Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and,probably, D3 receptors in the dorsal striatum,but not in the nucleus accumbens

Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies across both structures. Using microdialysis, we therefore investigated whether intracerebrally administered quinpirole, a dopamine D2-like receptor agonist, and PD 128907, (S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol, a dopamine D3 receptor preferring agonist, differentially alter the tyrosine-induced increase of extracellular dopamine in the dorsal striatum and the nucleus accumbens, respectively. Perfusion of tyrosine (100 microM) into the dorsal striatum and the nucleus accumbens enhanced extracellular dopamine in a physiological manner in both areas. Infusion of the Na(+) channel blocker tetrodotoxin (2 microM) suppressed the enhanced level of dopamine derived from exogenous tyrosine in both brain areas. Infusion of the dopamine D2-like receptor agonist quinpirole at a concentration (1 nM), which alone did not affect basal extracellular dopamine, reduced tyrosine-enhanced extracellular dopamine when infused into the dorsal striatum, but not into the nucleus accumbens; the preferential dopamine D3 receptor agonist, PD 128907, had similar effects. Haloperidol, a dopamine D2-like receptor antagonist, given systemically at a dose, which alone did not significantly affect basal dopamine levels (10 nmol/kg i.p.), enhanced extracellular dopamine derived from exogenous tyrosine. This haloperidol treatment antagonized only the quinpirole-induced, but not the PD 128907-induced reduction in dopamine levels seen in tyrosine-treated rats. The results show that extracellular dopamine derived from exogenous tyrosine is under inhibitory control of presynaptic dopamine D2-like receptors in the dorsal striatum, but not in the nucleus accumbens; to what extent the same holds for dopamine D3 receptors remains to be proven. Future studies are required to elucidate whether the noted difference is absolute or not.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

Prefrontal,accumbal [shell] and ventral striatal mechanisms in jaw movements and non-cyclase-coupled dopamine D1-like receptors

The effect on jaw movements of intracerebral injections of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), SK&F 38393 ([R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and of injections of the dopamine D2-like receptor agonist quinpirole into the ventrolateral striatum, accumbens shell or prefrontal cortex were studied. SK&F 38393 and SK&F 83959 injected into the ventrolateral striatum synergised with i.v. quinpirole; in the shell of accumbens, SK&F 38393 evidenced weaker synergism with quinpirole, while SK&F 83959 did not synergise with it; neither agent synergised with quinpirole in the prefrontal cortex. Co-injection of SCH 23390 or SK&F 83959 into the prefrontal cortex antagonised jaw movements induced by injection of SK&F 83959 into the ventrolateral striatum in combination with i.v. quinpirole. Injection of SK&F 83959 + quinpirole into the ventrolateral striatum, but not into the accumbens shell, resulted in synergism. These findings indicate a primary, but not exclusive, role for ventral striatal, non-cyclase-coupled dopamine D1-like receptors in the induction of jaw movements. These processes appear to require tonic activity of prefrontal cyclase-linked dopamine D1A [and/or D1B] receptors.     

Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia

These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic–cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic–basal forebrain–cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic–cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia.     

Inhibition by phencyclidine of excitatory amino acid-stimulated release of neurotransmitter in the nucleus accumbens

The effects of phencyclidine (PCP) on the release of acetylcholine and dopamine, stimulated by excitatory amino acid agonists was examined in slices of nucleus accumbens of the rat. In slices incubated in [3H]choline or [3H]dopamine, the amount of tritium efflux produced by 1 mM N-methyl-D-aspartate (NMDA), kainic acid (KA) or quisqualic acid (QA) was compared with that produced in the presence of varying concentrations of phencyclidine. N-Methyl-D-aspartate stimulated the calcium-dependent release of both ACh and DA, which was completely inhibited by physiological concentrations of magnesium and inhibited by 2-aminophosphonovalerate (2-APV). Kainic acid- and quisqualic acid-stimulated release of ACh and DA was partially inhibited by magnesium or by 2-APV. Phencyclidine inhibited NMDA-stimulated release of ACh and DA with IC50's around 100 nM. Phencyclidine (0.1 microM) also significantly inhibited kainic acid and quisqualic acid-induced release of ACh in magnesium-free but not magnesium-containing buffer, suggesting that the effect of PCP on kainic acid- and possibly quisqualic acid-stimulated release of ACh is on that part of the response which is mediated by NMDA receptors. The results suggest that the inhibition by PCP of the release of ACh and DA in the nucleus accumbens is selective for NMDA-type receptors.     

The role of afferents to the locus coeruleus in the handling stress-induced increase in the release of noradrenaline in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain

This study was aimed to identify the neuronal pathways that mediate the handling stress-induced increase in the release of noradrenaline in the medial prefrontal cortex of the rat brain. For that purpose a microdialysis probe was implanted in the vicinity of the locus coeruleus and a second probe was placed in the ipsilateral medial prefrontal cortex. Receptor specific antagonists acting on the alpha(2)-adrenoceptor (50 microM idazoxan), GABA(A) (50 microM bicuculline), GABA(B) (100 microM (3, 4-Dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid; CGP 52432), acetylcholine (10 microM atropine), corticotropin releasing factor (CRF) (100 microM butyl-ethyl-[2,5-dimethyl-7-(2,4, 6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine; CP-154, 526), NMDA glutamate (300 microM (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; CPP) and non-NMDA glutamate receptors (500 microM 6,7-dinitroquinoxaline-2, 3-dione; DNQX) were infused into the locus coeruleus by retrograde dialysis, whereas extracellular noradrenaline was recorded in the ipsilateral medial prefrontal cortex. During infusion of the various compounds rats were gently handled for 10 min. Infusion of idazoxan potentiates the handling-induced increase in the release of noradrenaline in the medial prefrontal cortex. The infusions of, atropine, bicuculline, CGP 52432 and DNQX were without effect on the handling response. Infusion of the NMDA receptor antagonist CPP or the non-peptide CRF receptor antagonist CP-154,526 suppressed the stimulation of noradrenaline during stress. It is concluded that alpha(2)-adrenoceptors, NMDA glutamate receptors and CRF receptors modify the handling stress response of locus coeruleus neurones. The data suggest no major role for glutamatergic, GABAergic, or cholinergic afferents to the locus coeruleus in mediating the stress response.     

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release

RATIONALE: Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. OBJECTIVES: To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. METHODS: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. RESULTS: The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. CONCLUSIONS: Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.     

Effect of chronic cocaine treatment on D2 receptors regulating the release of dopamine and acetylcholine in the nucleus accumbens and striatum.

The inhibition of electrically stimulated [3H]DA and [14C]ACh release by a submaximal concentration of quinpirole was measured 1 week after pretreating rats for 9 days with cocaine (15 mg/kg IP, twice per day). Although this pretreatment significantly enhanced behavioral response to a challenge injection of cocaine when compared with rats pretreated with saline only, no significant differences were apparent in the degree of inhibition of electrically evoked [3H]DA or [14C]ACh release by quinpirole in either the nucleus accumbens or striatum. In addition, the potentiation of electrically evoked [3H]DA release and corresponding inhibition of [14C]ACh release by 10 microM cocaine, measured in striatal slices only, was not significantly different between the two treatment groups. These results suggest that the enhanced behavioral response resulting from chronic cocaine treatment (behavioral sensitization) is not caused by a subsensitivity of D2 terminal autoreceptors or by a supersensitivity of postsynaptic D2 receptors on cholinergic neurons.     

Interactive effects of D1 and D2 agonists with scopolamine on radial-arm maze performance.

Pharmacological blockade of muscarinic cholinergic (ACh) receptors has been found to impair choice accuracy in a variety of tasks including the radial-arm maze. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the dopaminergic (DA) antagonist haloperidol as well as the selective D1 antagonist SCH 23390. In the current study, interactions were studied between scopolamine and selective agonists of D1 (SCH 38393) and D2 (quinpirole) receptors. Surprisingly, the D1 agonist SKF 38393 was found to significantly alleviate the scopolamine-induced choice accuracy deficit. In contrast, the D2 agonist quinpirole was not found to significantly alter the effects of scopolamine on choice accuracy but did have supra-additive effects of increasing choice latency. Both the D1 agonist SKF 38393 and the D1 antagonist SCH 23390 have been found to reverse the choice accuracy deficit caused by scopolamine and the deficit resulting from lesions of the medial projection from the basal forebrain to the cortex. Possible mechanisms for these effects are discussed.     

Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex

Previous experimental studies have shown that the prefrontal cortex (PFC) regulates the activity of the nucleus accumbens (NAc), and in particular the release of dopamine in this area of the brain. In the present report we review recent microinjections/microdialysis studies from our laboratory on the effects of stimulation/blockade of dopamine and glutamate receptors in the PFC that modulate dopamine, and also acetylcholine release in the NAc. Stimulation of prefrontal D2 dopamine receptors, but not group I mGlu glutamate receptors, reduces the release of dopamine and acetylcholine in the NAc and spontaneous motor activity. This inhibitory role of prefrontal D2 receptors is not changed by acute systemic injections of the NMDA antagonist phencyclidine. On the other hand, the blockade of NMDA receptors in the PFC increases the release of dopamine and acetylcholine in the NAc as well as motor activity which suggests that the hypofunction of prefrontal NMDA receptors is able to produce the neurochemical and behavioural changes associated with a dysfunction of the corticolimbic circuit. We suggest here that dopamine and glutamate receptors are, in part, segregated in specific cellular circuits in the PFC. Thus, the stimulation/blockade of these receptors would have a different net impact on PFC output projections to regulate dopamine and acetylcholine release in the NAc and in guided behaviour. Finally, it is speculated that environmental enrichment might produce plastic changes that modify the functional interaction between the PFC and the NAc in both physiological and pathological conditions.     

Reduction in acetylcholine release in the hippocampus of dopamine D5 receptor-deficient mice.

Activation of the dopamine D1-like receptor stimulates acetylcholine (ACh) release in the hippocampus, apparently through the molecularly defined d5 receptor. In the present study, we used a transgenic mouse completely deprived of functional d5 receptor (d5-/-) to confirm the role and elucidate the possible function of the d5 receptor subtype on hippocampal cholinergic neurotransmission. ACh release was measured using in vivo microdialysis in the mouse dorsal hippocampus of 4 months old homozygous (d5-/-), heterozygous (d5+/-), and the wild-type (d5+/+) littermates. Using the no net flux technique, a significant reduction in basal hippocampal ACh level was found in the d5-/- compared to d5+/- and d5+/+ mice. Moreover, the administration of SKF 38393, a D1-like receptor agonist, systemically (2.0 and 10.0 mg/kg ip), or locally through the dialysis probe (10 and 50 microM), produced a dose-dependent enhancement of ACh release in the d5+/+, a moderate stimulation in the d5+/- but had no effect in the d5-/- mice. Quantitative receptor autoradiography revealed significant increases in M1-like but not in M2-like muscarinic receptor binding sites in the hippocampal formation. These results confirm and extend the role of the d5 receptor in the modulation of hippocampal ACh release and provide evidence for long-term alteration of hippocampal cholinergic neurotransmission resulting from the absence of the d5 receptors including chronically reduced ACh release and change in M1-like receptor levels.     

[3H]Acetycholine release in rat striatal slices is not subject to dopamine heteroreceptor supersensitivity 30 months after 6-hydroxydopamine lesion of the substantia nigra

Using the rat model of Parkinson's disease described by Ungerstedt the release of [3H]acetylcholine ([3H]ACh) in the caudatoputamen was investigated to assess possible long-term effects of unilateral dopaminergic denervation on the modulation of cholinergic interneurons. This seemed of interest since rats with 6-hydroxydopamine (6-OHDA) lesions of the left substantia nigra showed an increase in the behavioural susceptibility to small doses of dopamine (DA) D2 receptor agonists 30 months after the lesion. Electrical field stimulation with 3 Hz elicited release of [3H]ACh in slices of both the lesioned and the intact striatum. The DA reuptake blocker nomifensine was ineffective on the lesioned side but diminished the release of [3H]ACh in the intact striatum. This inhibition was reversed by the D2 receptor antagonist domperidone and hence probably due to the effect of endogenously released DA. Single electrical pulses at 0.05 Hz, which neither induced autoinhibition of [3H]ACh release nor heteroinhibition by endogenous DA, elicited a higher release of [3H]ACh on the intact side. Under this stimulation paradigm activation of the D2 heteroreceptor with quinpirole depressed the release of [3H]ACh to a similar extent on both sides, irrespective of the absence or presence of the competitive NMDA receptor antagonist D-CPPene. Also blockade of the NMDA receptor channel by dizocilpine, or of AMPA receptors by NBQX, was ineffective on either side. The NMDA-evoked release of [3H]ACh was higher on the lesioned side. It was equally depressed by quinpirole and by ethanol on both sides. Thus, single electrical pulses and NMDA stimulation per se had opposite effects on the lesioned and the intact side, whereas the modulation of release was similar. Since the lesioned striata were considerably smaller, measurements of mRNA levels of choline acetyltransferase (ChAT) were used to assess the density of cholinergic interneurons and their content of ChAT mRNA. This analysis did not reveal any side difference. In conclusion, the function of D2 heteroreceptors on, and the density and ChAT mRNA content of, cholinergic interneurons are not or no longer altered after long-term DA denervation. Most probably, cholinergic interneurons are not involved in the increased behavioural susceptibility of 6-OHDA-lesioned rats to DA agonists.     

Gz proteins are functionally coupled to dopamine D2-like receptors in vivo

The receptors that couple to the G protein Gz in vivo are still relatively unknown. In this study, we investigated the effects of various dopamine receptor agonists in a mouse deficient in the alpha subunit of Gz. The dopamine D1-like receptor agonist SKF38393 stimulated comparable locomotor activity in both wildtype mice and mice lacking Galphaz. In contrast, the dopamine D2-like receptor agonist quinpirole suppressed locomotor activity in both groups of mice, but this suppression was significantly smaller in Galphaz knockout mice. Consistent with these behavioural observations, quinpirole inhibition of dopamine release in the forebrain nucleus accumbens evoked by electrical stimulation of dopamine axons was significantly attenuated in mice lacking Galphaz. In addition, hypothermia and adrenocorticotropic hormone release resulting from activation of dopamine D2-like receptors were also significantly reduced in Galphaz knockout mice. However, adrenocorticotropic hormone secretion induced by corticotrophin releasing hormone and the serotonin 1A receptor agonist 8-hydroxy-dipropylamino-tetralin were similar between wildtype and Galphaz knockout mice. Western blot analysis showed that the expression levels of Galphai, Galphao, Galphas, Galphaq and Gbeta were the same in the brains of mice of both genotypes. Overall, our data suggest that Gz proteins are functionally coupled to dopamine D2-like receptors in vivo.     

Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid.

We studied the effect of lithium chloride on dopaminergic neurotransmission via D2-like receptors coupled to phospholipase A2 (PLA2). In unanesthetized rats injected i.v. with radiolabeled arachidonic acid (AA, 20:4 n-6), regional PLA2 activation was imaged by measuring regional incorporation coefficients k* of AA (brain radioactivity divided by integrated plasma radioactivity) using quantitative autoradiography, following administration of the D2-like receptor agonist, quinpirole. In rats fed a control diet, quinpirole at 1 mg/kg i.v. increased k* for AA significantly in 17 regions with high densities of D2-like receptors, of 61 regions examined. Increases in k* were found in the prefrontal cortex, frontal cortex, accumbens nucleus, caudate-putamen, substantia nigra, and ventral tegmental area. Quinpirole, 0.25 mg/kg i.v. enhanced k* significantly only in the caudate-putamen. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, neither 0.25 mg/kg nor 1 mg/kg quinpirole increased k* significantly in any region. Orofacial movements following quinpirole were modified but not abolished by LiCl feeding. The results suggest that downregulation by lithium of D2-like receptor signaling involving PLA2 and AA may contribute to lithium's therapeutic efficacy in bipolar disorder.     

Heteromeric nicotinic acetylcholine-dopamine autoreceptor complexes modulate striatal dopamine release.

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D(2) autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D(2) autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-alpha(7) nACh receptor antagonist dihydro-beta-erythroidine or the D(2-3) receptor agonist quinpirole. Local perfusion of the D(2-3) receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-beta-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D(2) autoreceptor modulating the efficacy of non-alpha(7) nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between beta(2) subunits of non-alpha(7) nicotinic acetylcholine receptors and D(2) autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-alpha(7) nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.     

Opioid receptor-mediated inhibition of dopamine and acetylcholine release from slices of rat nucleus accumbens, olfactory tubercle and frontal cortex

The modulation of the electrically evoked release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) by opioid receptor activation was examined in superfused slices from rat nucleus accumbens, olfactory tubercle, and frontal cortex. In all brain areas examined, [3H]DA release was inhibited by the kappa agonist, U 50,488 (1-100 nM), and this inhibition was fully antagonized by the selective kappa antagonist, norbinaltorphimine (nor-BNI). In the frontal cortex, the mu agonist, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO, 0.01-1 microM), also inhibited the evoked release of tritium. However, further experiments (including the use of the D2-receptor agonist, LY 171555, and the alpha 2-adrenoceptor agonist, oxymetazoline) suggest strongly that in the frontal cortex DAGO only inhibits the release of [3H]catecholamine from noradrenergic nerve terminals, despite the use of desimipramine to prevent the uptake of [3H]DA into these terminals. [14C]ACh release from both the nucleus accumbens and olfactory tubercle, but not from the frontal cortex, was inhibited by DAGO (0.01-1 microM) and the delta agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE, 0.01-1 microM). These inhibitory effects were antagonized by 0.1 microM naloxone but not by 3 nM nor-BNI. The irreversible delta ligand, fentanyl isothiocyanate (FIT, 1 microM), only antagonized the inhibition caused by DPDPE. The results indicate that the inhibitory effects of opioids on the in vitro release of DA from dopaminergic nerve fibres arising from the substantia nigra and the ventral tegmental area are mediated by presynaptic kappa receptors only. In those regions where ACh release is modulated by opioids, the type of opioid receptor involved may depend on the type of neuron, i.e. interneuron or afferent neuron.     

Lesions of the mesotelencephalic dopamine system enhance the effects of selective dopamine D1 and D2 receptor agonists on striatal acetylcholine release.

In vivo microdialysis was used to determine the effects of 6-hydroxydopamine (6-OHDA) lesions of the mesotelencephalic dopamine system on dopamine receptor agonist induced changes in extracellular acetylcholine (ACh) concentrations in the striatum. Such lesions increased the inhibitory effect of a low dose of the D2 receptor agonist quinpirole (0.05 mg/kg s.c.) on striatal ACh release. In addition, 6-OHDA lesions enhanced the facilitatory effect of the selective D1 receptor agonist CY 208-243 on striatal ACh release, enabling a subthreshold (0.2 mg/kg s.c.) dose to increase striatal dialysate concentrations of ACh by over 60%. These results indicate that denervation supersensitivity potentiates both the facilitatory effects of D1 receptor agonists and the inhibitory effects of D2 receptor agonists on striatal cholinergic activity. It was also found that the 6-OHDA lesions reduced basal interstitial ACh concentrations by 75% in the ipsilateral striatum. The later results are consistent with the hypothesis that the prepotent action of dopamine in the forebrain is to enhance striatal ACh release via a D1 receptor mechanism.     

Pharmacological characterization of nicotine-induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse.

In this study, the mechanism of nicotine-induced hippocampal acetylcholine (ACh) release in awake, freely moving rats was examined using in vivo microdialysis. Systemic administration of nicotine (0.4 mg kg(-1), s.c.) increased the levels of ACh in hippocampal dialysates. The nicotine-induced hippocampal ACh release was sensitive to the pretreatment of neuronal nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine (3.0 mg kg(-1), s.c.) and dihydro-beta-erythrodine (DHbetaE; 4.0 mg kg(-1), s.c.) as well as systemic administration of the dopamine (DA) D1 receptor antagonist SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzaz epine; 0.3 mg kg(-1), s.c.). Local perfusion of mecamylamine (100 microM), DHbetaE (100 microM) or SCH-23390 (10 microM) through microdialysis probe did not increase basal hippocampal ACh release. Hippocampal ACh release elicited by systemic administration of nicotine (0.4 mg kg(-1), s.c.) was antagonized by local perfusion of SCH-23390 (10 microM), but not by MEC (100 microM) or DHbetaE (100 microM). Direct perfusion of nicotine (1 mM, but not 0.1 mM) increased hippocampal ACh levels; however, this effect was relatively insensitive to blockade by co-perfusion of either mecamylamine (100 microM) or SCH-23390 (10 microM). These results suggest that nicotine-induced hippocampal ACh release occurs by two distinct mechanisms: (1) activation of nAChRs outside the hippocampus leading to DA release and subsequent ACh release involving a permissive DA synapse, and (2) direct action of nicotine within the hippocampus leading to ACh release via non-DA-ergic mechanism.     

Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens.

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.     

The noradrenaline-dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis

Multi-probe microdialysis was used to investigate the interaction between the release of noradrenaline and dopamine in the medial prefrontal cortex. Retrograde microdialysis was used to stimulate or inhibit the activity of the locus coeruleus for a restricted period of time, and the response of extracellular noradrenaline and dopamine in the ipsilateral and contralateral medial prefrontal cortex was recorded with microdialysis probes. Infusion of clonidine into the locus coeruleus (100 microM for 45 min) suppressed noradrenaline release and slightly inhibited dopamine release in the ipsilateral medial prefrontal cortex. Application of carbachol to the locus coeruleus (100 microM for 45 min) stimulated both the noradrenaline and dopamine release in the ipsilateral medial prefrontal cortex. No changes were seen in the contralateral medial prefrontal cortex. In the ipsilateral nucleus accumbens, extracellular noradrenaline levels increased, but dopamine levels remained unchanged. Application to the locus coeruleus (during 10 min) of the glutamate receptor agonists N-methyl-D-aspartate (NMDA) (300 microM) or kainate (100 microM) strongly increased extracellular noradrenaline and dopamine levels in the ipsilateral medial prefrontal cortex. However, in the contralateral probe the release of dopamine (but not of noradrenaline) was also stimulated. Application of carbachol to the locus coeruleus was used as a model to further investigate the presumed noradrenaline-dopamine interaction. In a series of dual-probe experiments, alpha(1)-, alpha(2)-, and beta-adrenoceptor antagonists (prazosin, idazoxan, propranolol) or a reuptake-inhibitor (nomifensine) was administered during carbachol stimulation of the locus coeruleus. Prazosin and propranolol were administered systemically in a dose of 3 mg/kg, whereas idazoxan (10 microM) and nomifensine (100 microM) were infused into the medial prefrontal cortex. However, none of these pretreatments modified the effects of the control carbachol-infusions. The results did not identify a receptor-interaction or a common reuptake site that explained the presumed interaction between dopamine and noradrenaline in the medial prefrontal cortex. Therefore, the noradrenaline-dopamine interaction hypothesis could not be confirmed or refuted.