Regulation of cholecystokinin mRNA content in rat striatum: a glutamatergic hypothesis.

Changes in the cholecystokinin (CCK) mRNA content in rat striatum after the administration of specific glutamate and dopamine (DA) receptor agonists and antagonists were investigated. MK-801 (1 mg/kg i.p.), a selective noncompetitive N-methyl-D-aspartate (NMDA)-sensitive glutamatergic receptor antagonist, but not 6-cyano-7-nitroquinoxaline-2,3-dione (1.1-9.2 micrograms i.c.v.), a competitive non-NMDA glutamatergic receptor antagonist, produced a time- and dose-dependent decrease in striatal CCK mRNA. The maximum inhibition (50%) was observed after a daily treatment for 1 week with MK-801 (1 mg/kg). The activation of NMDA receptors by a single injection of NMDA (1.4 micrograms i.c.v.) elicited an 80% increase in CCK mRNA in rat striatum 8 hr after the injection. These data suggest that glutamate exerts a tonic regulation on striatal CCK mRNA, mainly through NMDA-sensitive glutamatergic receptors. B-HT 920, a DA D2 receptor agonist and benztropine, a DA uptake blocker, increased striatal CCK mRNA. This increase was partially blocked by the concomitant administration of MK-801. Moreover, the DA receptor antagonist haloperidol, at a dose that per se failed to change CCK mRNA (0.3 mg/kg i.p.), partially blocked the increase in CCK mRNA elicited by NMDA. Similarly, the NMDA effect was attenuated in rats with a 6-hydroxydopamine-induced nigrostriatal lesion. Our findings suggest that in rat striatum a complex DA-glutamate interaction tonically regulates CCK expression via D2 and/or NMDA receptor activation.     

Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies

Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.     

Sex- and estrous cycle-related differences in the effects of acute antipsychotic drug administration on neurotensin-containing neurons in the rat brain

The effects of a single injection of haloperidol (2.0 mg/kg), a typical antipsychotic drug, on neurotensin (NT) concentrations and NT/neuromedin N (NT/NN) mRNA expression in adult female and male rats were examined. There were significant estrous cycle stage-related differences in both NT concentrations and NT/NN mRNA expression in female control rats. Although acute administration of haloperidol increased NT concentrations and NT/NN mRNA expression in the caudate/putamen and nucleus accumbens of both male and female rats, haloperidol did not increase NT/NN mRNA expression during diestrus 2 or NT concentrations during proestrus in the nucleus accumbens of female rats. These results indicate the presence of both sex- and estrous cycle-related differences in the regulation of NT-containing neurons and in the effects of antipsychotic drug administration on the NT system of the rat brain.     

Nicotine reduces antipsychotic-induced orofacial dyskinesia in rats

Antipsychotics are an important class of drugs for the management of schizophrenia and other psychotic disorders. They act by blocking dopamine receptors; however, because these receptors are present throughout the brain, prolonged antipsychotic use also leads to serious side effects. These include tardive dyskinesia, repetitive abnormal involuntary movements of the face and limbs for which there is little treatment. In this study, we investigated whether nicotine administration could reduce tardive dyskinesia because nicotine attenuates other drug-induced abnormal movements. We used a well established model of tardive dyskinesia in which rats injected with the commonly used antipsychotic haloperidol develop vacuous chewing movements (VCMs) that resemble human orofacial dyskinesias. Rats were first administered nicotine (minipump; 2 mg/kg per day). Two weeks later, they were given haloperidol (1 mg/kg s.c.) once daily. Nicotine treatment reduced haloperidol-induced VCMs by ～20% after 5 weeks, with a significant ～60% decline after 13 weeks. There was no worsening of haloperidol-induced catalepsy. To understand the molecular basis for this improvement, we measured the striatal dopamine transporter and nicotinic acetylcholine receptors (nAChRs). Both haloperidol and nicotine treatment decreased the transporter and α6β2* nAChRs (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) when given alone, with no further decline with combined drug treatment. By contrast, nicotine alone increased, while haloperidol reduced α4β2* nAChRs in both vehicle and haloperidol-treated rats. These data suggest that molecular mechanisms other than those directly linked to the transporter and nAChRs underlie the nicotine-mediated improvement in haloperidol-induced VCMs in rats. The present results are the first to suggest that nicotine may be useful for improving the tardive dyskinesia associated with antipsychotic use.     

Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes

Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 muM) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (1 microM), the A(2A) receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (100 nM), and the A(3) receptor agonist N(6)-(3-iodobenzyl)adenosine-5'-methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.     

Neurotensin levels in specific brain regions and hypnotic sensitivity to ethanol and pentobarbital as a function of time after haloperidol administration in selectively bred rat lines

Evidence indicates that sensitivity to ethanol is a good predictor of the development of alcoholism. Thus, identification of neuronal processes that regulate ethanol sensitivity has been the subject of much recent research. The present studies were designed to further test the hypothesis that neurotensinergic processes mediate, in part, hypnotic sensitivity to ethanol. Single doses of haloperidol were administered to lines of rats [selectively bred for high and low sensitivity (HAS and LAS, respectively) to hypnotic effects of ethanol] to produce increases in neurotensin (NT) levels in brain regions. At 20 h after administration, haloperidol produced dose-dependent increases in NT immunoreactivity levels in nucleus accumbens (NA) and caudate putamen (CP) in both HAS and LAS lines. Levels of NT in NA and CP returned to control values at 48 h after 4 mg/kg haloperidol. These studies used two measures of hypnotic sensitivity to ethanol: duration of loss of righting reflex (sleep time) and blood ethanol concentration at regain of righting reflex (BECRR). At 20 h, but not 48 h, after haloperidol treatment, both HAS and LAS rats displayed increases in ethanol-induced sleep time with concomitant decreases in BECRR. Pentobarbital-induced sleep time was not increased 20 h after administration of 4 mg/kg haloperidol; however, hypnotic sensitivity to both pentobarbital and ethanol was increased by acute (30-min) pretreatment with 1 mg/kg. These results suggest that NT levels in NA, acting via NT receptors, enhance hypnotic sensitivity to ethanol, but not pentobarbital.     

Pharmacological characterization of a novel, potent adenosine A1 and A2A receptor dual antagonist, 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in models of Parkinson's disease and cognition

Central adenosine A(2A) receptor is a promising target for drugs to treat Parkinson's disease (PD), and the central blockade of adenosine A(1) receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A(1) and A(2A) dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A(1) and A(2A) receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A(1) and A(2A) agonist-induced increases of intracellular Ca(2+) concentration. ASP5854 ameliorated A(2A) agonist 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680)- and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and it also improved haloperidol-induced catalepsy in rats at doses higher than 0.1 mg/kg. In unilateral 6-hydroxydopamine-lesioned rats, ASP5854 significantly potentiated l-dihydroxyphenylalanine (L-DOPA)-induced rotational behavior at doses higher than 0.032 mg/kg. ASP5854 also significantly restored the striatal dopamine content reduced by 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in mice at doses higher than 0.1 mg/kg. Furthermore, in the rat passive avoidance test, ASP5854 significantly reversed the scopolamine-induced memory deficits, whereas the specific adenosine A(2A) antagonist 8-((E)-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine- or 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801)-induced impairment of spontaneous alternation in the mouse Y-maze test was ameliorated by ASP5854, whereas KW-6002 did not exert improvement at therapeutically relevant dosages. These results demonstrate that the novel, selective, and orally active dual adenosine A(1) and A(2A) receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A(2A) antagonism, and also enhances cognitive function through A(1) antagonism.     

The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu?), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu? PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu? in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu? PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu? PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu? PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists.     

Cooperation of NMDA and tachykinin NK(1) and NK(2) receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5 M HCl or saline. IG HCl caused many neurons in the NTS and some neurons in the AP to express c-fos mRNA. The NMDA glutamate receptor antagonist MK-801 (2 mg/kg), the NK(1) tachykinin receptor antagonist GR-205,171 (3 mg/kg) and the NK(2) receptor antagonist SR-144,190 (0.1 mg/kg) failed to significantly reduce the NTS response to IG HCl, whereas the triple combination of MK-801, GR-205,171 and SR-144,190 inhibited it by 45--50%. Only in rats that had been preexposed IG to HCl 48 h before the experiment was MK-801 alone able to depress the NTS response to IG HCl. In contrast, the c-fos mRNA response in the AP was significantly augmented by MK-801, an action that was prevented by coadministration of GR-205,171 plus SR-144,190. Inhibition of neuronal nitric oxide synthase with 7-nitroindazole (45 mg/kg) was without effect on the IG HCl-evoked c-fos mRNA expression in the NTS and AP. Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK(1) and NK(2) receptors cooperate in the vagal afferent input from the acid-threatened stomach to the NTS and participate in the processing of afferent input to the AP in a different and complex manner. These opposing interactions in the AP and NTS and the increase in NMDA receptor function in the NTS after a gastric acid insult are likely to have a bearing on the neuropharmacology of dyspepsia.     

Dosing time-dependent tolerance of catalepsy by repetitive administration of haloperidol in mice

To investigate the effect of repeated administration time on the development of tolerance, male ICR mice, housed under 12:12-h light/dark cycle (7:00 AM, lights on), were treated with haloperidol 4 mg/kg/day i.p. at 9:00 AM or 9:00 PM, the time nearly corresponding to the maximal or minimal catalepsy responses to a single dose, respectively, for 14 days and catalepsy responses were monitored at 1 h after administration each day. The findings indicated that, on day 1 to day 6, a greater development of tolerance was seen in the group of mice treated at 9:00 AM, and catalepsy behavior exhibited a significant difference between the two dosing times (P < 0.01). The study of D(2) receptor mRNA expression in mouse striatum revealed that the phase of D(2) receptor mRNA rhythm was similar to that of catalepsy response, with the maximum around mid-light and the minimum around mid-dark. After repeated administration, the increase in D(2) receptor mRNA levels in mice treated with haloperidol at 9:00 AM was higher than that of mice treated with haloperidol at 9:00 PM. In addition, from a [(3)H]spiperone binding study, the amount of binding site [(3)H]spiperone after repeated injection of haloperidol at 9:00 AM was greater than that after repeated injection at 9:00 PM. These findings demonstrate the importance of dosing time on the susceptibility to extrapyramidal effects and the relation of administration time to D(2) receptor change and tolerance.     

Effects of acute and subchronic administration of typical and atypical antipsychotic drugs on the neurotensin system of the rat brain

The acute and subchronic effects of a variety of doses of a prototype typical (haloperidol) or one of several atypical antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine, or sertindole) on regional brain neurotensin (NT) tissue concentrations, and NT receptor binding were examined. Acute administration of haloperidol, clozapine, olanzapine, and risperidone dose-dependently increased NT tissue concentrations in the nucleus accumbens. Haloperidol, olanzapine, risperidone, and sertindole also increased NT tissue concentrations in the caudate nucleus. NT tissue concentrations in the nucleus accumbens and caudate remained elevated after 14-day administration of haloperidol, olanzapine, sertindole, and risperidone. In contrast, at the doses studied, quetiapine decreased NT tissue concentrations in the nucleus accumbens; clozapine had no effect. Haloperidol significantly increased NT receptor binding in the substantia nigra after 14-day administration. All of the atypical antipsychotic drugs decreased NT receptor binding in the nucleus accumbens and in the substantia nigra. Although these studies do not conclusively support the hypothesis that increased NT neurotransmission is involved in the clinically relevant effects of all antipsychotic drugs, the extant evidence clearly suggests that further study is warranted. Inconsistencies in the data suggest that differential effects of antipsychotic drug administration on subpopulations of NT neurons must be scrutinized further.     

Activation of adenosine₁ receptors induces antidepressant-like, anti-impulsive effects on differential reinforcement of low-rate 72-s behavior in rats

Stress and psychiatric illness have been associated with a dysregulation of glutamatergic neurotransmission. Recently, positive allosteric modulators (PAMs) of the metabotropic glutamate 2 (mGlu?) receptor have been found to exert antidepressant-like activity in rats performing under a differential reinforcement of low rate (DRL) 72-s schedule. An autoreceptor role at glutamatergic synapses is the most salient physiological role played by the mGlu? receptor. Adenosine A? receptors play a heteroreceptor role at many of the same forebrain synapses where mGlu? autoreceptors are found. Agonists and/or PAMs of mGlu? receptors act similarly to adenosine A? receptor agonists with respect to a wide range of electrophysiological, biochemical, and behavioral responses mediated by limbic circuitry thought to play a role in the pathophysiology of neuropsychiatric disease and to mediate therapeutic drug effects. Therefore, the role of adenosine A? receptor activation on rat DRL 72-s behavior was explored to provide preclinical evidence consistent or inconsistent with potential antidepressant effects. The adenosine A? receptor agonist N?-cyclohexyladenosine (CHA) increased the reinforcement rate, decreased the response rate, and induced a rightward shift in inter-response time distributions in a dose-dependent fashion similar to most known antidepressant drugs. The adenosine A? receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) blocked these antidepressant-like effects. These novel observations with CHA and DPCPX suggest that activation of adenosine A? receptors could contribute to antidepressant effects, in addition to previous preclinical reports of anxiolytic and antipsychotic effects. By implication, targeting a dysregulated glutamatergic system may be an important principle in discovering novel antidepressant agents that may also possess anti-impulsive activity.     

Sigma receptor "antagonist" BMY 14802 increases neurotensin concentrations in the rat nucleus accumbens and caudate

Acute and chronic treatment with antipsychotic drugs, such as haloperidol, selectively increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate of the rat. These increases in NT concentration in the nucleus accumbens and caudate have been hypothesized to underlie the therapeutic and extrapyramidal effects of antipsychotic drugs, respectively. The present study evaluates the effects of the putative antipsychotic and selective sigma receptor "antagonist" BMY 14802 on regional brain NT concentrations. NT concentrations in discrete brain regions of adult, male, Sprague-Dawley rats were measured by a sensitive and specific radioimmunoassay. Like haloperidol (1 mg/kg i.p.), acute and chronic treatment with BMY 14802 (35 mg/kg/day i.p.) produced significant increases in the concentrations of NT in the nucleus accumbens and anterior and posterior caudate. This effect was dose-dependent. Maximal increases in NT concentration were observed 18 hr after a single dose of BMY 14802. Neither acute nor chronic treatment with the sigma "agonist" (+)-SKF 10,047 (20 mg/kg i.p.), the N-methyl-D-aspartate-phencyclidine binding site antagonist MK-801 (0.25 mg/kg i.p.) or the selective D2 antagonist sulpiride (100 mg/kg i.p.), produced the pattern of NT alterations observed after the administration of BMY 14802. These findings suggest that the blockade of sigma receptors modulates NT concentrations in these brain regions.     

Effect of omeprazole on gastric adenosine A1 and A2A receptor gene expression and function

Adenosine has been shown to inhibit immunoreactive gastrin (IRG) release and to stimulate somatostatin-like immunoreactivity (SLI) release by activating adenosine A(1) and A(2A) receptors, respectively. Since the synthesis and release of gastrin and somatostatin are regulated by the acid secretory state of the stomach, the effect of achlorhydria on A(1) and A(2A) receptor gene expression and function was examined. Omeprazole-induced achlorhydria was shown to suppress A(1) and A(2A) receptor gene expression in the antrum and corporeal mucosa, but not in the corporeal muscle. Omeprazole treatment produced reciprocal changes in A(1) receptor and gastrin gene expression, and parallel changes in A(2A) receptor and somatostatin gene expression. The localization of A(1) and A(2A) receptors on gastrinsecreting G-cells and somatostatin-secreting D-cells, respectively, suggests that changes in adenosine receptor expression may modulate the synthesis and release of gastrin and somatostatin. Thus, the effect of omeprazole on adenosine receptor-mediated changes in IRG and SLI release was also examined in the vascularly perfused rat stomach. After omeprazole treatment, the A(1) receptor-mediated inhibition of IRG and SLI release induced by N(6)-cyclopentyladenosine (A(1) receptor-selective agonist) was not altered, but the A(2A) receptor-mediated augmentation of SLI release induced by 2-p-(2-carboxyethyl-)phenethylamino-5'-N-ethylcarboxamidoadenosine (A(2A)-selective agonist) was significantly attenuated. These findings agree well with the corresponding omeprazole-induced decrease in antral A(2A) receptor mRNA expression. Overall, the present study suggests that adenosine receptor gene expression and function may be altered by omeprazole treatment. Acid-dependent changes in adenosine receptor expression may represent a novel purinergic regulatory feedback mechanism in controlling gastric acid secretion.     

Low-level N-methyl-D-aspartate receptor activation provides a purinergic inhibitory threshold against further N-methyl-D-aspartate-mediated neurotransmission in the cortex.

N-methyl-D-aspartate (NMDA) is 33 times more potent at releasing adenosine than it is at releasing [3H]norepinephrine from slices of rat parietal cortex. Consequently, maximal adenosine release occurs at levels of NMDA receptor activation which release little norepinephrine. The potential modulatory role of the adenosine released during NMDA receptor activation on NMDA-evoked [3H]norepinephrine release was investigated. The A1-selective agonist R-(-)N6-(2-phenylisopropyl)adenosine (10 microM) decreased 100 microM NMDA-evoked [3H]norepinephrine release by 27%; this was reversed by the P1 antagonist 8-phenyltheophylline (8-PT, 10 microM), indicating that NMDA-evoked norepinephrine release from cortical slices is susceptible to purinergic modulation. On the other hand, 8-PT had no effect on [3H]norepinephrine release evoked by 100 microM NMDA, suggesting that endogenous adenosine, released during NMDA receptor activation, does not modulate [3H]norepinephrine release. However, [3H]norepinephrine release precedes adenosine release, so that the released adenosine may not be temporally available to modulate [3H]norepinephrine release. Pretreatment with a concentration of NMDA (10 microM) which releases substantial endogenous adenosine, but very little [3H]norepinephrine decreased subsequent 100 microM NMDA-evoked [3H]norepinephrine release by 52%. 8-PT partially reversed this inhibition, indicating that prereleased adenosine, acting at P1 purinoceptors, modulated subsequent NMDA-evoked [3H]norepinephrine release. These results suggest that adenosine, released during submaximal NMDA receptor activation, may provide an inhibitory threshold which must be overcome in order for other NMDA-mediated processes to proceed maximally.     

Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases

Clozapine is an atypical antipsychotic that has a unique clinical profile that distinguishes it from other typical and atypical antipsychotics. At present, the underlying mechanisms of action of clozapine are unclear. Recent studies in the field of schizophrenia suggest that compounds that potentiate N-methyl-d-aspartate (NMDA) receptor function in the appropriate brain regions might be an effective antipsychotic agent. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. Therefore, we investigated the regulation of NMDA receptor currents and excitatory postsynaptic currents (EPSCs) by clozapine in nucleus accumbens neurons. Whole-cell patch-clamp recordings were performed in rat brain slices. We demonstrate that bath application of clozapine but not haloperidol or the selective 5-hydroxytryptamine 2A antagonist MDL100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluoro-phenyl)ethyl]-4-piperidine methanol] induces a robust potentiation of NMDA-evoked currents and of glutamatergic EPSCs and that this potentiation is dependent on dopamine release and postsynaptic activation of D1 receptors. Furthermore, the effect of clozapine is selective for NR2B subtype-containing NMDA receptors and is blocked by the selective Src family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and the protein kinase A-selective inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide but not by the protein kinase C-selective inhibitor bisindolylmaleimide I. This effect of clozapine in the nucleus accumbens might underlie the unique clinical profile of this atypical antipsychotic and provides a basis for novel treatment approaches.     

Dipyridamole in the treatment of schizophrenia: adenosine-dopamine receptor interactions

OBJECTIVE: There is growing interest in investigating the adenosine-dopamine interaction in the ventral striatum. Adenosine plays a role opposite to dopamine in the striatum and adenosine antagonists, like caffeine, produce similar effects to increased dopaminergic neurotransmission in the striatum. In particular, a strong antagonistic interaction between adenosine A2A and dopamine D2 receptors takes place in the striopallidal GABAergic neurones. Therefore, adenosine agonists or uptake inhibitors provide a potential new treatment for schizophrenia. We undertook a pilot trial to investigate whether the combination of haloperidol with dipyridamole, an uptake inhibitor of adenosine, was more effective than haloperidol alone. METHODS: Thirty patients who met the DSM IV criteria for schizophrenia completed the study. Patients were allocated in a random fashion, 16 to haloperidol 20 mg/day plus dipyridamole 75 mg/day and 14 to haloperidol 20 mg/day plus placebo. RESULTS: Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of haloperidol and dipyridamole was significantly better than haloperidol alone in decreasing positive and general psychopathology symptoms as well as PANSS total scores. CONCLUSION: Dipyridamole may be of therapeutic benefit in treating schizophrenia in combination with neuroleptics. However, a larger study to confirm our results is warranted.     

Protective effect of rutin, a polyphenolic flavonoid against haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes

The occurrence and irreversibility of tardive dyskinesia (TD), a motor disorder of the orofacial region, resulting from chronic neuroleptic treatment has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism underlying the pathophysiology of TD is not completely known. Several animal studies have demonstrated an enhancement of oxidative damage and increased glutamatergic transmission after chronic administration of neuroleptics. The present study investigated the effect of rutin, an antioxidant in haloperidol-induced orofacial dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypic rearing, locomotor activity, percent retention), biochemical [lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase)] and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements, tongue protrusions and facial jerking in rats, which were significantly inhibited by rutin. Chronic administration of haloperidol also resulted in dopamine receptor sensitivity as evident by a well-shaped response (initial decrease followed by increase) in locomotor activity and stereotypic rearing and also decreased percent retention time on elevated plus maze paradigm. Pretreatment with rutin reversed these behavioural changes. Besides, haloperidol also induced oxidative damage in all regions of brain which was prevented by rutin, especially in the subcortical region containing striatum. Although turnover of dopamine and noradrenaline decreased in both cortical and subcortical regions after chronic administration of haloperidol, it was significantly reversed by high-dose rutin treatment. The findings of the present study suggested the involvement of free radicals in the development of neuroleptic-induced orofacial dyskinesia, a putative model of TD, and rutin as a possible therapeutic option to treat this hyperkinetic movement disorder.     

Dopamine and neurotensin storage in colocalized and noncolocalized neuronal populations

The effects of reserpine on dopamine (DA) and neurotensin (NT) levels were studied in four different brain regions of the rat. Reserpine (0.5-5.0 mg/kg i.p., 6, 18, 48 and 72 hr) produced a dose- and time-dependent decrease in both DA and NT levels in the prefrontal cortex, a brain region innervated by a mixed DA/NT projection. The effect of reserpine was not mimicked by alpha-methylparatyrosine (200 mg/kg i.p.) pretreatment. Furthermore, the reserpine-induced decline in prefrontal cortex DA and NT levels occurred after gamma-butyrolactone (GBL)-induced inhibition of impulse flow (750 mg/kg i.p.). In contrast, in the nucleus accumbens and striatum, regions which contain colocalized (nucleus accumbens) and intrinsic (striatum and nucleus accumbens) neurotensin perikarya, reserpine produced declines in DA and increases in NT levels. alpha-Methylparatyrosine decreased striatal and nucleus accumbens DA levels without altering NT levels in these structures. GBL produced an increase in DA levels in the nucleus accumbens and striatum while decreasing nucleus accumbens and striatal NT levels. Reserpine attenuated the decline in nucleus accumbens and striatal NT levels produced by GBL. In the periaqueductal grey, a brain region densely innervated by NT which has a small population of DA perikarya, reserpine had no effect on NT levels. Because there is no known colocalization of DA and NT in the striatum, the increases in striatal NT levels after depletion of DA may indicate that striatal DA afferents control the release and/or synthesis of NT within NT cells in the striatum, thus leading to alterations in striatal tissue levels.(ABSTRACT TRUNCATED AT 250 WORDS)