Phencyclidine induces D-1 dopamine receptor mediated Fos-like immunoreactivity in discretely localised populations of striatopallidal and striatoentopeduncular neurons in the rat

Phencyclidine (PCP), a non-competitive antagonist of the NMDA subtype of glutamate receptor, which also acts as an indirect dopamine agonist and at sigma sites, can induce a long lasting psychotic state when taken acutely. It is well established that PCP is toxic to specific limbic structures and we have recently demonstrated that it induces apoptosis of a subpopulation of striatal neurons. These neurons lie predominantly in the dorsomedial striatum and project to the globus pallidus. The mechanisms mediating this neuronal death are unclear though manipulations of dopamine transmission can induce striatal c-fos expression and continuous c-fos expression has been implicated in the molecular cascades controlling apoptosis. We accordingly undertook a series of experiments to determine the action of PCP on striatal Fos-like immunoreactivity (FLI). PCP (80 mg/kg, s.c.) elicited FLI in three distinct striatal areas, namely dorsomedial, dorsolateral and the nucleus accumbens. The level of PCP-induced FLI was consistently attenuated by the co-administration of the D-1 antagonist, SCH 23390. Vehicle injections also induced modest levels of FLI in the dorsomedial striatum and the nucleus accumbens which again were attenuated by SCH 23390. The type of striatal neuron in which PCP-induced FLI was determined by the use of a retrograde anatomical tracer. A colloidal gold tracer was thus injected into the major areas of termination of striatal projection neurons prior to the administration of PCP. This procedure demonstrated that the majority of the FLI positive striatal cells were striatopallidal neurons, though some FLI positive striatoentopeduncular neurons were also seen. The potential pharmacological mechanisms underlying the results are discussed. It is argued that the complex pattern of PCP-induced striatal FLI might be accounted for by a differential action upon extracellular dopamine levels whereby they are elevated in some striatal areas and simultaneously reduced in others.     

Characterization of phencyclidine-induced effects on neuropeptide Y systems in the rat caudate-putamen

Multiple administrations of the psychotominetic drug, phencyclidine-HC1 (PCP), decreased striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels in a dose-dependent manner. Single or multiple PCP administrations decreased striatal NPY levels after 10–12 h; levels returned to control 24 h after a single dose or 58 h after multiple doses. In contrast, no significant changes were seen in nigral NPY levels with either acute or multiple-dose PCP treatments. The role of monoamine, σ or opioid receptors in PCP-induced striatal NPY changes was evaluated. When administered alone, the α₁-adrenergic antagonist, prazosin, the σ antagonist, BMY 14802, and the dopamine D₂ antagonist, sulpiride decreased striatal NPY levels; however, only prazosin and the dopamine D₁ antagonist, SCH 23390, significantly attenuated PCP-induced changes. Administration of the γ-aminobutyric acid transaminase (GABA-T) inhibitors, amino-oxyacetic acid (AOAA) or γ-vinyl-GABA (GVG, vigabatrin, MDL 71,754) alone had no effect on striatal NPY-LI levels while administration of these indirect GABA agonists prior to or concurrently with PCP treatment completely blocked PCP-induced changes in striatal NPY-LI levels. The effect of the non-competitive (NMDA) receptor antagonist, MK-801, on striatal NPY-LI content resembled that of PCP and was also blocked by the two indirect GABA agonists. These data suggest that NPY systems are modulated by glutamatergic activity (specifically by the NMDA receptor) and that the interaction between these two transmitter systems is mediated by GABAergic mechanisms.     

A within-subjects microdialysis/behavioural study of the role of striatal acetylcholine in D1-dependent turning.

In rats lesioned with 6-hydroxydopamine (6-OHDA) the effect of the noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, MK-801, the dopamine (DA) D2 receptor agonist quinpirole and the A2A adenosine antagonist SCH 58261 was studied on acetylcholine (ACh) release in the lesioned striatum and contralateral turning behaviour stimulated by the administration of the DA D1 receptor agonist CY 208-243. Administration of CY 208-243 (75, 100 and 200 microg/kg) to 6-OHDA-lesioned rats dose-dependently stimulated ACh release and induced contralateral turning. MK-801 (50 and 100 microg/kg) reduced basal ACh release (max 22%) and did not elicit any turning. MK-801 (50 and 100 microg/kg) potentiated the contralateral turning, but failed to modify the stimulation of ACh release elicited by 100 and 200 microg/kg of CY 208-243. MK-801 (100 microg/kg) prevented the increase in striatal ACh release evoked by the lower dose of CY 208-243 (75 microg/kg) but contralateral turning was not observed. The D2 receptor agonist quinpirole (30 and 60 microg/kg) elicited low-intensity contralateral turning and decreased basal ACh release. Quinpirole potentiated the D1-mediated contralateral turning behaviour elicited by CY 208-243 (100 microg/kg), but failed to affect the increase in ACh release elicited by the D1 agonist. The adenosine A2A receptor antagonist SCH 58261 (1 microg/kg i.v.) failed per se to elicit contralateral turning behaviour. SCH 58261 potentiated the contraversive turning induced by CY 208-243 but failed to affect the increase of ACh release. The results of the present study indicate that blockade of NMDA receptors by MK-801. stimulation of DA D2 receptors by quinpirole and blockade of adenosine A2A receptors by SCH 58261 potentiate the D1-mediated contralateral turning behaviour in DA denervated rats without affecting the action of the D1 agonist on ACh release. These observations do not support the hypothesis that the potentiation of D1-dependent contralateral turning by MK-801, quinpirole or SCH 58261 is mediated by changes in D1-stimulated release of ACh in the striatum.     

Effect of chronic food restriction on Fos-like immunoreactivity (FLI) induced in rat brain regions by intraventricular MK-801

The noncompetitive NMDA antagonist, MK-801, produces stimulant and rewarding effects that are mediated by a combination of dopamine-dependent and -independent mechanisms. It was recently demonstrated that, similar to amphetamine, the rewarding and locomotor effects of intraventricular (i.c.v.) MK-801 are potentiated by chronic food restriction. Because food restriction also increases c-Fos expression induced by i.c.v. amphetamine in several subcortical dopamine (DA) terminal areas, Fos-like immunoreactivity (FLI) induced by i.c.v. MK-801 was evaluated in an effort to identify responses that are common to amphetamine and MK-801 and similarly augmented by food restriction. Unlike amphetamine, MK-801 did not increase FLI in caudate-putamen, bed nucleus of the stria terminalis, or ventral pallidum. Similar to amphetamine, MK-801 increased FLI in cingulate cortex, central nucleus of the amygdala and nucleus accumbens (NAC) core, but in none of these areas was the response augmented by food restriction. In medial prefrontal cortex, retrosplenial cortex, and NAC shell, however, MK-801 induced FLI that was augmented by food restriction. An effect that is common to amphetamine and MK-801 is the augmentation of FLI by food restriction in NAC shell. It is therefore suggested that increased releasability of DA, or upregulation of the D-1 receptor linked signal transduction pathway, in NAC shell may mediate the enhanced behavioral sensitivity of food-restricted subjects to drugs of abuse.     

Alterations in striatal dopamine overflow during rotational behavior induced by amphetamine,phencyclidine, and MK-801

Rats lesioned unilaterally in the medial forebrain bundle with 6-OHDA rotated ipsilateral to the lesion following injections of amphetamine, phencyclidine (PCP), and MK-801. Concurrent measurement of striatal dopamine (DA) in the intact striatum with in vivo microdialysis revealed a dissociation between rotational behavior and alterations in DA overflow induced by the three drugs. Amphetamine produced robust ipsilateral rotational behavior and a substantial elevation in striatal DA (∼130% increase at asymptote). PCP produced comparable increases in rotational behavior, but only ∼30% increase in striatal DA. MK-801 also had a comparable behavioral effect but failed to alter DA overflow in the intact striatum. Since MK-801, a noncompetitive NMDA antagonist which does not enhance extracellular dopamine in the striatum, is able to produce ipsilateral rotational behavior in rats with unilateral nigrostriatal lesions, it is likely that the effects of PCP may also be determined predominantly through NMDA blockade in this model. Synapse 26:218–224, 1997. © 1997 Wiley-Liss Inc.     

On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801

Summary The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.     

Role of striatal acetylcholine on dopamine D1 receptor agonist-induced turning behavior in 6-hydroxydopamine lesioned rats: a microdialysis-behavioral study

The effects of MK-801, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, of quinpirole, a dopamine (DA) D₂ receptor agonist, and of SCH 58261, an A_2A adenosine antagonist, were studied on acetylcholine (ACh) release in the striatum of 6-hydroxydopamine (60HDA) lesioned rats and on turning behavior induced by the administration of the DA D₁ agonist CY 208-243. Administration of CY 208-243 to 60HDA lesioned rats induced turning behavior and dose-dependently stimulated ACh release. At the dose of 50 μg/kg, MK-801 failed to affect basal ACh, while at 100 μg/kg MK-801 reduced it; however, MK-801 (50 and 100 μg/kg) potentiated the turning behavior elicited by CY 208-243, but failed to affect the CY 208-243-induced increase of striatal ACh release. The administration of quinpirole induced low-intensity turning behavior and decreased basal ACh release; on the other hand, quinpirole potentiated the turning behavior induced by CY 208-243, but failed to affect the CY 208-243-elicited increase of ACh release. Finally, intravenous administration of SCH 58261 stimulated basal ACh release but not turning behavior, SCH 58261, however, potentiated turning behavior induced by CY 208-243, while failing to affect the D₁-elicited increase of ACh release. These results indicate that potentiation of D₁-dependent turning behavior by MK-801, quinpirole and SCH 58261 is not mediated by a reduced ability of D₁-agonists to stimulate ACh release from the denervated striatum.     

The role of dopamine in regulation of thyrotropin-releasing hormone in the striatum and nucleus accumbens of the rat.

The effect of alpha-methyl-p-tyrosine (alpha-MT), FLA-63, amphetamine, apomorphine and quinpirole on the concentration of thyrotropin-releasing hormone (TRH) in the striatum and nucleus accumbens was studied in rats. It has been found that the TRH content was increased in both those structures after alpha-MT, an inhibitor of tyrosine hydroxylase which reduced the concentration of both dopamine (DA) and noradrenaline (NA), but not after FLA-63, an inhibitor of DA-beta-hydroxylase which decreased the NA level without affecting DA. On the other hand, the indirectly acting dopaminomimetic amphetamine, the non-selective DA receptor agonist apomorphine, and the selective D2 receptor agonist quinpirole reduced the TRH level in the striatum, but not in the nucleus accumbens. Moreover, the decrease in the striatal peptide content induced by DA-mimetics was antagonized by the selective D2-receptor antagonist sulpiride, but not by the selective D1 receptor antagonist SCH 23390. The effect of amphetamine was not modified by the selective alpha 1-adrenoceptor antagonist prazosin. These results indicate that DA and D2 receptors play a significant role in the regulation of the striatal TRH.     

多巴胺D1和谷氨酸NMDA受体参与调控异动症大鼠纹状体△FosB蛋白的表达

目的研究多巴胺D1和D2受体以及谷氨酸NMDA受体对△FosB蛋白表达水平的影响,由此探讨它们在左旋多巴诱导的异动症(Levodopa-induced Dyskinesia,LID)发病机制中的作用。方法对单侧黑质纹状体6-羟多巴胺(6-OHDA)损毁致帕金森病(PD)大鼠给予左旋多巴治疗28d制作LID模型,将大鼠分为7组:正常对照组、PD组、LID组、SCH23390治疗组、MK-801治疗组、raclopride治疗组和非LID组,分别观察各组行为学改变并进行异常不自主运动(abnormal involuntary movement,AI M)评分,用免疫组化和免疫印迹方法测定各组△FosB蛋白表达水平。结果多巴胺D1受体阻断剂SCH23390和谷氨酸NMDA受体阻断剂MK-801明显减轻LID大鼠行为学异常,而多巴胺D2受体阻断剂raclopride对异常不自主运动无明显影响;LID大鼠损毁侧纹状体△FosB蛋白表达较PD大鼠和非LID大鼠明显增加;与LID大鼠相比,MK-801和SCH23390均使△FosB蛋白表达显著下降,而raclopride没有这种效应;各组大鼠健侧纹状体△FosB蛋白表达水平没有显著差异。结论多巴胺D1受体和谷氨酸NMDA受体均通过参与调控纹状体△FosB蛋白的表达而影响大鼠LID的发生。     

Differential Effects of MK-801 on Brain-Derived Neurotrophic Factor mRNA Levels in Different Regions of the Rat Brain

We have studied the effects of MK-801, a noncompetitive antagonist of N -methyl- -aspartate-type glutamate receptors, on brain-derived neurotrophic factor (BDNF) mRNA levels in the rat brain. MK-801 decreased BDNF mRNA in the hippocampus and in the superficial layers of the cerebral cortex. However, in single cells of the middle layer of the cerebral cortex and the midline thalamic nuclei BDNF mRNA levels were markedly increased by MK-801. The highest density of these cells was found in the limbic cortex, especially in the retrosplenial and medial entorhinal cortex. Pentobarbital (an enhancer of gabaergic functions) and scopolamine (a muscarinic receptor antagonist) blocked the effects of MK-801 on BDNF mRNA levels in the retrosplenial cortex, but the nicotinic and dopaminergic receptor antagonists mecamylamine and haloperidol, respectively, were ineffective. Pilocarpine, a muscarinic cholinergic agonist increased BDNF mRNA in some, but not all, cortical areas, where MK-801 had elicited an increase in BDNF mRNA. Thus, the observations made with MK-801 demonstrate that depending on the neuronal connections and the transmitter systems involved, a given compound can elicit either a decrease or an increase in BDNF mRNA levels. This may open up pharmacological possibilities to a regionally more refined regulation of the neurotrophin synthesis.     

Maturation of locomotor and Fos responses to the NMDA antagonists, PCP and MK-801

Antagonists at the N-methyl-D-aspartate (NMDA)-type glutamate receptor, such as phencyclidine (PCP) and dizocilpine (MK-801), are well-known to evoke increases in locomotor activity in adult rats and mice. However, little is known about the effects of NMDA antagonists on locomotor activity as a function of development. The present study examined locomotor responses to PCP or MK-801 in male rats of varying ages and found that prepubertal rats were more sensitive to the locomotor-elevating effects of PCP (1.5 mg/kg and 3. 0 mg/kg, s.c.) than were adults. Locomotor responses to MK-801 (0.1 and 0.2 mg/kg, s.c.) were not dependent on age. The age-dependent response to PCP may be related to developmental events in the motor cortex, since more Fos-immunoreactive neurons were observed in the motor cortex of prepubertal animals after PCP administration relative to adult animals. An opposite pattern of age-dependent Fos responses was observed in the posterior retrosplenial cortex. The results suggest that locomotor responses to NMDA antagonists can be influenced in an age- and drug-dependent manner and that maturational events in the motor cortex may modify responses to PCP.     

Protection of striatal neurons by joint blockade of D1 and D2 receptor subtypes in an in vitro model of cerebral hypoxia

Massive increases in extracellular dopamine have been reported in the ischemic rodent striatum, implicating this neurotransmitter in toxic events. We have examined whether dopamine receptor antagonists are protective against hypoxic insult, using brain slices containing the rostral striatum obtained from adult male C57/BLIcrfa(t) mice. Slices were subjected in vitro to 20 min nitrogen hypoxia, with or without addition of: (i) 50 microM haloperidol (D2 receptor antagonist and sigma ligand), (ii) 10 microM SCH23390 (selective D1 receptor antagonist), (iii) 10 microM eticlopride (selective D2 receptor antagonist), (iv) 10 microM SCH23390 and 10 microM eticlopride in combination, and (v) 10 microM MK-801 (noncompetitive NMDA receptor antagonist). Subsequently, slices were reoxygenated, fixed 2 h postinsult, and processed for light microscopy. Damage was assessed by calculating pyknotic profiles as a percentage of total neuronal profiles present. No pyknotic profiles were detected in normoxic control tissue, but this phenotype predominated in most slices subject to hypoxia alone (60.1 +/- 30.6% pyknotic profiles). Marked protection was produced by haloperidol (7.1 +/- 7.6%, P = 0.002), MK-801 (8.6 +/- 6.9%, P = 0.007), and the combined application of SCH23390 and eticlopride (5.9 +/- 9.4%, P = 0.001). No protection was demonstrated for SCH23390 or eticlopride when applied separately. These data suggest that hypoxic damage in the rostral mouse striatum is mediated via NMDA, D1, and D2 receptors. Protection against hypoxic damage by dopamine receptor antagonists requires the combined blockade of both classes of dopamine receptor.     

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine

Summary Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK-801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.     

SCH 23390-induced behavioral supersensitivity is not related to striatal c-fos levels

Stereotyped behavior and striatal c-fos levels induced by chronic treatment with the D₁ dopamine antagonist SCH 23390 have been investigated in rats which received subsequent subacute dopamine agonist treatment. SCH 23390 treatment (0.5 mg/kg/day) for 21 days increased both apomorphine-induced orofacial stereotypies and striatal c-fos levels. Treatment with the D₁ dopamine agonist SKF 38393 (10 mg/kg/day) and the combination of SKF 38393 with the D₂ dopamine agonist quinpirole (1 mg/kg/day), for 5 consecutive days, attenuated apomorphine-induced stereotypies without changing c-fos levels in rats previously treated with SCH 23390. These findings suggest that SCH 23390-induced behavioral supersensitivity and the increased striatal c-fos levels are concomitant but unrelated phenomena.     

Selective stimulation of striatal dopamine receptors of the D1- or D2-class causes opposite changes of fos expression in the rat cerebral cortex

It has been suggested that activation of striatal neurons expressing D1 or D2 dopamine receptors elicits opposite changes in the net output of the basal ganglia circuitry and, consequently, in the functional interactions of the circuit with the cerebral cortex. In particular, it has been recently reported that striatal D1 receptors may regulate cortex function. To further address this issue, we mapped cerebral expression of Fos protein following intrastriatal stimulation of D1- or D2-class receptors in freely moving animals. Using permanent cannulas implanted in the right striatum, Sprague-Dawley rats received intrastriatal microinfusions of SKF 38393 (D1 agonist) or quinpirole (D2 agonist) or saline (controls), combined with systemic administration of D1 antagonist SCH 23390 or D2 antagonist eticlopride or saline. Animals treated with SKF 38393 showed dose-dependent, massive Fos increases in the motor, somatosensory, auditory, visual and limbic regions of the cerebral cortex, ipsilaterally to the injected striatum. Consistent Fos expression was also found in the injected striatum and, bilaterally, in the nucleus accumbens shell. These increases were effectively counteracted by systemic SCH 23390. Conversely, quinpirole did not induce significant cortical or striatal expression of Fos, which was instead observed after the systemic administration of eticlopride. Fos was not detected in any of the other basal ganglia nuclei, regardless of the dopamine agonists or antagonists used. Our results confirm that striatal D1 dopamine receptors play a central role in the modulation of cortical activity, thus providing additional information on the functional interaction between basal ganglia circuitry and cerebral cortex.     

Dopamine D1- and D2-dependent catalepsy in the rat requires functional NMDA receptors in the corpus striatum, nucleus accumbens and substantia nigra pars reticulata

This study investigated the anticataleptic activity of MK-801 versus the D₁ antagonist SCH 23390 and the D₂ antagonist raclopride, using the horizontal bar test in the rat. MK-801, 0.2 mg/kg i.p., strongly opposed the cataleptogenic actions of SCH 23390 and raclopride administered systemically (1 and 3 mg/kg i.p., respectively), or directly into the corpus striatum (CS) or nucleus accumbens (NAc; 1 and 10 μg, respectively). Conversely, intraCS and intraNAc pretreatment with MK-801 (10 μg) markedly attenuated the cataleptic response to a systemic injection of SCH 23390 or raclopride. In the latter experiments the anticataleptic effect of MK-801 was pronounced and sustained (>2 h), except with intraCS MK-801 versus raclopride, where it was initially profound but only short-lived (15 min). Stereotaxic injection of MK-801 (1 μg) into the substantia nigra pars reticulata (SNr) prevented catalepsy developing to either dopamine D₁ or D₂ receptor antagonism. These results indicate there must be unimpeded glutamate neurotransmission in the CS and NAc before catalepsy can develop fully to D₁ and D₂ dopamine receptor blockade in these structures. The weaker glutamate–D₂ interaction in the CS than in the NAc may be related to differences in the N-methyl-

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-aspartate receptor subpopulations in these nuclei. Finally, the ability of intranigral MK-801 to diminish both D₁- and D₂-dependent catalepsy suggests the SNr acts as a common output pathway for the expression of both forms of catalepsy in the rat.     

Facilitation of dopaminergic neural transmission does not affect [(11)C]SCH23390 binding to the striatal D(1) dopamine receptors, but the facilitation enhances phosphodiesterase type-IV activity through D(1) receptors: PET studies in the conscious monkey brain.

The present study evaluated the effects of methamphetamine and scopolamine on the striatal dopamine D(1) receptor binding, measured by [(11)C]SCH23390, and D(1) receptor-coupled cAMP messenger system, determined as phosphodiesterase type-IV (PDE-IV) activity, were evaluated in the brains of conscious monkeys using positron emission tomography (PET) with microdialysis. When methamphetamine (0.1, 0.3, and 1 mg/kg) or scopolamine (0.01, 0.03, and 0.1 mg/kg) was systemically administered, [(11)C]SCH23390 binding to D(1) receptors was not affected. With administration of methamphetamine, the striatal PDE-IV activity, as measured with R-[(11)C]rolipram (active form) and S-[(11)C]rolipram (inactive form), was dose-dependently facilitated with enhanced dopamine level in the striatal ECF. Administration of scopolamine also induced facilitated PDE-IV activity without any apparent changes in the ECF dopamine. These facilitations of PDE-IV activity were abolished by preadministration of SCH23390, but not by raclopride. These results demonstrate that, as evaluated by PDE-IV activity, the inhibition of muscarinic cholinergic receptors actually facilitated dopamine neuronal signal transduction through D(1) receptors, as observed previously on D(2) receptors with no apparent increase in the striatal ECF dopamine level, but the enhanced dopamine transmission could not detected by [(11)C]SCH23390.     

Co-administration of either a selective D1 or D2 dopamine antagonist with methamphetamine prevents methamphetamine-induced behavioral sensitization and neurochemical change, studied by in vivo intracerebral dialysis.

Repeated administration of amphetamine or methamphetamine (MAP) causes behavioral sensitization in animals. Recently, several studies have revealed that in vivo release of dopamine from presynaptic nerve terminals of mesotelencephalic dopamine neurons is enhanced when sensitized animals are rechallenged with a psychostimulant. The present study investigated the effect of co-administration of SCH 23390 (a selective D1 dopamine receptor antagonist) or YM-09151-2 (a selective D2 dopamine receptor antagonist) prior to each MAP injection for 14 days on dopamine efflux in the striatal perfusates using in vivo dialysis. After 3 months drug abstinence, MAP challenge alone produced augmented stereotypy in the MAP group, but not in the control, the SCH 23390 + MAP or the YM-09151-2 + MAP group. In parallel with this behavioral observation, the degree to which dopamine efflux increased following the MAP challenge was significantly greater in the MAP group than that in the control, SCH 23390 + MAP group and the YM-09151-2 + MAP groups. While dopamine efflux after MAP challenge did not differ between the control and the YM-09151-2 + MAP group, it was greater in the SCH 23390 + MAP group than the control group. These results indicate that both D1 and D2 dopamine receptors play a role in the formation of behavioral sensitization, but with different mechanisms.     

Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone

Summary. The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP). On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA. These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone. Accepted February 9, 1998; received December 16, 1997     

Antagonism of ceruletide, a cholecystokinin analog, to the neurochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and MK-801, on regional dopaminergic neurons in the rat brain.

In the present study, we investigated the effects of ceruletide (CL), a cholecystokinin analog, on the neurochemical response to non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine (PCP) and MK-801, of the dopaminergic neuron systems in the discrete regions of the rat brain. Systemically administered PCP (7.5 mg/kg, i.p.) or MK-801 (1.0 mg/kg, i.p.) produced significant increases in the tissue contents of dopamine metabolite, homovanillic acid (HVA), in the prefrontal cortex, the nucleus accumbens and the olfactory tubercle but not in the nucleus caudatus putamen after 60 min. The effects of NMDA receptor antagonists in the nucleus accumbens and the prefrontal cortex were partially antagonized by pretreatment with CL (80 and 400 micrograms/kg, i.p., at 60 min prior to the drugs). While CL alone decreased the dopaminergic metabolism only in the nigrostriatal pathways in naive rats, the present results indicated that CL also attenuates the activities of the meso-limbic and meso-cortical dopaminergic neuron systems when these are enhanced by either PCP or MK-801.