Dopamine and adenosine mediate substance P-induced depression of evoked IPSCs in the rat nucleus accumbens in vitro

The major projection cells of the nucleus accumbens (NAc) are under a strong inhibitory influence from GABAergic afferents and depend on afferent excitation to produce their output. We have earlier reported that substance P (SP), a peptide which is colocalized with GABA in these neurons, depresses excitatory synaptic transmission in this nucleus (Kombian, S.B., Ananthalakshmi, K.V.V., Parvathy, S.S. & Matowe, W.C. (2003) J. Neurophysiol., 89, 728-738). In order to better understand the role of this peptide in the synaptic physiology of the NAc, it is important to determine its effects on inhibitory synaptic responses. Using whole-cell recording in rat forebrain slices, we show here that SP also depresses evoked inhibitory postsynaptic currents (IPSCs) in the NAc via intermediate neuromodulators. SP caused a partially reversible, dose-dependent decrease in evoked IPSC amplitude. This effect was present without measurable changes in the holding current, input resistance of recorded cells or decay rate (tau) of IPSCs. It was mimicked by a neurokinin-1 (NK1) receptor-selective agonist, [Sar9, Met (O2)11]-SP, and blocked by an NK1 receptor-selective antagonist, L 732 138. The SP-induced IPSC depression was prevented by SCH23390, a dopamine D1-like receptor antagonist and by 8-cyclopentyltheophylline, an adenosine A1 receptor blocker. Furthermore, the SP effect was also markedly attenuated by exogenous adenosine, dipyridamole, rolipram and barium. These data show that SP, acting on NK1 receptors, depresses inhibitory synaptic transmission indirectly by enhancing extracellular dopamine and adenosine levels. SP therefore acts in the NAc to modulate both excitatory and inhibitory afferent inputs using the same mechanism(s).     

Heterogeneous expression of gamma-aminobutyric acid and gamma-aminobutyric acid-associated receptors and transporters in the rat suprachiasmatic nucleus

The hypothalamic suprachiasmatic nucleus (SCN) is the primary mammalian circadian clock that regulates rhythmic physiology and behavior. The SCN is composed of a diverse set of neurons arranged in a tight intrinsic network. In the rat, vasoactive intestinal peptide (VIP)- and gastrin-releasing peptide (GRP)-containing neurons are the dominant cell phenotypes of the ventral SCN, and these cells receive photic information from the retina and the intergeniculate leaflet. Neurons expressing vasopressin (VP) are concentrated in the dorsal and medial aspects of the SCN. Although the VIP/GRP and VP cell groups are concentrated in different regions of the SCN, the separation of these cell groups is not absolute. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is expressed in most SCN neurons irrespective of their location or peptidergic phenotype. In the present study, immunoperoxidase labeling, immunofluorescence confocal microscopy, and ultrastructural immunocytochemistry were used to examine the spatial distribution of several markers associated with SCN GABAergic neurons. Glutamate decarboxylase, a marker of GABA synthesis, and vesicular GABA transporter were more prominently observed in the ventral SCN. KCC2, a K(+)/Cl(-) cotransporter, was highly expressed in the ventral SCN in association with VIP- and GRP-producing neurons, whereas VP neurons in the dorsal SCN were devoid of KCC2. On the other hand, GABA(B) receptors were observed predominantly in VPergic neurons dorsally, whereas, in the ventral SCN, GABA(B) receptors were associated almost exclusively with retinal afferent fibers and terminals. The differential expression of GABAergic markers within the SCN suggests that GABA may play dissimilar roles in different SCN neuronal phenotypes.     

Excitatory and inhibitory postsynaptic currents of the superior salivatory nucleus innervating the salivary glands and tongue in the rat

The excitatory and inhibitory synaptic inputs to parasympathetic preganglionic neurons in the superior salivatory (SS) nucleus were investigated in brain slices of neonatal (4-8 days old) rat using the whole-cell patch-clamp technique. The SS neurons innervating the submandibular and sublingual salivary glands and innervating the lingual artery in the anterior region of the tongue were identified by retrograde transport of a fluorescent tracer. Whole-cell currents were evoked by electrical stimulation of tissue surrounding the cell. These evoked postsynaptic currents were completely abolished by antagonists for N-methyl-D-aspartate (NMDA) glutamate, non-NMDA glutamate, gamma-aminobutyric acid type A (GABAA), and glycine receptors, suggesting that SS neurons receive glutamatergic excitatory, and GABAergic and glycinergic inhibitory synaptic inputs. In SS neurons for the salivary glands, the ratio of the NMDA component to the total excitatory postsynaptic current (EPSC) was larger than that of the non-NMDA component. This profile was reversed in the SS neurons for the tongue. In SS neurons for the salivary glands, the ratio of the GABAA component to the total IPSC was larger than the ratio of the glycine component to total inhibitory postsynaptic current (IPSC). The decay time constants of the GABAA component were slower than those for glycine. These characteristics of the excitatory and inhibitory inputs may be involved in determining the firing properties of the SS neurons innervating the salivary glands and the tongue.     

Postsynaptic modulation of AMPA- and NMDA-receptor currents by Group III metabotropic glutamate receptors in rat nucleus accumbens

Whole cell patch clamp recordings from rat nucleus accumbens neurons were made in order to study the effect of metabotropic glutamate receptors and dopamine on postsynaptic glutamate receptor mediated currents. AMPA- and NMDA-R currents were evoked by flash photolysis of caged glutamate, while spike-dependent release of neurotransmitters was prevented by adding tetrodotoxin and bicuculline to the bath solution. Spontaneous potentiation of NMDA- but not AMPA-R current was observed in the early phase of stimulation, followed by depotentiation and subsequent stabilization. The Group III metabotropic glutamate receptor antagonist MAP4 induced a transient potentiation of both AMPA- and NMDA-R current amplitudes, without affecting rise times and decay time constants. In contrast, the Group I-II metabotropic glutamate receptor antagonist MCPG and the neurotransmitter dopamine did not exert significant effects on either AMPA- or NMDA-R currents. These data suggest that at least one of the Group III subtypes is located postsynaptically in the nucleus accumbens and is able to dampen the activity of ionotropic glutamatergic receptors. In contrast, our results do not support a modulation of postsynaptic AMPA- and NMDA-R currents by Group I/II metabotropic glutamate receptors or dopamine. Modulation of both AMPA- and NMDA-R currents in the nucleus accumbens is likely to play a major role in setting the cellular excitability in response to behaviourally relevant limbic inputs, and in regulating the plasticity of these responses.     

The involvement of GABA-C receptors in paired-pulse depression of inhibitory postsynaptic currents in rat hippocampal CA1 pyramidal neurons

In rat hippocampal CA1 pyramidal neurons, γ-aminobutyric acid (GABA) A receptor-mediated inhibitory postsynaptic currents (IPSCs) undergo a paired-pulse depression (PPD) by the second of two pulses, with inter-pulse intervals of 100-2000 ms, applied to the stratum radiatum. While GABA-C receptors are described in the CA1 area, their functional significance is unknown. In this study, the involvement of GABA-C receptors in PPD was examined using an in vitro hippocampal slice preparation. IPSCs evoked by stimulations in stratum radiatum were recorded with patch pipettes from CA1 pyramidal cells. PPD, when induced in the above fashion, was blocked by the GABA-C receptor antagonist (1,2,5,6-Tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA, 10 μM, applied in the superfusing medium). GABA-A and GABA-B receptor-mediated IPSCs, as well as the baclofen-induced suppression of the GABA-A receptor mediated IPSC, were not antagonized by TPMPA (10-20 μM). These results indicate that PPD of the IPSC is mediated by the activation of GABA-C receptors.     

Neurotensin peptides antagonistically regulate postsynaptic dopamine D2 receptors in rat nucleus accumbens: a receptor binding and microdialysis study

Summary An in vitro receptor binding and in vivo microdialysis study was performed to further investigate the modulation of dopamine (DA) D₂ receptors by neurotensin (NT) peptides. Saturation experiments with the D₂ agonist [³H]NPA (N-propylnorapomorphine) showed that 10 nM of NT, 10 nM of neuromedin N (NN) and 1 nM of the C-terminal NT-(8–13) fragment significantly increased the K_D values by 125%, 181%, and 194%, respectively without significantly affecting the B_max value of the [³H]NPA binding sites in coronal sections of rat ventral forebrain mainly containing the nucleus accumbens (Acb) and the olfactory tubercle.In line with the previous findings that NT can increase GABA release in the Acb and that NT receptors are not found on DA terminals in this brain region, the present in vivo microdialysis study demonstrated that local perfusion of NT (1 nM) counteracted the D₂ agonist pergolide (2M) induced inhibition of GABA, but not of DA release in the rat Acb. This result indicates that NT counteracts the D₂ agonist induced inhibition of GABA release in the rat Acb, via an antagonistic postsynaptic NT/D₂ receptor interaction as also suggested by the inhibitory regulation of D₂ receptor affinity in the Acb by the NT peptides demonstrated in the present receptor binding experiments. Thus, the neuroleptic and potential antipsychotic profile of the NT peptides may involve an antagonistic NT/D₂ receptor regulation in the ventral striatum.Abbreviations Acb nucleus accumbens - DA dopamine - NPA N-propylnorapomorphine - NT neurotensin     

Opioids suppress spontaneous and NMDA-induced inhibitory postsynaptic currents in the dorsal raphe nucleus of the rat in vitro

Recently, local injection of morphine in the dorsal raphe nucleus (DRN) has been shown to increase serotonin release in the forebrain of unanesthetized rats. This study investigated the site of action of opioids in rat brain slices containing the DRN. Postsynaptic currents (PSCs), measured intracellularly under voltage clamp, were induced in serotonergic neurons with bath and microiontophoretic applications of NMDA to activate local neurons. Met-enkephalin (ENK) suppressed spontaneous and NMDA-induced GABAergic inhibitory PSCs. This effect, which was mimicked by the μ agonist DAMGO but not the κ-agonist U50488 or the δ-agonist DPDPE, was reversed by the μ antagonist CTOP. ENK also suppressed spontaneous and NMDA-induced glutamatergic excitatory PSCs. By searching with focal microiontophoretic NMDA applications, GABAergic and glutamatergic cells projecting on serotonergic neurons were found in the DRN and the adjacent periaqueductal gray. Consistent with the reduction in PSCs, ENK inhibited/hyperpolarized the great majority (81%) of non-serotonergic neurons recorded extra- and intracellularly in the DRN; the ENK effect reversed polarity at −99±9 mV, close to the potassium reversal potential. In contrast, ENK inhibited/hyperpolarized only 28% of serotonergic neurons; in the affected cells, the ENK effect, blocked by CTOP, had its reversal potential shifted with change of extracellular potassium in agreement with the value predicted by the Nernst equation for a potassium conductance; serotonin occluded the ENK inhibition. Taken together, these results indicate that opioids inhibit both local GABAergic and glutamatergic cells projecting onto DRN serotonergic neurons.     

Substance P and cocaine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro

Substance P (SP) has been reported to produce effects on excitatory synaptic transmission in the nucleus accumbens (NAc) that are similar to those induced by cocaine. To address the question of whether SP serves as an endogenous mediator producing cocaine‐like effects that are known to be D1‐receptor‐mediated, we tested the hypothesis that the effects of SP and cocaine on excitatory postsynaptic currents (EPSCs) in the NAc occlude one another. We report here that SP and SP_5–11 actions occlude the effect of cocaine and vice versa. SP, SP_5–11 and cocaine all depressed evoked, non‐N‐methyl‐d ‐aspartate (NMDA) receptor‐mediated synaptic currents in a concentration‐dependent manner, with EC₅₀ values of 0.12, 0.17 and 8.3 μm , respectively. Although cocaine was the least potent, it was most efficacious. SP, SP_5–11 and cocaine all suppressed isolated NMDA receptor‐mediated evoked EPSCs. SP_5–11 (1 μm )‐induced EPSC depression was blocked by the neurokinin‐1 antagonist L732138 and by the D1‐like receptor antagonist SCH23390. Pretreatment of slices with cocaine (30 μm ) depressed the EPSC by 39.1% ± 4.8%. Application of SP or SP_5–11 (1 μm ) at the peak of the cocaine depressive effect on the EPSC did not produce any additional diminution of the response (5.7% ± 2.8%). In the reverse experiments, in which either SP or SP_5–11 was applied first, subsequent application of cocaine at the peak of the peptide’s effect (30.3% ± 2.3%) produced a further but smaller depression (15.5% ± 3.6%) of the remaining EPSC. These data indicate that cocaine and SP produce similar effects on excitatory synaptic transmission in the NAc, and that their actions occlude one another. This suggests that SP may act like cocaine in its absence, and may be an endogenous trigger for the reward and behaviors associated with cocaine.     

Hippocampal modulation of locomotor activity induced by focal activation of postsynaptic dopamine receptors in the core of the nucleus accumbens

The locomotor effects of intra-NAcc injection of dopamine receptor agonists following discrete lesion or inhibition of the DH or the VH have been poorly investigated using only the indirect dopamine receptor agonist amphetamine. In the present study, we investigated how lidocaine in the DH or the VH modulated hyperlocomotion induced by focal injection into the NAcc core of the selective D1-like receptor agonist, SKF 38393, or coinjection of SKF 38393, and the selective D2-like receptor agonist, LY 171555; the latter pharmacological condition being required for the full expression of the postsynaptic effects of D2-like receptor agonists, and recognized to produce a locomotor response mainly mediated by D2-like postsynaptic receptors. Rats were given the D1-like receptor agonist SKF 38393 alone or in combination with the D2-like receptor agonist LY 171555 into the NAcc core, and lidocaine into the DH or the VH. Then, locomotor activity was recorded. Focal injection into the NAcc core of SKF 38393 alone or in combination with LY 171555 resulted in an increase of locomotor activity. Administration of lidocaine into the DH further potentiated the increase in locomotor activity induced by activation of D1-like receptors or co-activation of D1-like and D2-like receptors in the NAcc core. Administration of lidocaine into the VH also potentiated the increase in locomotor activity induced by D1-like receptor activation, but decreased that produced by co-activation of D1-like and D2-like receptors in the NAcc core. Taken together, these results suggest that under lidocaine-free conditions the DH may exert a tonic inhibitory modulation on hyperlocomotion mediated by D1-like and D2-like postsynaptic receptors in the NAcc core, while the VH may exert a tonic inhibitory on hyperlocomotion mediated by D1-like receptors and a tonic facilitatory control on hyperlocomotion mediated by D2-like postsynaptic receptors.     

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

Norepinephrine (NE) activates adrenergic receptors (ARs) in the hypothalamic paraventricular nucleus (PVN) to increase excitatory currents, depolarise neurones and, ultimately, augment neuro‐sympathetic and endocrine output. Such cellular events are known to potentiate intracellular calcium ([Ca²⁺]_i); however, the role of NE with respect to modulating [Ca²⁺]_i in PVN neurones and the mechanisms by which this may occur remain unclear. We evaluated the effects of NE on [Ca²⁺]_i of acutely isolated PVN neurones using Fura‐2 imaging. NE induced a slow increase in [Ca²⁺]_i compared to artificial cerebrospinal fluid vehicle. NE‐induced Ca²⁺ elevations were mimicked by the α₁‐AR agonist phenylephrine (PE) but not by α₂‐AR agonist clonidine (CLON). NE and PE but not CLON also increased the overall number of neurones that increase [Ca²⁺]_i (ie, responders). Elimination of extracellular Ca²⁺ or intracellular endoplasmic reticulum Ca²⁺ stores abolished the increase in [Ca²⁺]_i and reduced responders. Blockade of voltage‐dependent Ca²⁺ channels abolished the α₁‐AR induced increase in [Ca²⁺]_i and number of responders, as did inhibition of phospholipase C inhibitor, protein kinase C and inositol triphosphate receptors. Spontaneous phasic Ca²⁺ events, however, were not altered by NE, PE or CLON. Repeated K⁺‐induced membrane depolarisation produced repetitive [Ca²⁺]_i elevations. NE and PE increased baseline Ca²⁺, whereas NE decreased the peak amplitude. CLON also decreased peak amplitude but did not affect baseline [Ca²⁺]_i. Taken together, these data suggest receptor‐specific influence of α₁ and α₂ receptors on the various modes of calcium entry in PVN neurones. They further suggest Ca²⁺ increase via α₁‐ARs is co‐dependent on extracellular Ca²⁺ influx and intracellular Ca²⁺ release, possibly via a phospholipase C inhibitor‐mediated signalling cascade.     

A topographically organized gamma-aminobutyric acid projection from the ventral pallidum to the nucleus accumbens in the rat

Anatomical and electrophysiological studies have indicated that a reciprocal projection from the ventral pallidum back to the nucleus accumbens exists and has functional relevance. In this study, the topographical projection from the ventral pallidum to the nucleus accumbens was examined by using retrograde tracing with fluoro-gold iontophoresed in subcompartments of the nucleus accumbens in rats combined with either in situ hybridization for glutamic acid decarboxylase and preproenkephalin mRNA or substance P immunoreactivity. Deposits made into the medial nucleus accumbens preferentially labeled neurons in the medial ventral pallidum, while deposits into the dorsolateral nucleus accumbens, at or lateral to the anterior commissure, labeled primarily cells in the dorsal and lateral ventral pallidum. A mediolateral to rostrocaudal topography was also observed, with the medial deposits preferentially labeling cells in rostral ventral pallidum and the lateral deposits resulting in retrogradely labeled cells in the ventral pallidum below the crossing of the posterior anterior commissure (subcommissural) as well as below the globus pallidus (sublenticular). The majority of cells retrogradely labeled with fluoro-gold were double-labeled for glutamic acid decarboxylase mRNA. In contrast, very few retrogradely labeled neurons in the ventral pallidurn were double labeled for mRNA for preproenkephalin. These data demonstrate a topographically organized projection from the ventral pallidum, to the nucleus accumbens that is primarily γ-aminobutyric acid (GABA)-ergic and reciprocal to the GABAergic projection from the nucleus accumbens to the ventral pallidum. © 1994 Wiley-Liss, Inc.     

Chronic nicotine and smoke treatment modulate dopaminergic activities in ventral tegmental area and nucleus accumbens and the gamma-aminobutyric acid type B receptor expression of the rat prefrontal cortex

Dopaminergic afferents from the mesencephalic areas, such as ventral tegmental area (VTA), synapse with the gamma-aminobutyric acid (GABA)-ergic interneurons in the prefrontal cortex (PFC). Pharmacological and electrophysiological data show that the reinforcement, the dependence-producing properties, as well as the psychopharmacologic effects of nicotine depend to a great extent on activation of nicotinic receptors within the mesolimbocortical dopaminergic projection. To explore further the relationship between the mesencephalic dopaminergic neurons and PFC GABAergic neurons, we investigated the effects of nicotine and passive exposure to cigarette smoke on the regulation of tyrosine hydroxylase (TH) in VTA and substantia nigra (SNC) and dopamine (DA) D1 receptor levels in nucleus accumbens (NAc) and caudate-putamen (CPu). Also, the simultaneous changes in GABAB receptors mRNAs in the PFC were studied. The results showed that chronic nicotine and smoking treatment differentially changed the levels of TH protein in VTA and SNC and DA D1 receptor levels in Nac and CPu. GABAB1 and GABAB2 receptor mRNA levels also showed different change patterns. Ten and thirty minutes of smoke exposure increased GABAB1 receptor mRNA to a greater extent than that of GABAB2, whereas GABAB2 was greatly enhanced after 1 hr of smoke exposure. The TH levels in VTA were closely related to DA D1 receptor levels in NAc and with GABAB receptor mRNA changes in PFC. These results suggest that the mesolimbic pathway and GABAB receptor mRNA in PFC are modulated by nicotine and cigarette smoke, implying an important role in nicotine's psychopharmacological effects.     

Changes in gamma-aminobutyric acid, mu-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens

Discrete quinolinic acid lesions in the nucleus accumbens altered [3H]muscimol binding to gamma-aminobutyric acid receptors, [125I]neurotensin binding to neurotensin receptors, [125I]Tyr-D-Ala-Gly-NMePHe-Gly-OH binding to mu-opioid receptors, and [3H]quinuclidinyl benzilate binding to muscarinic receptors. Within lesions of the lateral accumbens core, [3H]muscimol binding increased and [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH, [125I]neurotensin and [3H]quinuclidinyl benzilate binding decreased. Lesions of the medial nucleus accumbens resulted in decreased [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH and [3H]quinuclidinyl benzilate binding while no alterations were observed for [3H]muscimol or [125I]neurotensin binding. These data support anatomical distinctions between medial and lateral nucleus accumbens. Destruction of intrinsic neurons in the dorsomedial nucleus accumbens core increased [3H]muscimol binding in the dorsal rim of the ventral pallidum and the rostral globus pallidus without altering [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH binding. Destruction of neurons in the lateral nucleus accumbens core or medial shell did not alter [3H]muscimol binding in the ventral pallidum. The lack of upregulation in gamma-aminobutyric acid receptors suggests that the gamma-aminobutyric acid-containing projection from the dorsomedial core to the dorsal rim of the ventral pallidum differs from the projection from the lateral accumbens core and medial shell to the more ventral regions of the pallidum. Fluoro-gold retrograde tracer histochemistry confirmed the specific projection from the dorsomedial core to the dorsal ventral pallidum; and from the shell of the nucleus accumbens to more ventral regions of the ventral pallidum.     

Blockade of D-1 dopamine receptors in the medial prefrontal cortex produces delayed effects on pre- and postsynaptic indices of dopamine function in the nucleus accumbens

The actions mediated by limbic system output projections of the basal ganglia were investigated by studying the effects of ventral pallidum (VP) stimulation on the activity of neurons in thalamic target nuclei, including several of the dorsal thalamic nuclei and the nucleus reticularis, using in vivo intracellular recordings in rats. Intracellular injection of Lucifer yellow was used in a subset of experiments to identify the neurons recorded and to confirm their location with respect to the specific thalamic nuclei targeted. Stimulation of the VP evoked ipsps in 79% of the mediodorsal cells recorded. In the reticular nucleus, 73% of the neurons tested responded with evoked ipsps. In contrast, in other dorsal thalamic nuclei VP stimulation evoked depolarizations in 58% of the cells recorded. The latency to onset of the ipsps in the mediodorsal nucleus and in the reticular nucleus were not substantially different (1.7 ± 1.1 msec vs. 2.7 ± 1.1 msec), whereas the depolarizing response evoked in dorsal thalamic nucleus neurons typically occurred at longer and more variable latencies (3.5 ± 2.7 msec).     

Group III metabotropic glutamate receptors and D1-like and D2-like dopamine receptors interact in the rat nucleus accumbens to influence locomotor activity

Evidence for functional interactions between metabotropic glutamate (mGlu) receptors and dopamine (DA) neurotransmission is now clearly established. In the present study, we investigated interactions between group III mGlu receptors and D1- and D2-like receptors in the nucleus accumbens (NAcc). Administration, into the NAcc, of the selective group III mGlu receptor agonist, AP4, resulted in an increase in locomotor activity, which was blocked by pretreatment with the group III mGlu receptor antagonist, MPPG. In addition, pretreatment with AP4 further blocked the increase in motor activity induced by the D1-like receptor agonist, SKF 38393, but potentiated the locomotor responses induced by either the D2-like receptor agonist, quinpirole, or coinfusion of SKF 38393 and quinpirole. MPPG reversed the effects of AP4 on the motor responses induced by D1-like and/or D2-like receptor activation. These results confirm that glutamate transmission may control DA-dependent locomotor function through mGlu receptors and further indicate that group III mGlu receptors oppose the behavioural response produced by D1-like receptor activation and favour those produced by D2-like receptor activation.     

Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area

Cholinergic and glutamatergic neurons in the laterodorsal tegmentum (LDT) and neighbouring mesopontine nuclei are thought to influence mesolimbic dopaminergic neuronal activity involved in goal-directed behaviours. We measured the changes in dopamine oxidation current (corresponding with dopamine efflux) in the nucleus accumbens (NAc) in response to electrical stimulation of the LDT using in vivo chronoamperometry in urethane-anaesthetized rats. LDT stimulation (35 Hz pulse trains for 60 s, 1 s intertrain interval) evoked a three-component change in dopamine efflux in the NAc: (i) an initial stimulation time-locked increase in the dopamine signal above baseline, followed by (ii) an immediate decrease below baseline, and thereafter by (iii) a prolonged increase in the dopamine signal above baseline. Intra-VTA infusion of the nicotinic receptor antagonist mecamylamine (5 microg/0.5 microL) or the ionotropic glutamate receptor antagonist kynurenate (10 microg/microL) attenuated the first LDT-elicited component. The second suppressive component was abolished by intra-LDT infusions of either the nonselective or the M2-selective muscarinic receptor antagonists scopolamine (100 microg/microL) and methoctramine (50 microg/microL), respectively. In contrast, intra-VTA infusions of scopolamine (200 microg/microL) resulted in a selective attenuation of the third facilitatory component, whereas both second and third components were abolished by systemic injections of scopolamine (5 mg/kg). These results suggest that the initial increase, subsequent decrease, and final prolonged increase in extracellular dopamine levels in the NAc are selectively mediated by LDT-elicited activation of (i) nicotinic and glutamatergic receptors in the VTA, (ii) muscarinic M2 autoreceptors on LDT cell bodies, and (iii) muscarinic receptors in the VTA, respectively.     

The distribution of noradrenaline, serotonin and gamma-aminobutyric acid in the monkey nucleus accumbens

1. 1. The recent histochemical studies have shown that the primate nucleus accumbens (NAC) can be subdivided into at least three subdivisions,

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2. 2. The medial subdivision possesses dense peptide- and dopamine-immunoreactive (IR) fibers.

3. 3. In order to further investigate the neurochemical characteristics of the primate NAC, the distribution of structures that contain noradrenaline (NA), serotonin (5-HT) and gammaaminobutyric acid (GABA) were examined in the macaque monkey by using transmitterimmunohistochemical methods.

4. 4. Many NA-IR fibers were observed in the dorsal part of the NAC, corresponding to the medial subdivision. Fine varicose 5-HT-IR fibers were evenly distributed in the NAC. GABA-IR cell bodies and puncta were observed throughout the NAC as well as in the caudate nucleus and putamen.

5. 5. The monkey rostral NAC displays a highly homogeneous distribution of all neuropeptides and neurotransmitters studied so far and we propose that this region be termed of the NAC.

     

Relationship between D 1 dopamine receptors,adenylate cyclase,and the electrophysiological responses of rat nucleus accumbens neurons

Summary The electrophysiological effects of three selective D 1 dopamine (DA) receptor agonists, which exhibit different potencies and efficacies for stimulation of adenylate cyclase, were compared in the rat nucleus accumbens (NAc) using single unit recording and microiontophoretic techniques. The partial agonists SKF 75670 and SKF 38393, and the full agonist SKF 81297 produced nearly identical current-response curves for the inhibition of firing of NAc neurons. In rats acutely depleted of DA by-methyl-p-tyrosine (AMPT) pretreatment, all three D 1 agonists enabled the inhibition of firing produced by the selective D 2 receptor agonist quinpirole, with SKF 38393 exerting the greatest efficacy, followed by SKF 81297 and SKF 75670. Thus, no apparent relationship was found between the previously reported ability of these compounds to stimulate cyclic adenosine monophosphate (cAMP) production and their ability either to inhibit the firing of NAc neurons or to enable quinpirole-mediated inhibition of firing in DA-depleted rats. In addition, the membrane-permeable cAMP analog 8-bromo-cAMP also caused a current-dependent inhibition of the firing of NAc neurons, but failed to enable quinpirole-mediated inhibition in AMPT-pretreated animals. These results suggest either that only a small percentage of D 1 receptors need to be stimulated to produce these electrophysiological effects, or that D 1 receptors exist within the rat NAc which are linked to transduction mechanisms other than, or in addition to, adenylate cyclase.     

A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus

The pyramidal neurons in the CA1 area of hippocampal slices from 17- to 19-day-old rats have been investigated by means of patch clamp. Excitatory postsynaptic currents (EPSCs) were elicited by stimulating the Schaffer collateral at a frequency below 0.2 Hz. It was found that inhibition of glutamatergic transmission by 20 μm 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 100 μm 2-amino-5-phosphonovaleric acid (D-APV) left a small component of the EPSC uninhibited. The amplitude of this residual EPSC (rEPSC) comprised 25 ± 11% of the total EPSC when measured at a holding potential of ?50 mV. The rEPSC was blocked by selective P2 blocker pyridoxal phosphate-6-azophenyl-2′-4′-disulphonic acid (PPADS) 10 μm and bath incubation with non-hydrolysable ATP analogues, ATP-γ-S and α,β-methylene-ATP at 50 and 20 μm , respectively. The rEPSC was dramatically potentiated by external Zn²⁺ (10 μm ). In another series of experiments exogenous ATP was applied to the CA1 neurons in situ. An inward current evoked by ATP was inhibited by PPADS to the same extent as the rEPSC. It is concluded that, depending on membrane voltage, about one-fifth to one-quarter of the EPSC generated by the excitatory synaptic input to the hippocampal CA1 neurons of rat is due to the activity of P2X receptors.     

Baclofen: Effects on evoked field potentials and amino acid neurotransmitter release in the rat olfactory cortex slice

A study has been made of the in vitro effects of (+/-)- and (-)-baclofen on the evoked field potentials and release of endogenous amino acid neurotransmitter candidates (aspartate, glutamate, GABA and possibly taurine) which accompany electrical stimulation of the excitatory input to the olfactory cortex slice, the lateral olfactory tract. Baclofen appears to reduce the excitatory input to the GABA-utilizing inhibitory interneurones; this action was manifest as a drug-induced abolition of the field potential known as the P-wave (IC50 for (-)-baclofen, 1.7 +/- 0.4 microM) together with a simultaneous reduction in the synaptically evoked release of aspartase and glutamate from the cut surface of slices. Both these actions of baclofen exhibited concentration dependence and stereospecificity and were not antagonized by picrotoxin (25 microM) thereby suggesting that they are directly related. The consequence of this action of baclofen was the abolition of GABA-mediated presynaptic and postsynaptic inhibition together with their respective field potential correlates, the late N- and I-waves. (+/-)-Baclofen (5 and 25 microM) also inhibited the potassium-evoked release of aspartate and glutamate from small cubes of tissue but, except at a high concentration (1 mM), had no effect on GABA release. Baclofen (up to 1 mM) did not affect transmission either at the lateral olfactory tract-superficial pyramidal cell synapse, a site where aspartate is the likely neurotransmitter, or at the superficial pyramidal cell collateral-deep pyramidal cell excitatory synapse. It is proposed that: (i) the actions of baclofen on the olfactory cortex are the result of inhibition of aspartate and glutamate release, probably from deep pyramidal cell collaterals; and (ii) not all neurones utilizing excitatory amino acids as their neurotransmitters are subject to the inhibitory action of baclofen.