Response of nucleus accumbens neurons to amygdala stimulation and its modification by dopamine

Extracellular single unit recordings were obtained from the nucleus accumbens of urethane anesthetized rats. It was found that electrical stimulation of the basal lateral and basal medial nuclei of the amygdala produced strong excitatory responses in neurons of the nucleus accumbens, in particular the medial region. Latencies of activation were relatively short with a mean of 10.7 ms.Dopamine applied iontophoretically had a marked attenuating effect on the excitatory response of nucleus accumbens neurons to amygdala stimulation. The spontaneous activity of all neurons recorded from the nucleus accumbens was also suppressed by dopamine, but the excitatory response was more sensitive to dopamine inhibition than the spontaneous activity.Neurons in the nucleus accumbens showed a variety of responses to single-pulse electrical stimulation of the ventral tegmental area (VTA). Some units in the nucleus accumbens received convergent inputs from both the amygdala and the VTA. Stimulation of the VTA also attenuated the response of nucleus accumbens neurons to excitatory inputs from the amygdala. A train of 10 pulses (0.15 ms, 200–600 αA) at 10 Hz delivered to the VTA at 100 ms before stimulation of the amygdala caused attenuation of the original excitatory response. The attenuating effect could be observed irrespective of whether individual single-pulse stimulation of the VTA elicited a response in that particular accumbens neuron or not. 6-Hydroxydopamine injected into the VTA 2 days prior to the recording experiment, or haloperidol injected intraperitoneally 1 h before the recording session, abolished this attenuating effect. However, responses to single-pulse stimulations of the VTA were not abolished. The results suggest that the attenuation of the excitatory response to amygdala stimulation was due to the release of dopamine from mesolimbic dopaminergic neurons. Responses to single-pulse stimulations of the VTA were probably due to activation of non-dopaminergic neurons projecting from the same area.It is suggested as a working hypothesis that this inhibitory effect of dopamine may be an important function of the mesolimbic dopamine pathway in modulating the extent to which limbic structures can exert an influence on the motor system through the accumbens.     

Mechanisms of excitation and inhibition in the nigrostriatal system

The extracellular responses of neurones in the neostriatum following single pulse stimulation of the substantia nigra were investigated in urethane anaesthetized rats. Low intensity stimulation (< 10 V) evoked single large amplitude spikes while higher intensities (10–20 V) elicit a high frequency burst of small amplitude spikes or waves. When spontaneous or glutamate-induced large spikes are recorded, nigral stimulation causes their inhibition coincidentally with the development of a burst. If the burst is prevented, the inhibitory response disappears. Both the nigral evoked inhibition and burst response are unaffected by iontophoretically or systemically administered antagonists of dopamine or by chemical lesions of the dopamine-containing nigral neurones. The monosynaptic activation of large amplitude striatal neurones, which could also be identified antidromically by stimulation of the globus pallidus, was reversibly blocked by dopamine antagonists.It is concluded (a) that the burst responses are induced through the antidromic excitation of striatonigral axons within the striatum; (b) that the striatal neurones thus activated are inhibitory interneurones and (c) that the dopamine-containing neurones of the nigra make excitatory synaptic contact with a population of striatal output cells, some of which at least project to the globus pallidus.     

Terminal excitability of the corticostriatal pathway. I. Regulation by dopamine receptor stimulation

Glutamatergic cortical and dopaminergic nigral afferents converge onto neurons of the neostriatum forming synapses in close proximity. Studies, mainly using pharmacological methods, suggest presynaptic interactions between these afferents. The influence of dopaminergic transmission on the cortical terminal fields in the striatum was assessed electrophysiologically using the terminal excitability method. Antidromic action potentials recorded from neurons in the prefrontal cortex were elicited by bipolar electrical stimulation (250 microns wire, 0.5 mm tip separation) of the cortical terminal field in the contralateral dorsomedial neostriatum. Threshold excitability was defined as the minimum current sufficient to elicit 95-100% antidromic response on non-collision trials. Under control conditions, the mean threshold current was 1.7 +/- 0.2 mA. Drugs were applied in a volume of 312 nl delivered over 5 min to the striatal stimulation site. Following local striatal administration of amphetamine (10 microM) or electrical stimulation of the nigrostriatal pathway (1-2 pulses, 1.5 mA/0.5 ms/1 Hz) an increase in striatal stimulating current was required in order to reinstate threshold levels of antidromic response. This decrease in the excitability of corticostriatal afferents could be reversed by local infusion of haloperidol (1 microM) or L-sulpiride (10 nM) and did not occur following depletion of dopamine stores with alpha-methylparatyrosine and reserpine. The possible participation of postsynaptic dopamine receptor stimulation was ruled out as these effects were still seen in animals with kainic acid induced lesions of the striatum. In addition, terminal excitability was not modified by the muscarinic agonist carbachol (10 microM). Striatal administration of apomorphine (10 microM) decreased terminal excitability similar to amphetamine. The specific D-2 agonist, quinpirole (10-20 microM) did not affect excitability. These results indicate that manipulations which have been shown to increase the release of endogenous dopamine decrease the excitability of prefrontal corticostriatal afferents by stimulation of presynaptic dopamine receptors which are insensitive to low doses of quinpirole but sensitive to L-sulpiride and apomorphine. The mechanisms underlying dopamine-induced changes in terminal excitability are likely to be similar to those which have been shown to alter conductance at postsynaptic sites.     

Electrophysiological responses of neurones in the nucleus accumbens to hippocampal stimulation and the attenuation of the excitatory responses by the mesolimbic dopaminergic system

Extracellular single unit recordings were obtained from neurones in the nucleus accumbens of urethane anaesthetized rats. Single pulse stimulation (300-800 microA, 0.15 ms, 0.5-1.5 Hz) of the ventral subiculum of the hippocampus strongly excited silent and spontaneously active (3-6 spikes/s) medial accumbens neurones. The majority of neurones excited by hippocampal stimulation were quiescent and identified only by the elicited action potentials. Neurones on the dorso-medial border of the nucleus accumbens and adjacent lateral septum, with a faster spontaneous discharge rate (8-12 spikes/s), were inhibited by hippocampal stimulation. In the ventral border of the accumbens and the olfactory tubercle, hippocampal stimulation also inhibited the fast-firing (greater than 20 spikes/s) neurones. When trains of 10 conditioning pulses (300-800 microA, 0.15 ms, 10 Hz) were delivered to the ventral tegmental area (VTA) 100 ms before each single-pulse stimulation of the hippocampus, the excitatory responses of the silent and spontaneously active accumbens neurones were attenuated. The possibility of this relatively prolonged attenuation effect being dopamine-mediated was supported by several lines of evidence. Dopamine, applied iontophoretically, reduced markedly the excitatory response of accumbens neurones to hippocampal stimulation. Iontophoretically applied dopamine mimicked the attenuating effect produced by VTA conditioning stimulation in the same neurone. The attenuating effects of VTA conditioning stimulation on the activation of accumbens neurones by hippocampal stimulation was reduced by: (1) administration of 6-hydroxydopamine to the VTA 2 days and 7-9 days prior to the recording session, (2) the intraperitoneal injection of haloperidol 1 h before the recording session, and (3) the iontophoretic application of trifluoperazine to accumbens neurones. These observations support the hypothesis that the attenuating effects of the mesolimbic dopamine system on limbic inputs to the nucleus accumbens may have a role in limbic-motor integration.     

Inhibitory response of pallidal neurons to cortical stimulation and the influence of conditioning stimulation of substantia nigra

Single pulse stimulation of the sensory motor cortex of rats anesthetized with urethane was observed to inhibit the activity of neurons in the globus pallidus. When a train of 10 pulses delivered to the substantia nigra, preceded the cortical stimulation, the inhibitory response was significantly reduced in 46 of 66 globus pallidus neurons tested. A single pulse stimulus to the substantia nigra had no effect on the inhibitory response of globus pallidus neurons to cortical stimulation. Similar interaction experiments were performed in rats treated with haloperidol (HPL), a dopamine antagonist, or with 6-hydroxydopamine. In such experiments a train of stimulus pulses delivered to the substantia nigra did not attenuate the inhibitory response of globus pallidus neurons to cortical stimulation, suggesting that the observed interactions are dopamine-mediated.     

Stimulus-evoked changes in neostriatal dopamine levels in awake and anesthetized rats as measured by microdialysis

The effect of medial forebrain bundle (MFB) stimulation on neostriatal dopamine levels was examined using in vivo microdialysis in urethane-anesthetized and awake, freely-moving rats in conjunction with single unit extracellular recordings from antidromically identified nigral dopaminergic neurons. Dialysis samples were collected during baseline periods or while stimulating the MFB with trains of 5 or 10 pulses at different frequencies within a physiologically relevant range. When the perfusion solution contained 1.2 mM Ca2+, even intense, high frequency stimulation was ineffective at producing significant elevations in neostriatal dopamine levels whereas cocaine or amphetamine reliably caused several-fold elevations in dopamine levels. When the perfusate contained 2.4 mM Ca2+, modest MFB stimulation within the range of spontaneous nigral cell firing produced large and reliable increases in dopamine levels. There was a significant correlation between the proportion of dopaminergic neurons that could be antidromically activated from the MFB and the increase in neostriatal dopamine. There was no effect of stimulus pattern on the increase in dopamine levels, and results obtained in awake, freely-moving animals did not differ from those obtained in anesthetized animals. These data provide good evidence that in vivo microdialysis is sensitive to neostriatal dopamine overflow evoked by stimulation within the normal rate of firing of nigrostriatal neurons and that Ringer's Ca2+ concentration is a critical variable in the detection of stimulus-induced release of dopamine.     

Presynaptic D2 dopaminergic receptors mediate inhibition of excitatory synaptic transmission in rat neostriatum

The effect of dopamine (DA) on excitatory synaptic transmission was studied in rat neostriatal neurons using intracellular- and whole-cell voltage clamp-recording methods. Depolarizing excitatory postsynaptic potentials (EPSPs) were evoked by cortical stimulation. Superfusion of DA (0.01–10 μM) reversibly decreases EPSP in a concentration-dependent manner and with a estimated IC₅ of 0.3 μM. In addition, the inhibitory effect induced by DA at a low concentratiion (0.1 μM) was antagonized by sulpiride (1–10 nM), a selective D₂ dopaminergic receptor antagonist. However, D₁ dopaminergic receptor antagonist SKF-83566 (1–5 μM) did not affect the blocking effect by DA 0.1 μM. Based on these findings, we conclude that DA at a low concentration ( 0.1 μM) reduced the excitatory response of neostriatal neurons following cortical stimulation via the activation of D₂, but not D₁ dopaminergic receptors, located on the terminals of corticostriatal neurons.     

Modulation of Rat Striatal Glutamatergic Response in Search for New Neuroprotective Agents: Evaluation of Melatonin and Some Kynurenine Derivatives

Melatonin attenuates the excitatory response of striatal neurons to sensorimotor cortex (SMCx) stimulation, which may be the basis for its neuroprotective role. Searching for new compounds with melatonin-like properties, the effects of several kynurenine derivatives in the response of the rat striatum to SMCx stimulation were studied using electrophysiological and microiontophoretical techniques. Melatonin iontophoresis (−100 nA) significantly attenuated the striatal excitatory response in 89.4% of the recorded neurons, showing excitatory properties in the other 10.6%. Compound A [2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid] (−100 nA) displayed similar attenuating effects (86.7% of neurons inhibited vs. 13.3% excited). Compound B [2-acetamide-4-(2-amine-5-methoxyphenyl)-4-oxobutyric acid] (−100 nA) was more potent than melatonin itself to attenuate the excitatory response in 100% of the recorded neurons. Compound C [2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid] (−100 nA) significantly increased the excitatory response in 84.2% of the recorded neurons, showing attenuating effects on the other 15.8% of the neurons. Interestingly, compound C iontophoresis excited the neurons in which melatonin had attenuating properties, whereas it inhibited the neurons showing excitatory responses to melatonin. These data suggest melatonin inverse agonist properties for compound C. Also, the effects of compounds B and C appeared immediately after they were iontophoretized, whereas both melatonin and compound A onset latencies were longer (2–4 min). The lack of latency shown by these melatonin analogs points to the possibility that melatonin itself was metabolized before producing its effects on striatal neurons. The results show a family of structurally-related melatonin analogs that may open new perspectives in search for new neuroprotective agents, including its clinical potentiality.     

Dorsal raphe nucleus stimulation modulates the response of layers IV and V barrel cortical neurons in rat

The effect of dorsal raphe nucleus (DRN) electrical stimulation on response properties of layers IV and V barrel cortical neurons was studied. To assess the receptive field characteristics of cortical neurons, responses of neurons were recorded following the displacement of principal and adjacent whiskers individually or in a condition test paradigm. Then neuronal responses to the displacement of whiskers were analyzed following DRN stimulation at 0, 50, 100, 200 and 400 ms inter-stimulation intervals. Considering On responses, DRN stimulation suppressed the response magnitude of layer V neurons to principal whisker deflection, while it slightly increased that of layer IV neurons (not statistically significant). The response latency of layer IV neurons increased when DRN was stimulated 200 or 400 ms before principal whisker deflection, while the response latency of layer V was not changed. DRN stimulation had no effect on either magnitude or latency of neuronal response to the adjacent whisker deflections. We observed a decrease in the inhibitory effect of the adjacent whisker deflection on the magnitude of neuronal response to the principal whisker deflection in layer IV when DRN was stimulated 200 ms before the principal whisker deflection. Off responses did not show any significant effect of DRN stimulation. Our results suggest a modulating role for DRN in processing of the incoming information into barrel cortex. This effect might be location dependent.     

Neostriatal evoked inhibition and effects of dopamine on globus pallidal neurons in rat slice preparations

Spontaneous unit discharges were recorded extracellularly from globus pallidal (GP) neurons in rat slice preparations. The firing rates of GP neurons ranged from 2.0 to 24.0 spikes/s and their firing patterns were predominantly of two types: regular and irregular. Stimulation of the neostriatum evoked two distinct types of inhibition which were dependent on GP neuronal firing patterns, a brief inhibition (about 75 ms) followed by resetting rhythmic neuronal activities and a relatively long-term inhibition (about 100 ms). These inhibitions evoked by neostriatal stimulation were attenuated or completely blocked by bath application of either bicuculline or strychnine (2 X 10(-5)-10(-4) M) but not by naloxone. Bath application of dopamine (10(-4)-10(-3) M) produced slow increases in the firing rates by 30-65% in about a half of GP neurons tested. Iontophoretic application of dopamine (10-20 nA) attenuated inhibition in GP neurons by 40-55% induced by either iontophoretically applied GABA (5-30 nA) or neostriatal stimulation without affecting their spontaneous firings. These results suggest that dopamine may produce change in the firing patterns of GP neurons by either acting directly or attenuating GABAergic inhibitory transmission from the neostriatum.     

Intracellular responses of caudate neurons to stimulation of cortex and substantia nigra following large thalamic lesions

The contribution of thalamic pathways to caudate intracellular responses evoked by cortical and nigral stimulation was assessed in 5 cats. No changes were found in either the excitatory or inhibitory components of these responses as a consequence of thalamic destruction. This result, together with other data from this laboratory, suggest thatindirect thalamo-striatal or cortico-striatal pathways are not required for mediating the observed striatal responses.     

Biochemical and behavioral effects of serotonin neurotoxins on the nigrostriatal dopamine system: Comparison of injection sites

Unilateral injections of the serotonin neurotoxin, 5,7-dihydroxytryptamine (DHT), at various points along the 5-HT pathway to the forebrain produce a turning syndrome associated with alterations of dopamine synthesis in the ipsilateral striatum. Unilateral injections of DHT into the SN produced an ipsilateral increase in striatal dopamine (DA) turnover and contralateral rotation in response to amphetamine or apomorphine. Injection of DHT into the MFB produced an ipsilateral decrease in striatal DA turnover and tyrosine hydroxylase (TOH) activity, and ipsilateral rotation in response to amphetamine or apomorphine. After the injection of DHT into the SN or MFB, there was a significant correlation between the rates of drug-induced rotation, the decrease in cortical 5-HT turnover, and the change in striatal DA turnover, suggesting that the unilateral change in DA turnover (and, presumably, the increased stimulation of DA receptors) is causally linked to turning. Injection of DHT into the zones of the striatum and GP richest in 5-HT terminals produced the same responses as the MFB-lesioned rats: ipsilateral rotation and a decrease in striatal TOH activity. Injection of DHT into the area of the striatum richest in DA terminals failed to produce rotation or a significant change in TOH activity. We suggest that 5-HT neurons from the raphe nuclei exert a tonic inhibition on the nigrostriatal pathway at the level of the SN through direct synapses on DA neurons, whereas their neostriatal terminals have an indirect effect on DA terminals, perhaps via interaction with cholinergic and GABA-ergic neurons.     

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.     

Amphetamine alters evoked responses of nigral neurons in kittens and adult cats

The effects of i.p. amphetamine administration (5 mg/kg) on the evoked unitary responses of substantia nigra (SN) neurons to electrical stimulation of their afferents were tested in 4 kittens (3–27 days of age) and 4 adult cats. In adults, amphetamine had two major effects: (1) it blocked temporarily (15–30 min) all neuronal responses to caudate (Cd) and cortical (Cx) stimulation; neuronal responsiveness recovered by 75 min post-drug; and (2) after 15 min postdrug, Cd and Cx stimulation evoked initial excitatory responses that were almost never found predrug. The latencies of Cd-evoked excitations indicated the existence of a mono- or oligosynaptic excitatory strionigral pathway while latencies of Cx-evoked excitations suggested that corticonigral excitatory influences were mediated multisynaptically. In kittens, amphetamine also produced an initial blockade of Cd- and Cx-evoked responses. However, the sign of initial responses to Cd stimulation was not altered since excitations were found both before and after drug treatment. These results indicated that amphetamine reveals excitatory evoked responses of SN neurons to striatal and striatally-mediated inputs that are masked during the course of normal postnatal development. Drug-related alterations of afferent inputs to SN neurons may underlie amphetamine-induced shifts in spontaneous neuronal activity which have been reported frequently.     

Electrophysiological evidence of modulatory interaction between dopamine and cholecystokinin in the nucleus accumbens

Dopamine has been shown to modulate responses of accumbens neurones to excitatory inputs from the amygdala. The demonstration that cholecystokinin (CCK) co-exists and appears to be co-released with dopamine in the accumbens suggests that the modulatory action of dopamine in the accumbens may in turn be modified by CCK. This possibility was investigated in the present study. Single unit recordings were obtained in the medial and caudal accumbens of urethane-anaesthetized rats. These neurones were strongly excited by amygdala stimulation, and concurrent stimulation of the ventral tegmental area (VTA) at 10 Hz attenuated the responses, presumably due to dopamine release. Iontophoretic application of proglumide (PRG) at 30 nA enhanced the attenuating effect of VTA stimulation on the excitatory response to amygdala stimulation. Exogenous dopamine produced a similar attenuation in response and the attenuation was in turn suppressed by concurrent iontophoresis of sulphated CCK fragments applied at a current titrated not to produce significant effect on the spontaneous activity of the neurone nor its response to amygdala stimulation. These results demonstrate that exogenous and endogenous CCK can modify the postsynaptic action of dopamine in the nucleus accumbens in addition to modulating its release shown in other studies, and further suggests that CCK is likely an endogenous functional antagonist of dopamine, serving a comodulatory role in regulating synaptic transmission in the ventral striatum.     

Inhibitory influence of the mesocortical dopaminergic system on spontaneous activity or excitatory response induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex

Since the medial prefrontal cortex receives converging projections from the mediodorsal nucleus of the thalamus (MD) and the dopaminergic neurons located in the ventromedial mesencephalic tegmentum (VMT) the responses of cortical neurons to ipsilateral VMT and MD stimulation (50–150 μA; 0.2–0.5 ms duration) were analyzed in ketamine anaesthetized rats. MD stimulation at 1 Hz blocked the firing of 90% of the spontaneously active cortical units tested (mean latency, 15 ms; mean duration, 182 ms). MD stimulation at 5–10Hz evoked single spike responses (mean latency, 16 ms) in 80% of the units tested. Ten to 15 days after kainic acid injection into the MD the number of cortical neurons inhibited (1 Hz) or excitated (5–10 Hz) was reduced to 57 and 18%, respectively. Following stimulation of the VMT (at a frequency of 1–5 Hz), 85% of cortical neurons showed an arrest of spontaneous firing occurring after a mean latency of 17 ms and lasting 109 ms on the average. Most of the cells displaying the VMT inhibitory effect were excitated by MD stimulation. Moreover VMT stimulation, applied 3–45 ms before that of MD, blocked the excitation induced by MD in 75% of the units tested. After injection of 6-hydroxydopamine into the medial forebrain bundle or intraperitoneal administration of α-methyl-paratyrosine (α-MpT), the number of units tested responding to VMT stimulation was of 19 and 35%, respectively. Moreover in these treated rats, the proportion of excitatory responses to MD blocked by VMT stimulation was reduced to 5 and 6%. On the other hand, the effects induced by VMT stimulation were not affected after specific destruction of the noradrenergic ascending system. These results suggest that the mesocortical dopaminergic neurons modulate the influence of the main thalamic afferent on the prefrontal cortical cells.     

Neuronal response of the primary somatosensory cortex to paired stimulation of the infraorbital nerve and vibrissae of cats

Extracellular and intracellular response of 128 neurons to paired stimuli applied to the infraorbital nerve and vibrissae were studied in the SI cortical zone of immobilized cats. Conditioning stimulation evoked a complete depression of responsiveness for 10-120 ms in different neurons. Duration of the complete depression of test responses depended on location of stimulated vibrissa in the peripheral receptive field of the neuron. Stimulation of the receptive field centres evoked maximal excitatory and inhibitory actions. Functional significance of spatial decrements of the excitatory and inhibitory responses evoked by stimulation of different points in the receptive field is discussed.     

Dopaminergic modulation of sensory responses of striatal neurons: single unit studies

The extracellular single unit responses of striatal neurons to repetitive stimulation of the sciatic nerve were recorded in the urethane anesthetized rat. Changes in the magnitude of these responses after pharmacological manipulation of dopamine (DA) neurotransmission were evaluated. While the intravenous administration of 0.25 mg/kg i.v. amphetamine (AMPH) had no significant effect on baseline firing rates as compared to saline controls, the magnitudes of excitatory and inhibitory evoked single unit responses were significantly decreased by 68% by AMPH. Further, this reduction in response magnitude produced by AMPH was completely blocked by pretreatment with 0.5 mg/kg i.v. haloperidol or by intrastriatal 6-hydroxydopamine lesions. This indicates that the observed effect is mediated by dopamine located in nerve terminals within the striatum. These results suggest that DA functions to modulate the responsiveness of striatal neurons to afferent signals.     

The functional role of the nucleus accumbens in the control of the substantia nigra: Electrophysiological investigations in intact and striatum-globus pallidus lesioned rats

The effects of electrical stimulation of the nucleus accumbens on the activity of identified substantia nigra neurons were studied in intact and lesioned rats. The latter had both the caudate-putamen complex and globus pallidus destroyed by electrolytic lesions. In intact rats a total of 42 of 107 neurons (39.2%) responded to stimulation of the nucleus accumbens. Of the 107 neurons 32 (29.8%) were inhibited and 10 (9.4%) were excited. Pure short inhibitions, long latency inhibitions and excitations followed by inhibition were found in both parts of the substantia nigra. Pure long lasting inhibitions were determined on pars compacta cells only. In lesioned animals, in which the coactivation of striatal and/or cortical fibers traversing the accumbens region was avoided, the percentage of responsive neurons decreased to 20% (23/115). The predominant responses recorded in this situation were pure inhibitions of pars compacta cells (14/46) and long latency inhibitions of pars reticulata neurons (7/69). No pure excitation or excitation-inhibition sequence was recorded. In the two sets of experiments 5 cells were activated antidromically from the nucleus accumbens. The results provide electrophysiological evidence for an inhibitory pathway from the nucleus accumbens to the substantia nigra. The low percentage of responsive neurons, the lack of excitatory responses, the paucity of reciprocal connections and the different inhibitory effects on the two populations of nigral neurons demonstrate that the functional role of the nucleus accumbens in controlling the substantia nigra differs from that exerted by the striatum.     

Dopamine, acetylcholine and nitric oxide systems interact to induce corticostriatal synaptic plasticity

Two distinct forms of synaptic plasticity have been described at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Along with the massive glutamatergic inputs originating from the cortex, striatal neurons receive a myriad of other synaptic contacts arising from different sources. In particular, while the nigrostriatal pathway provides this brain area with dopamine (DA), intrinsic circuits are the main source of acetylcholine (ACh) and nitric oxide (NO). The three neurotransmitter systems interact with each other to determine whether corticostriatal LTP or LTD is triggered in response to repetitive synaptic stimulation. Two distinct subtypes of striatal interneurons produce ACh and NO in the striatum. These interneurons are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exert a feedforward control of the excitability of striatal projection neurons by ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse. The integrative action exerted by striatal projection neurons on the converging information arising from the cortex, nigral DA neurons, and from ACh- and NO-producing interneurons dictates the final output of the striatum to the other structures of the basal ganglia.