Tolbutamide- and diazoxide-sensitive K+ channel in neurons of substantia nigra pars reticulata

Summary Single-channel K⁺ currents were recorded in cell-attached patches from slices of rat substantia nigra. On the somata of neurons in the caudal half of the substantia nigra pars reticulata a K⁺ selective channel with a unitary conductance of 71 pS (154 mmol/l K⁺ in pipette filling solution) was identified. The channel was activated both by application of diazoxide (300 mol/l) and by energy-depleting conditions (200 mol/l cyanide) and was reversibly blocked by tolbutamide (0.1–1 mmol/l). It is concluded that neurons in the substantia nigra pars reticulata of the rat contain a typical ATP-sensitive K⁺ channel the activity of which can be modulated by diazoxide and sulfonylureas.Correspondence to: C. Schwanstecher at the above address     

Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata

Excitatory glutamatergic inputs to the subthalamic nucleus (STN), and subthalamic afferents to the substantia nigra pars reticulata (SNr) are believed to play a key role in the pathophysiology of Parkinson's disease (PD). Previously, we have shown that activation of the group I mGlus in the STN and SNr induces a direct depolarization of the neurons in these nuclei. Surprisingly, although both group I mGlus were present in the STN and SNr, mGlu5 alone mediated the DHPG-induced depolarization of the STN, and mGlu1 alone mediated the DHPG-induced depolarization of the SNr. We now report that both mGlu1 and mGlu5 are coexpressed in the same cells in both of these brain regions, and that both receptors play a role in mediating the DHPG-induced increase in intracellular calcium. Furthermore, we demonstrate that the induction of an acute PD-like state using a 16 h haloperidol treatment produces an alteration in the coupling of the group I receptors, such that post-haloperidol, DHPG-induced depolarizations are mediated by both mGlu1 and mGlu5 in the STN and SNr. Therefore, the pharmacology of the group I mGlu-mediated depolarization depends on the state of the system, and alterations in receptor coupling may be evident in pathological states such as PD.     

Further characterization of opioid receptors in the striatum mediating muscular rigidity in rats

Summary In previous studies, we had found that opioid receptors in the striatum can mediate muscular rigidity which can be recorded as a tonic EMG activity in the gastrocnemiussoleus muscle of rats. We have now tried to evaluate the type of opioid receptors mediating the EMG activity. For this purpose, opioids regarded to be selective agonists at one type of opioid receptors were injected into the striatum of unanesthesized rats.Morphine, a -type agonist, in the dose of 40 nmol induced a pronounced EMG activity, while 10 or 40 nmol of [D-Ala², D-Leu⁵] enkephalin, a -type agonist, led to no or little effect, respectively. -Endorphin, which reacts with the -type of receptors, was completely ineffective in doses of 3 or 15 nmol. The benzomorphan compound Mr 2033-Cl, which is a -type agonist, induced a moderate activity in the dose of 15 nmol; 3 nmol were ineffective. -Casomorphin-4 was the most potent of the drugs studied in our system, since 9 nmol induced a pronounced rigidity, which was naloxone-reversible (2 mg/kg i.p.). The doses of these opioids effective in comparison with their known in vitro potencies suggest that the rigidity is mediated by a group of striatal opioid receptors, which has some similarity to the -type, but also shows some differences.In contrast, haloperidol, injected either into the striatum (30 nmol) or systemically (2 mg/kg i.p.), did not induce any EMG activity, suggesting that a decrease in dopaminergic neurotransmission is not the primay mechanism inducing the rigidity. -LPH_62–67 and -LPH_66–77 (15 nmol) intrastritally] were also completely inactive.     

Characterization of extracellular GABA in the substantia nigra reticulata by means of brain microdialysis

Summary Brain microdialysis was used to characterize extracellular gamma-aminobutyric acid (GABA) in the substantia nigra reticulata (SNR) of freely moving rats. The extracellular GABA in the SNR was characterized using acutely implanted probes (4–8 h after surgery; day 1) and chronically implanted probes (24 h after surgery; day 2).3-Mercaptopropionic acid, a glutamic acid decarboxylase inhibitor, was used to identify GABA. This drug induced an immediate decrease in the extracellular GABA levels to 40% of basal values, suggesting that the detected GABA is, at least in part, newly synthesized.The basal levels of extracellular GABA measured either on day 1 or day 2 were not affected by infusion of micromolar amounts of tetrodotoxin. Therefore, a direct coupling between GABA dialysate concentrations and nerve-impulse flow does not seem to exist. Infusion of the GABA uptake inhibitor nipecotic acid (0.5 mmol/l) resulted in a 4-fold increase in the dialysate levels of GABA lasting at least for 3 h on both days. K⁺ stimulation (60 mmol/l) increased extracellular GABA levels in the SNR to 450% of basal values. This effect again did not differ significantly on day 1 and day 2.The origin of the extracellular GABA in the SNR, as recorded by microdialysis under the two experimental conditions, is discussed.Send offprint requests to W. Timmerman at the above address     

Morphine-induced muscular rigidity in rats

Morphine in doses of 7.5 to 17.5 mg/kg, i.p. induced dose-dependent, electromyographically recorded muscular activity (rigidity), which could be inhibited by the morphine antagonist, naloxone and by drugs increasing central dopaminergic activity, L-DOPA and apomorphine. The results suggest that the rigidity was morphine specific and was due to a functional dopamine deficiency in the striata. There was a good parallelism between catalepsy and rigidity. Since both effects were easily reversed by L-DOPA, it is suggested that in our system studied the primary action of morphine was a presynaptic effect in the nigrostriatal neurons and not blockade of striatal dopamine receptors. The results could be explained by ‘diversion’ of newly synthetized dopamine from storage sites to sites of catabolism resulting in a lack of dopamine at striatal receptor sites which might lead to a subsequent compensatory increase of dopamine utilization.     

On the possible role of excitatory amino acids in the striatum in mediating morphine-induced muscular rigidity

The possible role of excitatory amino acids in the striatum in mediating tonic activity in the electromyogram (EMG) was studied. Glutamate diethylester (GDEE) (100-400 nmoles) induced a tonic activity in the EMG in a dose-dependent way when injected into the striatum. This effect was well antagonized by intrastriatal injection of quisqualic acid (5 and 25 nmoles), less by kainic acid (5 nmoles) and not significantly by N-methyl-D-aspartate (NMDA) (30 nmoles). Systemic administration of naloxone (2 mg/kg IP) did not inhibit the GDEE-induced activity in the EMG. The tonic activity in the EMG, induced by systemic administration of morphine (15 mg/kg IP) was not significantly influenced by injection of GDEE (200 nmoles) into the striatum, but was first decreased and then slightly enhanced by intrastriatal injection of quisqualic acid (25 and 50 nmoles), not affected by kainic acid (5 nmoles) and first slightly decreased and then strongly enhanced by NMDA (15 and 30 nmoles). Injection of kainic acid (5 nmoles), quisqualic acid (5 or 25 nmoles) or NMDA (30 nmoles) alone into the striatum did not produce any tonic activity in the EMG. Our results support the assumption that quisqualic acid, kainic acid and NMDA react with different types of receptors for excitatory amino acids in the striatum. Both quisqualicacid and NMDA showed a biphasic action, whereas kainic acid was ineffective. Furthermore, the activity in the EMG induced by morphine might be at least partly due to a functional antagonism of morphine against glutamate in striatal neurons.     

Effect of chronic administration of methamphetamine on the responsiveness of substantia nigra zona reticulata neurons to GABA or a GABA agonist in rats

Summary The effects of chronic administration of methamphetamine on the responsiveness of neurons of the substantia nigra zona reticulata (SNR) to gammaaminobutyric acid (GABA) or to a GABA receptor agonist were examined. Neuronal activity was recorded from the SNR of rats that had been pretreated twice daily, for 6 consecutive days, with saline or with 5 mg/kg methamphetamine. Intravenous administration of the GABA receptor agonist, muscimol, caused a dose-dependent decrease in the unit activity of the SNR neurons and the SNR neurons became less sensitive to the depressant effects of the drug after chronic treatment with methamphetamine. Iontophoretic application, with increasing currents, of GABA produced a progressive inhibition of unit activity in control animals, an effect that was significantly reduced in rats pretreated with methamphetamine. These results support the hypothesis that long-term administration of methamphetamine increases the activity of the striatonigral GABA system and thereby reduces the sensitivity of postsynaptic GABA receptors in the SNR.     

Effects of acute and chronic administration of olanzapine in comparison to clozapine and haloperidol on extracellular recordings of substantia nigra reticulata neurons in the rat brain

Rationale: Previously, we have shown that the atypical antipsychotics clozapine and risperidone, unlike haloperidol, decreased the firing rate of substantia nigra reticulata (SNR) neurons. As the SNR receives substantial input from the striatum, an area where motoric side-effects of antipsychotics are thought to be mediated, the SNR might be an interesting brain structure with regard to motor side-effects. Objective: The newly developed atypical antipsychotic olanzapine was studied for its effects on the firing rate of SNR cells. In addition, to gain insight in the implications of our experimental setup for clinical use, responses upon clozapine, olanzapine and haloperidol were studied after chronic treatment. Methods: In chloralhydrate-anaesthetized male Wistar rats, extracellular recordings were made from SNR neurons upon intravenously (IV) administered cumulative doses of the antipsychotics. Naive rats and rats that were subcutaneously (SC) injected for 21 days with an antipsychotic were used. Results: Olanzapine (50–1600 mg/kg; IV), significantly inhibited the firing rate of the SNR neurons. Upon 21 days of treatment with a daily SC injection of 20 mg/kg clozapine, the challenge on day 22 with cumulative injections of clozapine (200–6400 mg/kg; IV) significantly inhibited the firing rate of the SNR neurons. Olanzapine (50–1600 mg/kg; IV) also significantly inhibited the SNR activity when pretreated with olanzapine in an SC administered dose of 1 mg/kg, but not 5 mg/kg. Haloperidol (12.5–800 μg/kg; IV) did not significantly affect the SNR activity in rats pretreated with SC administered 0.5 mg/kg haloperidol. Conclusions: Upon acute and chronic administration of clozapine and olanzapine versus haloperidol, differential effects on SNR neuronal firing could be obtained. The experimental setup seem to be valid for further studies into the mechanism of action of typical versus (relatively low doses of) atypical antipsychotics. The implications of the inhibitory effect of atypical antipsychotics on the SNR firing rate are presently unknown, but could be associated with the lower propensity to induced motoric side-effects. On the other hand, the SNR activity might also reflect non-motoric activity possibly related to negative symptoms. Received: 11 December 1998/Final version: 20 January 1999     

Presynaptic modulation of the release of GABA by GABAA receptors in pars compacta and by GABAB receptors in pars reticulata of the rat substantia nigra

The effect of GABA agonists and antagonists on K⁺-stimulated [³H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABA_A autoreceptors in the pars compacta and by GABA_B receptors in the pars reticulata.     

GABA(B) receptor activation inhibits dopamine D1 receptor-mediated facilitation of [(3)H]GABA release in substantia nigra pars reticulata

GABA(B) receptors inhibit and dopamine D1 receptors stimulate the release of GABA from striatal terminals in the pars reticulata of the substantia nigra. Here we have studied the interaction between both classes of receptors by exploring the effect of GABA(B) receptors upon the stimulation of depolarization-induced [(3)H]GABA release induced by the activation of D1 receptors in slices of the pars reticulata of the rat substantia nigra. The activation of GABA(B) receptors with baclofen (100 microM) inhibited by 48+/-8% the evoked [(3)H]GABA release in normal slices but did not modify the release in slices from reserpine-treated rats, indicating that the inhibition was dependent on endogenous dopamine. The inhibitory effect of baclofen was also abolished by the D1 receptor antagonist SCH 23390 (1 microM), indicating a D1 receptor-dependence of the baclofen inhibition. Baclofen dose-dependently inhibited (IC(50)=3.6 microM) the stimulation of release induced by the D1 agonist SKF 38393 (1 microM). Baclofen also blocked the stimulation of release induced by forskolin but not that induced by 8-Br-cAMP, indicating that the inhibitory effect was exerted before cAMP synthesis. N-ethylmaleimide (NEM), a selective inactivator of PTX-sensitive G-proteins, abolished the baclofen inhibition of the SKF 38393-induced stimulation of the release without affecting the stimulation induced by the D1 agonist, suggesting that the baclofen effect was mediated by Galpha(i/o) proteins. These results might have relevance in the control motor disorders associated with D1 receptor supersensitivity.     

A comparison of behaviour following stimulation of the anterior substantia nigra by direct cholinergic agonists and anticholinesterases

Microinjections of carbachol, a muscarinic cholinergic receptor agonist, into the anterior substantia nigra increase feeding, drinking and sexual behaviour if there is a pre-existing tendency to respond and a low baseline rate of behaviour. The present experiment was undertaken to compare the effects of carbachol with other cholinergic stimulants. Groups of 6–12 satiated rats received 0.5 µl microinjections into the anterior substantia nigra of 0.1–5.0 µg carbachol, 0.1–5.0 µg nicotine, 2.5–10.0 µg eserine, and 1.25–5.0 µg or 0.1–1.0 µg neostigmine (each dissolved in sterile saline) and the effects on feeding, drinking, locomotion, grooming, rearing and sniffing were examined. Carbachol, nicotine and low doses of neostigmine stimulated eating in a dose-dependent manner. The increased feeding following neostigmine was over a shorter time-period than following carbachol or nicotine. Neither carbachol nor nicotine had any significant effect on behaviour other than eating. The higher doses of neostigmine increased the frequency of sniffing and rearing, but not eating, and no dose of eserine had a clear effect on behaviour. These data are discussed in terms of their relationship to the cholinergic input to substantia nigra which excites pars compacta dopamine-containing neurones.     

Diazepam potentiates GABA-, but not adenosine-mediated, inhibition of neurons of the nigral pars reticulata

Experiments were conducted to assess the relative roles of gamma-aminobutyric acid (GABA) and adenosine in mediating the inhibition of neuronal activity by diazepam injected intravenously. Recent studies have shown that benzodiazepines inhibit, in a dose-dependent manner, the firing of neurons in the substantia nigra pars reticulata. In support of a predominantly GABAergic mechanism for this inhibitory action, a small dose of diazepam (50 micrograms/kg, i.v.), which itself had little effect on cell firing, significantly potentiated the inhibitory responses of neurons of the pars reticulata to muscimol, a potent GABA agonist given intravenously, and significantly and selectively potentiated the inhibition of reticulata neurons by GABA applied iontophoretically. In contrast to their extreme sensitivity to GABAergic inhibition, neurons of the pars reticulata were comparatively insensitive to systemically and iontophoretically administered adenosine-related drugs. However, in those instances when inhibitions could be achieved with iontophoretically applied adenosine-5'-monophosphate, the inhibitory responses were not significantly modified by a 50 micrograms/kg (i.v.) dose of diazepam. These findings, considered in light of differences in GABA and adenosine receptor densities within the substantia nigra, suggest that the benzodiazepine-induced inhibition of neurons of the nigral pars reticulata most likely involves potentiation of GABA but not adenosine-mediated influences.     

The effect of substantia nigra stimulation and morphine on α-motoneurones and the tail-flick response

Rats were used to study the effect of unilateral stimulation of the substantia nigra on the reflex discharge of α-motoneurones and on the reaction time of the tail-flick response. In preparations with prenigral decerebration, nigral stimulation facilitated monosynaptic α-reflex activity ehilst γ-reflex activity remained unchanged. The facilitation of monosynaptic α-reflex activity was reduced by naloxone (1 mg/kg); morphine (2 mg/kg) did not change the number of α-reflex discharges, but it reduced the α-reflex latency, enhanced the effect of nigral stimulation on the latency and abolished the effect of naloxone on nigral facilatation. Nigral stimulation prolonged the reaction time of the tail-flick response in rats with an intact brain and after prenigral decerebration. Naloxone did not influence the anti-nociceptive effect of nigral stimulation, whilst morphine enhanced it in rats with an intact brain. The anti-nociceptive effect exerted by morphine in animals with an intact brain was abolished by prenigral decerebration, and an additional spinalization restored it. Inactivating the nigral neurones by unilateral microinjections of procaine or GABA into the substantia nigra depressed the nociceptive reflex. It is concluded that (1) activation of nigral neurones influenced mono- and polysynaptic reflexes in a reciprocal fashion by a pathway descending via brain stem relays to the spinal cord, (2) inactivation of nigral neurones produced similar changes in reflex activity by altering the function of the nigro-striatal feedback system, the outlet from the system to the spinal cord not being the substantia nigra, (3) morphine influenced the nociceptive reflex by an action at different levels of the central nervous system.     

Role of pars compacta of the substantia nigra in circling behavior

The significance of pars compacta of the substantia nigra in the mediation of ci circling behavior was assessed by placing unilateral radio-frequency lesions in that neural region, in adjoining tegmental areas, or in the median raphe and adjacent reticular formation; additional ablations were made by infusing 8 μg/4 μl 6-hydroxydopamine (6-OHDA) into the ventral mesencephalon. Rotational behavior was recorded in a photocell apparatus during 15 min sessions. Precise and virtually complete lesions of pars compacta, as evidenced by histological and histochemical analyses, resulted in spontaneous contralateral circling for a postoperative period of 5 days. More vigorous and sustained contralateral rotations were observed in animals with lesions in the region of the median raphe. Other thermal or 6-OHDA mesencephalic lesions did not produce spontaneous circling. On postoperative days 9–23, the animals were administered in random sequence d-amphetamine (1.5 and 5.0 mg/kg) and apomorphine (1.0 mg/kg). At least 48 hr separated each drug test. Amphetamine (1) facilitated contralateral turning in animals with damage to the median raphe and adjacent regions but induced ipsilateral circling in animals sustaining variable degrees of pars compacta damage as a result of midbrain 6-OHDA injections, (2) produced ipsilateral turning in rats with lesions involving portions of pars compacta in addition to the medial lemniscus (at 1.5 but not 5.0 mg/kg drug), pars reticulata (at 5.0 but not 1.5 mg/kg drug), or the ventromedial tegmentum and, in some cases, subthalamic regions (at 5.0 but not 1.5 mg/kg drug), and (3) had no effect upon circling in animals with discrete pars compacta lesions in a dose of 1.5 mg/kg but produced ipsiversive circling after 5.0 mg/kg. Apomorphine did not elicit turning in animals with relatively precise lesions of pars compacta but did produce turning in experimental groups that sustained simultaneous damage to pars compacta and additional systems including portions of the ventromedial tegmentum, pars reticulata of the substantia nigra, or medial lemniscus. The contralateral turning induced by apomorphine in rats with 6-OHDA or radio-frequency lesions of the ventral mesencephalon suggests that mechanisms mediating this drug-induced behavior, although previously attributed almost exclusively to dysfunctions in nigral function, probably include systems involving extra-nigral regions as well. Coupling this consideration with the finding that lesions in the median raphe and contiguous areas elicited more intense circling than nigral ablations suggests that the role of pars compacta in rotational behavior may be less significant than previously believed.     

Unilateral injection of morphine into the nucleus accumbens induces akinesia and catalepsy,but no spontaneous muscular rigidity in rats

Summary The role of the nucleus accumbens in the generation of the signs of morphine-induced catatonia, namely akinesia, catalepsy and muscular rigidity, was studied in rats. Morphine was injected into the nucleus accumbens and either spontaneous locomotor activity or catalepsy or activity in the electromyogram of the gastrocnemius-soleus muscle, signalling the appearance of rigidity, were recorded.Unilateral injections of 5 g of morphine induced a decrease of locomotor activity and weak catalepsy; 15 g of morphine completely abolished locomotor activity (akinesia) and produced a very pronounced catalepsy. All these effects were antagonized by naloxone (2 mg/kg i.p.). Injections of morphine into the nucleus accumbens did not induce muscular rigidity. In contrast, injection of morphine (15 g) into the head of the caudate nucleus, which induced a pronounced muscular rigidity, did not noticeably alter the locomotor activity nor did it produce catalepsy.Our results suggest that 1) the nucleus accumbens is relevant for systemically administered morphine to produce akinesia and catalepsy, but is not noticeably involved in the development of muscular rigidity; 2) they provide evidence that morphine-induced catalepsy is largely due to a strong akinesia, and that muscular rigidity, observed after morphine administration, does not contribute to positive scores in the catalepsy test.with technical assistance of C. Bode and H. Kügler     

Substantia nigra as an out-put station for striatal dopaminergic responses: Role of a GABA-mediated inhibition of pars reticulata neurons

Summary Intranigral administration of kainic acid results in loss of pars reticulata neurons without damage to axons traversing or terminating within the nigra. Unilateral nigral lesions with kainic acid result in an ipsilateral turning upon administration of apomorphine, a dopamine (DA)-receptor agonist and in contralateral turning upon administration of haloperidol, a DA-receptor blocker. Destruction of post-synaptic structures in the striatum of the side contralateral to that injected with kainic acid results in a drastic reduction, abolition or even reversal of the turning effects elicited by apomorphine and haloperidol. Unilateral intranigral microinjection of nanogram amounts of the GABA-receptor antagonists picrotoxin and bicuculline elicits ipsilateral circling upon apomorphine administration. Kainic-induced lesion or micro-injection of picrotoxin or bicuculline in the nigra ipsilateral to a 6-OHDA-lesion of nigro-striatal DA-neurons results in reduction, abolition or reversal of the contralateral circling produced by apomorphine. The results indicate that the nigra pars reticulata is a station for dopaminergic impulses originating from the striatum and suggest that the turning behavior in response to striatal DA-receptor stimulation is due to a GABA-mediated inhibition of ipsiversive pars reticulata neurons.     

Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats

Rationale We have recently found that blockade of dopamine D1-type receptors in the ventral tegmental area reduces the rewarding effects of intravenous cocaine; here, we explored the possibility that blockade of D1 receptors in the adjacent substantia nigra (SN)—not usually considered part of reward circuitry—might have similar effects.Objective To test the hypothesis that blockade of dopamine D1 receptors in the SN reduces the rewarding effects of cocaine.Methods Twenty one rats were prepared with intravenous catheters and with bilateral guide cannulae implanted such that injections could be made directly into the SN or just dorsal to the SN. The rats were trained to self-administer intravenous cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR1) schedule of reinforcement. After stable responding developed, 13 of the animals were tested following pretreatment with bilateral microinjections of SCH 23390 at doses of 0, 1, 2 or 4 g/0.5 l into the SN and 8 were tested with injections of 0 g or 4 g/0.5 l into a site 2 mm dorsal to the SN site.Results Microinjections of SCH 23390 in the SN significantly increased rates of cocaine self-administration, while injections dorsal to SN had no significant effect on responding.Conclusions These data suggest that blockade of dendritically released DA in the SN reduces the rewarding effects of cocaine. These findings complement accumulating evidence that the rewarding effects of cocaine are not restricted to the drugs ability to elevate dopamine levels in the nucleus accumbens.     

Long-term effect of perphenazine on the substantia nigra in rats

A controlled blind study was made of the long-term effect of perphenazine enanthate (3.4 mg/kg/14 days for 12 months and 40 mg/kg/14 days for 6 months) upon the number of nerve cells (light microscopy) and the uptake of ³H-uridine (autoradiography) in the substantia nigra of rats. No significant differences were found between the numbers of nerve cells in treated and untreated animals, neither in the pars compacta nor in the pars reticularis. Nor were any significant differences found with regard to cell cytology or uptake of ³H-uridine. On the basis of the present data and certain clinical and neuroanatomic studies of patients with persistent signs of encephalopathy following long-term neuroleptic treatment it is suggested that perphenazine and related neuroleptics may exert an irreversible neurotoxic effect on the cells in the nigro-striatal system, but that this effect is not manifest until an elevated sensitivity to neuroleptics is present, e.g. in the form of age phenomena and/or psychiatric disease processes.     

In vivo evidence for GABAergic control of serotonin release in the cat substantia nigra

Push-pull cannulae were used for estimating the release of endogenously synthesized [3H]serotonin in both substantia nigra and caudate nuclei of halothane-anaesthetized cats. The unilateral nigral application of GABA (10-5 M) reduced the local release of [3H]serotonin picrotoxin induced an opposite effect. Both treatments failed to modify [3H]serotonin release in the caudate nuclei or in the contralateral substantia nigra. These results suggest that GABAergic neurons innervating the substantia nigra may regulate nigral serotonin transmission. The possibility that such a regulation could be presynaptic (direct or through other nigral neurotransmitters) or related to a change in the activity of the nigro-raphe projection is discussed.     

Dose-dependent feeding in the rat following substantia nigra acetylcholinesterase blockade

Microinjections of eserine sulphate into the substantia nigra elicited a dose-dependent increase in feeding, but not drinking, when both food and water were freely available. This response is strikingly similar to that elicited by other forms of cholinergic stimulation of the rat substantia nigra. It is suggested that nigro-striatal dopamine neurones might receive a cholinergic input within substantia nigra and play an important role in mediating this response.