose levels also just threshold for inducing Fos, using either (i) systemic haloperidol or (ii) intrastriatal (-)sulpiride. Both systemic and intrastriatal blockade of D2-class receptors sharply increased the numbers of striatal neurons exhibiting cortically evoked Fos induction. These findings suggest that local activation of intrastriatal D2-class dopamine receptors can regulate the number of striatal neurons responsive to cortical inputs, thus dynamically shaping the flow of information through the striatum.

3-Methoxytyramine formation following monoamine oxidase inhibition is a poor index of dendritic dopamine release in the substantia nigra.

This study was undertaken, using microdialysis, to compare the extracellular concentration of 3-methoxytyramine and dopamine in dialysate from the striatum and substantia nigra, after pargyline (75 mg/kg), after pargyline plus amphetamine (3 mg/kg), and after pargyline plus reserpine (5 mg/kg) administration. Treatment with pargyline alone increased the extracellular dopamine concentration by 70% in the striatum and by 140% in the substantia nigra and induced in both regions a time-dependent accumulation of 3-methoxytyramine. The addition of d-amphetamine to pargyline increased the extracellular dopamine concentration, compared with pargyline-treated controls, to the same extent in both the substantia nigra (maximally by 360%) and the striatum (maximally by 400%), but the concomitant increase of 3-methoxytyramine accumulation in the dialysate was relatively smaller in the substantia nigra compared with the striatum. Reserpine treatment decreased the extracellular dopamine concentration in both regions below the detection level (<10% of basal value). When pargyline was added to reserpine, the striatal extracellular dopamine concentration increased to 50% of pargyline-treated controls and the striatal 3-methoxytyramine accumulation was less than in pargyline-treated controls. However, in the substantia nigra, the addition of pargyline to reserpine resulted in dopamine concentrations as high as after pargyline only and the 3-methoxytyramine accumulation was not changed compared with pargyline-treated controls. In summary, our results indicate that dopamine in the substantia nigra is released from reserpine-sensitive storage sites and that pargyline-induced 3-methoxytyramine accumulation is a poor indicator of the local dopamine release. The latter observation may be explained by the fact that the dopamine-metabolizing enzyme, catechol-O-methyltransferase, is located inter alia in the dopamine-containing cell bodies/dendrites in the substantia nigra, in contrast to the situation in the terminals in the striatum where catechol-O-methyltransferase is located only in nondopaminergic cells.

Tremulous Characteristics of the Vacuous Jaw Movements Induced by Pilocarpine and Ventrolateral Striatal Dopamine Depletions

Vacuous jaw movements induced by the muscarinic agonist pilocarpine and striatal dopamine depletions were examined using a slow motion videotape system. With this procedure, rats were videotaped in a Plexiglas tube so that the profile of the head region could be seen. Vacuous jaw movements were analyzed by examining the tape at 1/6 normal speed. An observer recorded each jaw movement using a computer, and the computer program re-calculated the temporal characteristics of jaw movement responses back to normal speed. The interresponse time was recorded for each jaw movement, and each jaw movement interresponse time was assigned to a 50 ms wide time bin. Thus, the distribution of interresponse times could be used to analyze the temporal characteristics of jaw movement responses. In the first experiment, rats were administered saline vehicle, 1.0 mg/kg and 2.0 mg/kg pilocarpine. The rats were videotaped 10–15 min after injection, and the data were analyzed as described above. Pilocarpine induced very high levels of vacuous jaw movements, and the vast majority of all movements occurred in “bursts” with interresponse times of 1.0 s or less. Analysis of the interresponse time distributions showed that most of the jaw movements were within the 150–350 ms range. The modal jaw movement interresponse time was in the 150–200 ms range, which corresponds to a local frequency of 5–6.66 Hz. In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the ventrolateral striatum in order to produce a local dopamine depletion. The dopamine-depleted rats were observed for jaw movements 7 days after surgery. The overall level of jaw movement activity resulting from dopamine depletion was much lower than that produced by pilocarpine. There was a significant inverse correlation between ventrolateral striatal dopamine levels and total number of vacuous jaw movements. Videotape analysis indicated that the temporal characteristics of jaw movements induced by dopamine depletions were similar to those shown with pilocarpine. These experiments indicate that vacuous jaw movements induced by pilocarpine and striatal dopamine depletion occur in a frequency range similar to that shown in parkinsonian tremor.

Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule.

Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1-specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II.

Functional neuroanatomy of the nigrostriatal and striatonigral pathways as studied with dual probe microdialysis in the awake rat—I. Effects of perfusion with tetrodotoxin and low-calcium medium

In the present study we employed the dual probe approach to investigate functional interactions between the nigrostriatal dopaminergic and striatonigral GABAergic pathways in the awake, freely moving rat and their role in motor function. One microdialysis probe of concentric design was implanted in the substantia nigra pars reticulata and another in the ipsilateral dorsolateral striatum. Perfusion with a low-Ca2+ (0.1 mM) medium and with the voltage-dependent Na(+)-channel blocker tetrodotoxin (10 microM) was alternatively performed in both brain regions and the dialysate dopamine, glutamate and GABA levels were simultaneously measured in the dorsolateral striatum, whereas GABA levels alone were monitored in the substantia nigra. Perfusion with a low-Ca2+ medium in the substantia nigra pars reticulata did not affect local GABA levels, but transiently increased striatal dopamine release (+40%) without modifying striatal glutamate and GABA levels. Conversely, intranigral perfusion with tetrodotoxin transiently increased local GABA levels (+40%), while it decreased striatal dopamine (-60%) and increased glutamate (+70%) and GABA (+50%) levels. Perfusion with a low-Ca2+ medium in the dorsolateral striatum reversibly decreased local dopamine (-70%), glutamate (-20%) and GABA (-20%) levels, while local perfusion with tetrodotoxin decreased dopamine (-70%), increased glutamate (+30%) but did not affect dialysate GABA levels in this brain area. Neither of these intrastriatal treatments significantly affected GABA levels in the substantia nigra. Intranigral but not intrastriatal perfusion with tetrodotoxin was also associated with an increase in spontaneous locomotor activity as expressed by contralateral turning. Intranigral and intrastriatal perfusion with low-Ca2+ medium did not influence locomotor activity. On the basis of these neurochemical and behavioural findings, we propose a new dynamic model for the study of motor behaviour as mediated by basal ganglia circuitry.

Functional neuroanatomy of the nigrostriatal and striatonigral pathways as studied with dual probe microdialysis in the awake rat--II. Evidence for striatal N-methyl-D-aspartate receptor regulation of striatonigral GABAergic transmission and motor function.

In the present study we used the dual probe approach to investigate striatal N-methyl-D-aspartate receptor regulation of GABA release from the substantia nigra pars reticulata of the awake, freely moving rat. One microdialysis probe of concentric design was implanted in the dorsolateral striatum and another in the ipsilateral substantia nigra pars reticulata. Perfusion with N-methyl-D-aspartate (100 microM) in the dorsolateral striatum decreased local dopamine release (-25%) and increased both glutamate (+40%) and GABA (+35%) release. Moreover, perfusion with N-methyl-D-aspartate (100 microM) in the dorsolateral striatum increased GABA release (+20%) in the substantia nigra pars reticulata. Perfusion with the lower (10 microM) N-methyl-D-aspartate concentration in the dorsolateral striatum did not affect striatal dopamine, glutamate and GABA release or nigral GABA release. Intrastriatal perfusion with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (10 microM), at a dose which by itself did not affect basal striatal or nigral neurotransmitter levels, prevented the effects of striatal perfusion with N-methyl-D-aspartate on both striatal and nigral neurotransmitter release. Intrastriatal dizocilpine maleate was also perfused concurrently with intranigral tetrodotoxin (10 microM) (see accompanying paper). Intrastriatal perfusion with dizocilpine maleate prevented the tetrodotoxin-induced rise in both striatal and nigral GABA levels and profoundly reduced the tetrodotoxin-induced contralateral turning. In addition, intrastriatal dizocilpine maleate delayed the increase in striatal glutamate release evoked by intranigral tetrodotoxin without affecting the associated decrease in striatal dopamine release. The present study demonstrates that N-methyl-D-aspartate receptors in the dorsolateral striatum regulate GABA release in the substantia nigra pars reticulata of the awake rat and provides evidence that this regulation plays a key role in motor function.

Eye movements in monkeys with local dopamine depletion in the caudate nucleus. II. Deficits in voluntary saccades

Unilateral infusion of MPTP into the monkey caudate nucleus produced deficits in task-specific saccades, in addition to the deficits in spontaneous eye movements (preceding article). We trained three monkeys to perform two kinds of saccade tasks: (1) saccade task for eliciting visually guided saccades and (2) delayed saccade task for eliciting memory-guided saccades. After the MPTP infusion, dopaminergic function, estimated by tyrosine hydroxylase (TH) immunoreactivity, was shown to be decreased locally around the infusion site at the head-body junction of the caudate. We found that the deficits were prominent in the saccades directed to the side contralateral to the infusion (contralateral saccades). Memory-guided saccades were sometimes misdirected to the ipsilateral side even when the cue stimulus was presented on the contralateral side. Among the parameters of saccades, a selective change was found in the saccade latency: the latency was prolonged consistently in contralateral memory-guided saccades. The amplitude and velocity of saccades decreased in contralateral saccades, either memory guided or visually guided. The duration of saccades tended to increase in visually-guided saccades and memory-guided saccades, in both directions. Only one monkey, in which the decrease in TH activity included a large part of the putamen and the head of the caudate, showed prolongation of manual reaction time for lever release.

Eye movements in monkeys with local dopamine depletion in the caudate nucleus. I. Deficits in spontaneous saccades

The basal ganglia contribute to the suppression and initiation of saccadic eye movements through the inhibitory connection from the substantia nigra pars reticulata (SNr) to the superior colliculus. This mechanism consists of serial and parallel connections, which are mostly inhibitory and GABAergic. Dopamine is known to exert powerful modulatory effects on the basal ganglia function, but its nature and mechanism are still unclear, especially in relation to voluntary behavior. The purpose of this series of investigation was to study the role of dopamine in the control of saccadic eye movements. We examined, in the monkey, whether and how the deficiency of the nigrostriatal dopaminergic innervation affects saccadic eye movements. The present article is focused on spontaneous saccades that the monkey made with no incentive to obtain reward; the next paper will describe task-specific saccades. Using an osmotic minipump we infused 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) unilaterally into the head-body junction of the caudate nucleus of monkeys where presaccadic neurons were clustered. Tyrosine hydroxylase activity, visualized using an immunohistochemical method, decreased locally around the injection site with some effects extending into the ipsilateral putamen and locally in the ipsilateral substantia nigra. Changes of eye movements started to appear 3-5 d after starting the infusion. Spontaneous saccades became less frequent. The area scanned by the saccades became narrower and shifted to the hemifield ipsilateral to the infusion site. The saccade amplitudes and peak velocities decreased; durations were prolonged. These effects were more prominent for saccades directed toward the side contralateral to the infusion site. These monkeys showed no obvious skeletomotor symptoms. These results suggest that the local deprivation of the dopaminergic innervation in the caudate nucleus facilitates neuronal activity of the SNr leading to suppression of saccadic eye movements.

Differential cholinergic and non-cholinergic actions of acetylcholinesterase in the substantia nigra revealed by fasciculin-induced inhibition

The effects of the peptide fasciculin (FAS), a potent inhibitor of acetylcholinesterase (AChE) have been examined, following unilateral microinfusion, on tissue levels of monoamines in the rat substantia nigra nad concomittant circling behaviour. Although FAS inhibited 87% of total AChE, the levels of dopamine and its metabolites remained unchanged. Furthermore, the treatment induced modest contraversive rotation which was markedly enhanced in the presence of a systemic challenge with apomorphine. This behavioural effect of FAS was partially reversed by systemically administered atropine. Any possible interaction of FAS with nigral dopamine systems was further investigated by testing the peptide in animals that five day earlier had undergone a 6-hydroxydopamine (6-OHDA) lesion of the SN such that dopamine and AChE were significantly but not completely reduced. In a majority of these animals, FAS treatment caused a reversal of the lesion induced ipsiversive rotation, ie restored contraversive rotation. It is concluded that in the SN, FAS can have biochemical and behavioural actions independent of local dopamine systems and linked to cholinergic transmission. In addition, treatment with FAS in the substantia nigra also reveals the possible existence of at least two distinct pools of AChE with, respectively, non-cholinergic and cholinergic actions.

Monoamines and their metabolites in Huntington's disease brain: Evidence for decreased catechol-O-methyltransferase activity

Alterations in dopaminergic neurotransmission in the degenerating neostriatum have been implicated in the generation of choreic movements in Huntington's disease (HD), Arguments cited in support are the contrast with parkinsonian hypokinesia and the effects of dopamine (DA) agonists and antagonists in, respectively, exacerbating and suppressing involuntary movements (Klawans et al 1972). Striatal concentrations of DA have generally been reported to be normal (Bird and Iversen 1974; Melamed et al 1982; Reynolds and Garrett 1986; Beal et al 1990), although elevated levels were found in single studies in the caudate (Spokes 1980) or putamen (Melamed et al 1982), and a decreased level was found by Kish et al (1987) in the caudal eaudate. Physiologically more important, however, may be the relative concentrations of DA and its metabolites, as these may indicate local dopamine turnover. The literature on DA metabolites in HD brains is scarce. Normal homovanillic acid (HVA) concentrations were reported by Melamed et al (1982) and Beal et al (1990), but Reynolds and Garrett (1986) found significantly low levels. As with DA itself, the concentration of HVA was found by Kish et al (1987) to be decreased in the caudal caudate. Only Beal et al (1990) studied 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methox_vtyramine (MET); their levels were not significantly abnormal in the putamen, although the mean concentration in HD was 119% of control for DOPAC and 81% for MeT. Naudon et al (1992) recently reported that, 2 days after a kainic acid (KA) lesion of rat striatum, there are elevated levels of DOPAC and HVA but markedly reduced levels of MeT. They interpreted their data as indicating a loss of cateeholamine-Ometh'~l transferase (COMT) in the lesioned striatum. A substantial decrease in COMT acti.vi:y in KA-lesioned striatum was

D 1 and D 2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons

The expression of Fos, the product of the proto-oncogene c-fos, is thought to be a marker of neuronal activity. D 1, but not D 2, dopamine receptor agonists have previously been shown to increase Fos immunoreactivity in striatonigral neurons ipsilateral to a 6-hydroxydopamine lesion of the nigrostriatal pathway. In the present study, it was demonstrated that the D 1 receptor agonist SKF 38393 rarely increased Fos in striatopallidal neurons of the 6-hydroxydopamine denervated striatum. Conversely, in the intact striatum, the D 2 receptor antagonist haloperidol enhanced Fos expression predominantly in striatopallidal neurons labelled retrogradely from the globus pallidus or with an oligonucleotide probe complementary to mRNA encoding enkephalin. These results are consistent with studies suggesting that D 1 receptors are located predominantly on striatonigral neurons and that D 2 receptors reside principally on enkephalin-containing striatopallidal neurons. They also provide a neuroanatomical basis for neurochemical and neurophysiological observations indicating that dopamine facilitates the activity of striatonigral neurons but inhibits striatopallidal neurons. In another experiment the selective D 2 receptor agonist quinpirole was found to increase Fos immunoreactivity in the globus pallidus ipsilateral to a 6-hydroxydopamine lesion. It is proposed that this may have been due to a D 2 receptor-mediated inhibition of enkephalin and GABA release from striatopallidal terminals that in turn disinhibited the pallidal neurons. In a final series of experiments, brain microdialysis was used to determine the location of dopamine receptors regulating striatal Fos expression. Local application of the selective D 1 receptor agonist CY 208–243 in the 6-hydroxydopamine-denervated striatum, or of haloperidol in the intact striatum via the dialysis probe increased Fos immunoreactivity in the immediate vicinity of the probe. Hence, the inductive effects of these systematically administered compounds on Fos expression in the striatum are mediated at least partly by local dopamine receptors in the striatum. Taken together, these results suggest that the differential regulation of striatonigral and striatopallidal activity by dopamine is mediated by the largely separate location of D 1 and D 2 receptors on these outputs.

Non-cholinergic effects of acetylcholinesterase in the substantia nigra: a possible role for an ATP-sensitive potassium channel.

Within the substantia nigra acetylcholinesterase has non-cholinergic actions that can be demonstrated at both behavioural and cellular levels: the aim of this study was, thus, to explore, in the in vitro guinea pig substantia nigra, the ionic mechanisms which mediate these non-classical phenomena. Acetylcholinesterase had a reversible hyperpolarizing action, via an opening of potassium channels, on a selective population of nigral neurons. These neurons could be identified by an ability to generate bursts of action potentials and by a sensitivity to either amphetamine or to a reduction of glucose in the perfusing medium. The acetylcholinesterase-induced hyperpolarization could not be attributed to a contaminant in the exogenous solution, since a highly purified preparation was even more potent. Furthermore, enzymatic action of any kind could be eliminated as boiled acetylcholinesterase was equally efficacious. The effect of acetylcholinesterase was not subject to tachyphylaxis and was resistant to blockade of potassium channels with tetraethylammonium: since both these phenomena are features of the D2 autoreceptor for dopamine within the substantia nigra, it seems unlikely that acetylcholinesterase is operating on the same target as dendritically released local dopamine. On the other hand, the actions of acetylcholinesterase were enhanced by low glucose and blocked by the sulfonylurea, tolbutamide. These results strongly suggest that acetylcholinesterase can exert a nonenzymatic action and that this action, in the substantia nigra, is mediated by an ATP-sensitive potassium channel.

Suppression of conditioned avoidance behavior by the local application of (−)sulpiride into the ventral, but not the dorsal, striatum of the rat

The local application of (−)sulpiride, 200 ng side −1, into the nucleus accumbens produced a suppression of conditioned avoidance behavior in male rats, 10 and 90 min after injection. The decrease in avoidance behavior was accompained by a decrease in motor activity, as evidenced by changes in the number of intertrial crosses. When injected into the dorsolateral neostriatum, or the amygdala, (−)sulpiride produced a suppression of conditioned avoidance behavior at the 90-min time interval only. Considering diffusion from the injection site, as indicated by an increase in local dopamine turnover [( DO- PAC+ HVA) DA −1], the effects obtained in the dorsolateral neostriatum, and possibly also the amygdala, 90 min after injection could be due to diffusion to the nucleus accumbens. The local application of (-) sulpiride into the posterior neostriatum, or into the prefrontal cortex, produced no statistically significant effect on conditioned avoidance behavior 10 or 90 min after injection. It is concluded that the performance of conditioned avoidance behavior in the rat is critically dependent on an intact dopaminergic neurotransmission in the nucleus accumbens or adjacent areas of the ventral striatum.

Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications.

This minireview deals with the possible roles of monoamines in feeding and feeding disorders. The introduction sketches the results of earlier studies with local drug injections and selective neurotoxins which provided pharmacological evidence that monoamines can influence food intake and body weight. A table summarizing this evidence is used to list monoamine changes that could underlie anorexia or hyperphagia. It is apparent that abnormalities in the monoamines, along with their cotransmitters, could cause many forms of feeding disorder. It is proposed as a working hypothesis that several varieties of hyperphagia leading to obesity have a common element. This common factor is a change in excitability of a lateral hypothalamic reinforcement system as manifested in self-stimulation at a stimulation-bound feeding site. Understanding this feeding reward-aversion system helps us understand hyperphagia and anorexia. The neurochemistry of reward and aversion involves the monoamines. This paper focuses on dopamine and serotonin. The data support the hypothesis that dopamine systems projecting to the nucleus accumbens and other forebrain areas from the mid-brain ventral tegmental area (VTA) are important for approach and positive reinforcement in ingestive behavior and self-stimulation. Serotonin is hypothesized to facilitate satiety and inhibition of feeding reward in the hypothalamus. The next section abstracts our recent experiments that measured pharmacological and physiological release of the monoamines in the hypothalamus and nucleus accumbens during ingestive behavior and self-stimulation. In vivo microdialysis in freely moving rats suggested the following: (1) Norepinephrine was released in the paraventricular nucleus during the active, feeding period of the circadian cycle. (2) The serotonin metabolite 5-HIAA also increased in the PVN at the same time if there was food to eat. (3) Amphetamine infused into the lateral hypothalamus (LH) by reverse dialysis increased synaptic dopamine, norepinephrine, and serotonin. (4) The anorectic drug d-fenfluramine increased synaptic serotonin in the LH and also increased the dopamine metabolite DOPAC, suggesting that serotonin and dopamine in the LH might contribute to fenfluramine-induced satiety. Local d-fenfluramine injection into the LH or local infusion by reverse dialysis again increased serotonin and decreased 5-HIAA and interfered with local dopamine metabolism as reflected in decreased DOPAC and HVA. (5) Tryptophan, a serotonin precursor, given systemically at an anorectic dose, increased extracellular serotonin in the LH, but this effect was only detectable in food-deprived rats. This was seemingly pH independent (between 5.8 and 8). The passage other cations through CFo is strictly suppressed (even at pH 8 and with 300 mM NaCl in the medium).(ABSTRACT TRUNCATED AT 400 WORDS)