Dopaminergic Axon Terminals Research Articles

Regulation of GAP-43 protein and mRNA in nigrostriatal dopaminergic neurons after the partial destruction of dopaminergic terminals with intrastriatal 6-hydroxydopamine.

Changes in the level of GAP-43 and its mRNA in nigrostriatal dopaminergic neurons in an animal model of the presymptomatic period of Parkinson's disease were measured to find the characteristic features of GAP-43 in nigrostriatal dopaminergic neurons. Since the dopaminergic neurons possess a relatively large amount of GAP-43 protein and mRNA, the dopaminergic neurons must be endowed with specific functions related to those of GAP-43. In this study, dopaminergic axon terminals were partially destroyed by intrastriatal 6-hydroxydopamine (6-OHDA). Rats were decapitated 3, 14, and 56 days following treatment. Levels of GAP-43 and tyrosine hydroxylase (TH) in the striatum were detected by immunoblotting and quantified. The number of GAP-43 mRNA-positive neurons and that of TH mRNA-positive neurons in the substantia nigra pars compacta (SNc) were detected by in situ hybridization using alkaline phosphatase (ALP)-labeled probes. Levels of GAP-43 in the striatum showed no significant alteration during the period of the experiment, although levels of TH were gradually restored. The number of GAP-43 mRNA-positive neurons as well as that of TH mRNA-positive neurons in the SNc decreased. These results suggests that dopaminergic neurons restore their axon terminals with little change in GAP-43, and that transcription and/or stability of GAP-43 mRNA in the dopaminergic neurons are susceptible to the toxin, although the dopaminergic neurons can maintain the translational product in the terminals. This feature may be related with a degeneration of dopaminergic neurons in Parkinson's disease.

Regulation of GAP-43 protein and mRNA in nigrostriatal dopaminergic neurons after the partial destruction of dopaminergic terminals with intrastriatal 6-hydroxydopamine

Changes in the level of GAP-43 and its mRNA in nigrostriatal dopaminergic neurons in an animal model of the presymptomatic period of Parkinson's disease were measured to find the characteristic features of GAP-43 in nigrostriatal dopaminergic neurons. Since the dopaminergic neurons possess a relatively large amount of GAP-43 protein and mRNA, the dopaminergic neurons must be endowed with specific functions related to those of GAP-43. In this study, dopaminergic axon terminals were partially destroyed by intrastriatal 6-hydroxydopamine (6-OHDA). Rats were decapitated 3, 14, and 56 days following treatment. Levels of GAP-43 and tyrosine hydroxylase (TH) in the striatum were detected by immunoblotting and quantified. The number of GAP-43 mRNA-positive neurons and that of TH mRNA-positive neurons in the substantia nigra pars compacta (SNc) were detected by in situ hybridization using alkaline phosphatase (ALP)-labeled probes. Levels of GAP-43 in the striatum showed no significant alteration during the period of the experiment, although levels of TH were gradually restored. The number of GAP-43 mRNA-positive neurons as well as that of TH mRNA-positive neurons in the SNc decreased. These results suggests that dopaminergic neurons restore their axon terminals with little change in GAP-43, and that transcription and/or stability of GAP-43 mRNA in the dopaminergic neurons are susceptible to the toxin, although the dopaminergic neurons can maintain the translational product in the terminals. This feature may be related with a degeneration of dopaminergic neurons in Parkinson's disease.

Induction of Interleukin-1 Associated with Compensatory Dopaminergic Sprouting in the Denervated Striatum of Young Mice: Model of Aging and Neurodegenerative Disease

Young mice challenged with the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which selectively destroys the substantia nigra dopaminergic neurons in the midbrain, exhibit spontaneous recovery of dopaminergic nerve terminals. However, such recovery becomes attenuated with age. Here we report that newly sprouted fibers originate from spared dopaminergic neurons in the ventral tegmental area. We found that interleukin-1 (IL-1), an immune response-generated cytokine that can enhance dopaminergic sprouting when exogenously applied, increased dramatically in the denervated striatum of young mice (2 months) compared with middle-aged mice (8 months) after MPTP treatment. Young mice displayed a maximal 500% induction of IL-1alpha synthesis that remained elevated for several weeks in the dorsal and ventral striatum, whereas middle-aged mice exhibited a modest 135% induction exclusively in the dorsal striatum for a week. IL-1alpha immunoreactivity was localized in GFAP-immunoreactive hypertrophied astrocytes and neurons within the denervated striatum of young mice. However, no induction of IL-1alpha mRNA was seen in the midbrain in either age group despite glial activation. Because we have reported that IL-1 can regulate astroglia-derived dopaminergic neurotrophic factors, it was surprising that no changes were observed in acidic and basic fibroblast growth factor or glial cell line-derived neurotrophic factor mRNA levels associated with MPTP-induced plasticity of dopaminergic neurons in the striatum of young mice. Interestingly, we found that dopaminergic neurons express IL-1 receptors, thus suggesting that IL-1alpha could directly act as a target-derived dopaminergic neurotrophic factor to initiate or enhance the sprouting of dopaminergic axonal terminals. These findings strongly suggest that IL-1alpha could play an important role in MPTP-induced plasticity of dopaminergic neurons.

Presynaptic opioid receptors on dopaminergic nerves in the rabbit caudate nucleus: coupling to pertussis toxin-sensitive G-proteins and interaction with D2 autoreceptors?

Slices of the rabbit caudate nucleus, preincubated with [3H]dopamine and subjected to electrical field stimulation, were used (1) to investigate the involvement of G-proteins in the signal transduction of presynaptic D2 (auto)receptors and kappa-opioid receptors on dopaminergic axon terminals in this tissue and (2) to study a possible mutual interaction of these two presynaptic receptors. Pretreatment of the slices with either pertussis toxin (8 micrograms/ml; 18 h), or N-ethylmaleimide (30 microM, 30 min) significantly reduced the inhibitory effects of both the D2 agonist quinpirole and the kappa-opioid receptor agonist U-50488H on the [3H]overflow evoked by 36 pulses (2 ms, 24 mA, 0.3 Hz), suggesting the coupling of both receptors to G-proteins. Experiments designed to study possible interactions of these two presynaptic receptors were carried out under stimulation conditions (only 1 pulse), which strongly diminish interference of endogenous transmitters released in the tissue with modulatory effects of exogenous drugs. For instance, due to the presence of endogenous dopamine, quinpirole was much less potent during 36-pulse-than during 1-pulse field stimulation, whereas the D2 antagonist domperidone was almost without effect in the latter case. Using the 1-pulse stimulation paradigm, the concentration/response curve of quinpirole was unaffected in the presence of the half-maximal inhibitory concentration of U-50,488 H (0.1 microM). On the other hand, also quinpirole at its half-maximal inhibitory concentration (0.1 microM), hardly affected the concentration/response curve of U-50,488 H: only high concentrations of U-50,488 H (above 1 microM) seemed to be slightly less effective in the presence than in the absence of the D2 agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Release-regulating dopamine autoreceptors in human cerebral cortex.

Slices from fresh specimens of human neocortex which had to be removed during neurosurgery to reach subcortical tumours were labelled with [3H]-dopamine and stimulated electrically. Quinpirole, a selective dopamine D2 receptor agonist, inhibited the stimulated tritium overflow (EC50 = 25 nM; maximal inhibition: about 80% at 10 microM). The selective D1 receptor agonist, SKF 38393, was inactive up to 10 microM. Quinpirole was antagonized by the D2 receptor antagonist (-)-sulpiride (apparent pA2 = 8.26). Thus dopaminergic axon terminals in the human mesocortical pathway possess autoreceptors of the D2 type.

Presence of somatostatin or neurotensin in lateral septal dopaminergic axon terminals of distinct hypothalamic and midbrain origins: convergence on the somatospiny neurons.

In the lateral septal area (LSA), both inhibitory and excitatory dopamine (DA) actions, as well as hypothalamic and midbrain DA efferents, have been described. Some neurons of the hypothalamic and midbrain DA systems contain somatostatin (SOM) or neurotensin (NT), and, in the LSA, the distribution of fibers containing these peptides overlaps with DA fibers. These data prompted us to test for the presence of SOM and NT in LSA dopaminergic axon terminals of hypothalamic and midbrain origins. To verify the origins of SOM and NT innervation of the LSA, the retrograde tracer horseradish peroxidase conjugated with wheat germ agglutinin (HRP-WGA) was injected into the LSA, and alternate brain sections were immunostained for SOM, NT, or tyrosine hydroxylase (TH) in group 1 rats. Numerous retrogradely labeled neurons were found immunopositive for SOM in the periventricular and basolateral hypothalamus, many HRP-WGA labeled cells contained NT immunoreactivity in the ventral tegmental area, and TH-immunoreactive retrogradely labeled neurons were observed in both brain areas. In a new approach, the presence of these peptides in dopaminergic boutons was assessed by combining peptide immunocytochemistry with acute 6-hydroxydopamine (6-OHDA) induced lesioning of DA cell groups. These groups of rats were treated with desipramine to protect the noradrenergic fibers, and 45 min later 1 microgram 6-OHDA (in 0.5 microliter saline) was unilaterally injected into the periventricular hypothalamus (group 2) or the ventral tegmental area (group 3). After 48 h the rats were killed and alternate septal sections of both groups were immunostained for TH, SOM, or NT. On the operated side of the LSA in both groups, electron microscopy revealed numerous axon terminals that were immunopositive for TH and contained autophagous cytolysosomes, an early sign of catecholamine fiber degeneration induced by 6-OHDA. In group 2, phagosome-containing boutons were found immunopositive for SOM, but not for NT; vice versa, in group 3, only NT-positive degenerated boutons were detected. SOM- and NT-positive degenerated axon terminals in both groups formed synaptic contacts with LSA neurons, in particular with somatospiny cells. On the contralateral side of the LSA, all of the axon terminals were intact. It has been shown that SOM exerts an inhibitory action, whereas NT has an excitatory effect on limbic area neurons. Thus, the results implicate that the differential peptide content of dopamine fibers marks their functional differences. It appears that LSA neurons receive double innervation from an inhibitory "somatostatinergic" DA system of the hypothalamus, and from an excitatory "neurotensinergic" DA system of the midbrain.

Dopamine-acetylcholine interaction in the rat striatum: A dual-labeling immunocytochemical study

The relationship between cholinergic neurons and dopaminergic axons in the rat striatum was examined by a dual-labeling immunocytochemical method. Cholinergic neurons were identified by their immunoreactivity for choline acetyltransferase (ChAT), and dopaminergic axon terminals were identified by their positive immunoreactivity for tyrosine hydroxylase (TH). Electron microscopic analysis of dual-labeled sections revealed that while most TH-positive terminals formed synapses with unlabeled striatal neurons and dendrites, a number of TH-positive terminals formed close appositions, highly suggestive of synapses, with both large and small dendrites as well as somata of ChAT-positive neurons. Tight appositions were also found between TH-positive terminals and ChAT-positive terminals. Moreover, TH-positive terminals and ChAT-positive terminals were found to form synapses with common dendrites of unlabeled striatal neurons. These results indicated that 1) dopaminergic axon terminals could interact directly with striatal cholinergic interneurons via tight appositions with distances comparable to conventional synapses; and 2) there is a convergence of dopaminergic and cholinergic axon terminals on noncholinergic striatal neurons.

Neuropeptide Y-immunoreactive neurons receive synaptic inputs from dopaminergic axon terminals in the rat neostriatum

Double immunocytochemistry using peroxidase-antiperoxidase and protein A-gold was performed to determine whether neuropeptide Y (NPY) immunoreactive neurons receive synaptic inputs from catecholaminergic axon terminals in the rat neostriatum. Tyrosine hydroxylase-immunoreactive axons were found to be in synaptic contact with the somas and proximal dendrites of NPY-immunoreactive neostriatal neurons. These latter neurons were medium-sized and had indented nuclei, and thus thought to be medium aspiny interneurons. Thus nigrostriatal dopaminergic neurons may monosynaptically influence striatal NPY neurons.

Striatal neuropeptide Y-immunoreactive neurons receive synaptic inputs from dopaminergic axon terminals in the rat

Striatal neuropeptide Y-immunoreactive neurons receive synaptic inputs from dopaminergic axon terminals in the rat

Haloperidol prevents the methamphetamine-induced apomorphine subsensitivity of dopamine metabolism in rat striatum.

Our previous experiment showed that the sensitivity of striatal dopaminergic metabolism to apomorphine was lowered after pretreating rats with methamphetamine. This study further demonstrated that haloperidol administered with methamphetamine prevented the effect of the methamphetamine pretreatment. Since gamma-butyrolactone was administered in combination with apomorphine so as to remove complications which might arise from the modification of impulse flow through the striatonigral feedback loop, it is possible that the observed effect of apomorphine upon striatal dopaminergic metabolism and its antagonism with haloperidol may be mediated by autoreceptors of dopaminergic axon terminals in rat striatum.

Perinatal, not adult, hypothyroidism suppresses dopaminergic axon sprouting in the deafferented olfactory tubercle of adult rat.

We reported recently that chronic thyroid deficiency in rat, beginning in utero and terminating after maturity, suppresses lesion-induced central catecholaminergic axon sprouting in the adult brain [Gottesfeld et al, 1985]. The present work was undertaken to define the critical period of hypothyroidism on subsequent neuronal sprouting. Thyroid hormones deficiency was induced in rats by methimazole during (a) gestational days 8-21 (20 mg/kg/day in the drinking water); (b) postnatal days 1-15 (0.2 or 0.4 mg/pup/day; i.p.), or (c) in the mature animal for 4 weeks (20 mg/kg/day in the drinking water). The olfactory tubercles (OTs) were used as a model to study sprouting of dopaminergic (DA) nerve terminals, elicited by olfactory bulbectomy. Animals in each group received lesions or sham operations as adults, and sacrificed 3 weeks after the operation. Thus, for each of the above treatments four subgroups were formed: (a) euthyroid/sham-operation, (b) euthyroid/lesion, (c) hypothyroid/sham-operation, and (d) hypothyroid/lesion. Sprouting of DA axon terminals in the OTs was identified by biochemical assays and quantitative immunofluorescent microscopy, using tyrosine hydroxylase (TH) as a marker. Serum thyroxine levels served as an index of the thyroid status. The results demonstrate that lesion-induced sprouting of DA axon terminals in OTs of adult rats is suppressed by hypothyroidism induced prenatally or during the early postnatal period, but not after maturity. Thus, there is a perinatal critical period during which altered thyroid function exerts long-term effects on neuronal plasticity.

Evidence for a Selective Localization of Voltage‐Sensitive Ca2+ Channels in Nerve Cell Bodies of Corpus Striatum

Specific binding sites for [3H]nitrendipine, an organic Ca2+ channel antagonist, were abolished in crude synaptosomal membranes of kainic acid-lesioned caudate nuclei. In contrast, specific lesions of dopaminergic or serotonergic axon terminals in caudate nuclei failed to alter the density or the affinity of [3H]nitrendipine binding sites. In addition, the basal and veratridine-stimulated 45Ca2+ accumulations were greatly impaired in slices prepared from kainic acid-lesioned caudate nuclei. The veratridine-elicited accumulation of 45Ca2+ in control slices was attenuated by addition of tetrodotoxin in the incubation medium. The present data provide evidence that most of the [3H]nitrendipine binding sites and the voltage-dependent Ca2+ channels are located in intrinsic neurons or interneurons in caudate nucleus. In contrast, destruction of dopaminergic or serotonergic nerve terminals emanating from other brain areas and innervating the caudate nucleus failed to change the apparent Bmax value for [3H]nitrendipine binding.

Radioautographic investigation of monoaminergic neurons: An evaluation

This review outlines the most relevant contributions currently available on the detection and ultrastructural characterization of monoaminergic neurons by radioautography after administration of radiolabeled monoamines. It includes methodological considerations and then a critical analysis of the diagnostic value of the radioautographic method for catecholaminergic and serotoninergic neurons, emphasizing in particular its recent applications to the visualization of dopaminergic axon terminals. An attempt is then made to evaluate the method in terms of specificity, sensitivity and resolution and its possibilities with regard to quantitative analysis. Lastly, its value for approaching the dynamic and metabolic properties of monoaminergic neurons is stressed.

Decreases in blood pressure in response to L-Glutamate microinjections into the A5 catecholamine cell group

Electrical stimulation of the A5 region in the rat has been shown to elicit a rise in blood pressure with no change in heart rate 25. However, electrical stimulation excites axons of passage as well as cell bodies. To activate A5 cells more selective, we have stimulated them with monosodium- l-glutamate. The l-glutamate was pressure injected from one barrel of a double-barrelled pipette. The other barrel, filled with Agar/KCl, was used for electrical stimulation. In midbrain-hemisected rats, electrical stimulation of the A5 region elicited a pressor response with no change in heart rate, as before. However, 30 nl microinjections of l-glutamate led to a dose-related decrease in blood pressure and heart rate. The threshold for the depressor response was about 10 mM l-glutamate, and a maximal depressor response of 30 mm Hg was elicited at about 500 mM. To determine if either the pressor or depressor response involved catecholamines, these experiments were repeated in midbrain-hemisected animals whose central noradrenergic and dopaminergic axon terminals were destroyed with intraventricular 6-hydroxydopamine. While the pressor response to electrical stimulation was still present in these animals, the bradycardic and depressor responses to l-glutamate injection were abolished. Finally, the bradycardic and depressor responses were markedly reduced in animals that had been sympathectomized with guanethidine. These results suggest that activation of A5 cells leads to a decrease in blood pressure and heart rate brought about mainly through the sympathetic nervous system.

Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum

The morphology and synaptic associations of dopaminergic axons in the n. caudate-putamen (neostriatum) of the adult rat brain are examined. Identification of dopaminergic axons is based upon the electron microscopic immunocytochemical localization of the catecholamine synthesizing enzyme, tyrosine hydroxylase. Immunoreactivity for the enzyme is detected in unmyelinated axons and axon terminals in serial sections collected throughout the neostriatum. The labeled terminals range from 0.1 to 1.5 micron in diameter and have peroxidase reaction product located around closely packed, round vesicles with a diameter of 40-60 nm. The tyrosine hydroxylase containing axon terminals constitute approximately 21% of the total number of terminals in the n. caudatus-putamen and include 3 types which differ in size and synaptic specializations. The most prevalent (82% of total), type I, is small (0.15-0.39 micron in diameter) and forms symmetric junctions with dendrites and dendritic spines. The other two terminal types (II and III) have a medium to large diameter (0.4-1.5 micron) and show either no membrane specializations or asymmetric junctions with dendrites. The axon terminals without observable membrane densities are occasionally oriented so as to suggest an association with dopaminergic and non-dopaminergic axon terminals. These findings indicate that while the dopaminergic terminals may form axoaxonic connections, the primary synaptic contacts are with dendrites of intrinsic neurons in all regions of n. caudatus-putamen.

High resolution radioautography of central dopaminergic fibers labelled in vitro with [ 3H]dopamine or [ 3H]norepinephrine

An original method is reported for the radioautographic visualizing of dopaminergic axon terminals in the rat central nervous system. This method is based on an in vitro labelling with either tritiated norepinephrine or dopamine under conditions of specificity previously established by fluorescence histochemistry. The immobilization of [ 3H]catecholamines in their sites of uptake and storage during post-fixation for electron microscopic processing was ensured by the use of osmic acid vapours instead of osmic acid solution. Selective labelling of the dopaminergic fibers may be achieved throughout large brain sections and the techniques should be applicable to human biopsy material.

Release of dopamine in both caudate nuclei and both substantia nigrae in response to unilateral stimulation of cerebellar nuclei in the cat

The effects of unilateral focal electrical stimulation of the deep cerebellar nuclei on the activity of the nigrostriatal dopaminergic neurons on both sides of the brain were examined in halothane anaesthetized cats. For this purpose, push-pull cannulae were inserted into both caudate nuclei and both substantia nigrae, and the release of [ 3H]dopamine ([ 3H]DA) continuously formed from [3,5- 3H] l-tyrosine was estimated in superfusates. The unilateral electrical stimulation of the right cerebellar dentate nucleus induced a long-lasting increase in the release of [ 3H]DA in the left caudate nucleus and a simultaneous decrease in the release of the [ 3H]transmitter in the right caudate nucleus. These changes were associated with opposite fluctuations in the release of [ 3H]DA from the corresponding substantia nigrae. Thus, the electrical stimulation of the right dentate nucleus induced a pronounced decrease in the release of the [ 3H]-amine in the contralateral substantia nigra, whereas the release in the ipsilateral substantia nigra was simultaneously increased. In contrast, the unilateral electrical stimulation of the right cerebellar fastigial nucleus resulted only in an increased release of [ 3H]DA in the ipsilateral (right) caudate nucleus, associated with a decreased release of the [ 3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral (left) dopaminergic system was not significantly affected. These results support a direct functional interaction between the cerebellum and the basal ganglia. They also suggest that the release of DA from dopaminergic axonal terminals is inversely correlated to the extent of the transmitter release from dendrites.

Reversible reduction of tyrosine hydroxylase enzyme protein during the retrograde reaction in mesolimbic dopaminergic neurons

Changes in the activity and amount of the neurotransmitter synthesizing enzyme tyrosine hydroxylase (TH) were measured in dopaminergic (DA) neurons of the A10-mesolimbic system of the rat following electrolytic lesions of their axons. Unilateral hypothalamic lesions in close proximity to the cell bodies resulted, within 24–48 h, in a permanent anterograde reduction of TH to 10–20% of control in the ipsilateral olfactory tubercle and nucleus accumbens. The retrograde reaction in the A10-DA nerve cell bodies was characterized by an initial increase in TH activity to 133% by 24–48 h followed by a gradual and permanent fall to 50% of control by day 14 due to retrograde cell death of DA neurons. In contrast, lesions of DA axon terminals in the olfactory tubercle resulted in a reversible retrograde reduction of TH activity in the A10. The enzyme activity declined during the first 7 days to 70% of control and then gradually recovered, reaching control levels by 28 days after the operation. The reduction in TH activity in the A10 was demonstrated by immunochemical titration with a specific antibody to TH to be entirely due to reduced amounts of enzyme protein. We conclude that in mesolimbic DA neurons: (a) the anterograde reaction is chaacterized by a rapid and permanent decline of TH in degenerating terminals; (b) the retrograde reaction is dependent upon the proximity of the lesion to the nerve cell body, and (c) a reversible reduced accumulation of TH characterizes the retrograde reaction in response to lesions of distal axons. The reaction of DA neurons of the mesolimbic system to axonal injury is comparable to that of the nigrostriatal system.

Electrically induced release of [ 3H]dopamine from slices obtained from different rat brain cortex regions. Evidence for a widespread dopaminergic innervation of the neocortex

Slices obtained from the deeper layers of the rat dorsal frontal, parietal and occipital brain cortex were incubated in vitro with6.25 × 10 −7 M [ 3H]dopamine (DA), and subsequently superfused and electrically stimulated, while held on quick transfer electrodes, and changes in the efflux of 3H and of the individual amines measured. The separation of the amines, with quantitative recoveries, was performed by chromatography on cation-exchange resins eluted sequentially with water,1 NHCl and 6 M urea in1 N HCl. When no drugs were used, the prestimulation efflux was entirely formed by deaminated metabolites, while following stimulation there was an increase in the efflux of deaminated metabolites, and considerable amounts of [ 3H]-noradrenaline (NA) now appeared. No DA was present in the pre- or poststimulation medium. Similar results were obtained in all the regions studied. When the slices were incubated with10 −5 M desmethylimipramine (DMI),10 −4 M nialamide and 10 −4 M tropolone, before and during incubation with [ 3H]DA, it was observed that, prior to stimulation, the efflux was composed of deaminated metabolites, DA and 3-methoxytyramine (MTA), and following the electrical stimulus there was an increased release of DA, NA and deaminated compounds (in order of decreasing release), while no change in that of MTA was evident. The stimulus-induced release of DA was greatest from frontal slices, intermediate from parietal, and lowest from occipital ones. DMI-resistant uptake of [ 3H]DA also diminished when passing from frontal to occipital. These findings are interpreted as due to the presence of dopaminergic axon terminals in all the regions studied, but with a density that diminishes in a rostrocaudal direction.

Substantia nigra of the rat contains a dopamine sensitive adenylate cyclase.

A LARGE body of evidence exists to support the hypothesis that most antipsychotic drugs exert their specific actions by antagonising the effects of dopamine at postsynaptic receptors within the central nervous system1–3. More recent evidence suggests that postsynaptic dopamine receptors may occur not only at sites of axon terminals, but also within the region of the cell bodies which give rise to the ascending dopaminergic projections. Iontophoretic application of dopamine to dopamine-containing neurone cell bodies in the zona compacta of the substantia nigra, inhibits firing of these cells4. Fluorescent histochemical examination of the substantia nigra with the glyoxylic acid technique has shown that dendrites arising from cell bodies of the zona compacta contain intensely fluorescent varicosities, and that these occur both in compacta and reticulata regions of the substantia nigra5. These varicosities may form the anatomical basis for a mechanism of self-inhibition whereby dopamine released from dendritic varicosities on stimulation subsequently inhibits the firing of the dopamine neurones themselves6. Direct support for the role of dendrites in the release of dopamine has been obtained by showing that slices of substantia nigra labelled by exposure to 3H-dopamine will release labelled dopamine when depolarised by high potassium concentrations7. We set out to explore further the hypothesis of self-inhibitory control by looking for biochemical evidence of a dopamine response in this region of the brain. Homogenates of tissues containing dopaminergic axon terminals respond to low concentrations of dopamine by increased production of cyclic AMP8–12. We now provide evidence that a similar dopamine sensitive adenylate cyclase is present in the rat substantia nigra, and that it is potently antagonised by antipsychotic drugs.