6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding

Behavioral responses to D1 and D2-dopamine agonists are enhanced when these agonists are administered systemically to 6-hydroxydopamine (6-OHDA)-lesioned rats. In the present investigation, microinjection of SKF-38393, a D1-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-OHDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY-171555, a D2-agonist, elicited less locomotor activity than did SKF-38393 after microinjection into this site. Administration of SKF-38393 or LY-171555 into the nucleus accumbens did not increase locomotion in unlesioned rats at the doses administered to lesioned animals. In adult-6-OHDA-lesioned rats, microinjection of SKF-38393 into the nucleus accumbens also increased locomotion more than did LY-171555. As described previously, systemic administration of SKF-38393 produced little locomotion in adult-6-OHDA-lesioned rats, whereas LY-171555 produced a markedly enhanced response. Administration of SKF-38393 or LY-171555 into the caudate nucleus of neonatally and adult-6-OHDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors occurred to a greater degree in the 6-OHDA-lesioned rats than in unlesioned controls. A regional specificity for certain behaviors induced by dopamine agonist administration was observed. In spite of the enhanced behavioral responses of D1 and D2-dopamine agonists after microinjection into the brain of 6-OHDA-lesioned rats, binding of [3H]spiperone (D2-receptor antagonist ligand) and [3H]SCH 23390 (D1-receptor antagonist ligand) to tissue from striatum and nucleus accumbens was not altered significantly. In contrast to this lack of change in binding characteristics in 6-OHDA-lesioned rats, blockade of dopaminergic transmission with haloperidol treatment caused an elevation of [3H]spiperone binding sites in striatum without affecting affinity for the site. However, chronic haloperidol treatment did not alter significantly [3H]SCH 23390 binding to striatal membranes. These latter findings suggest that chronic dopamine receptor blockade need not produce the same adaptive mechanisms as destruction of dopamine-containing neurons. Thus, a change in receptor characteristics as measured by dopamine antagonist binding does not account for the behavioral supersensitivity observed after D1- and D2-dopamine agonist administration to neonatally or adult-6-OHDA-treated rats.     

Neuromedin N mimics the actions of neurotensin in the ventral tegmental area but not in the nucleus accumbens

Neuromedin N (NN) is a hexapeptide recently isolated from porcine spinal cord that shares a four-amino acid homology with the C-terminus of the biologically active tridecapeptide neurotensin (NT). Microinjection with NT into the ventral tegmental area or nucleus accumbens of rats has been shown to increase locomotor activity and dopamine (DA) metabolism in some limbic areas or to inhibit the motor stimulant effect of intra-accumbens administration of DA, respectively. In this study the effects of microinjected NN were compared with those of NT. After injection into the ventral tegmental area, NN was shown to be more potent than NT at increasing spontaneous motor activity and to produce an increase in DA metabolism in the nucleus accumbens, prefrontal cortex, diagonal band of Broca and septum. However, when injected into the nucleus accumbens, NN was markedly less potent than NT at inhibiting DA-induced behavioral hyperactivity. In addition to DA-related effects, i.c.v. injection with NT causes hypothermia, and i.c.v. administration with NN was without effect on colonic temperature. These data demonstrate that NN has a behavioral profile distinct from that of NT.     

Characterization of [3H]quinpirole binding to D2-like dopamine receptors in rat brain.

The putative D2 dopamine receptor agonist quinpirole (LY 171,555) is the most widely used D2 agonist in in vivo and in vitro studies of D2 receptor-mediated effects. In addition, quinpirole may have even higher affinity for the recently described D3 dopamine receptor. The present study describes the in vitro binding properties of newly developed [3H]quinpirole in rat brain. [3H]Quinpirole binding was characterized in striatal membrane homogenate preparations using a filtration assay. Nonspecific binding was defined by 1 microM (+)-butaclamol. Specific [3H]quinpirole binding was saturable, and dependent on temperature, membrane concentration, sodium concentration and guanine nucleotides. Saturation analysis revealed high affinity binding characteristics (KD = 2.3 +/- 0.3 nM) which were confirmed by association-dissociation kinetics. The pharmacological profile of [3H]quinpirole binding in striatum was: (-)-N-n-propylnorapomorphine (+/-)-2-amino-6,7-dihydroxyl-1,2,3,4-tetrahydronaphthalene greater than or equal to quinpirole greater than apomorphine greater than bromocriptine greater than dopamine greater than SKF 38393 much greater than 5-hydroxytryptamine for putative dopamine agonists; spiperone greater than (+)-butaclamol greater than haloperidol greater than (-)-sulpiride greater than clozapine greater than SCH 23390 much greater than cinanserin for antagonists. [3H]Quinpirole binding exhibited stereoselectivity: (-)-sulpiride greater than (+)-sulpiride and (+)-butaclamol greater than (-)-butaclamol. This pharmacological profile is similar, though-not identical, to that observed for [3H] spiperone-labeled D2 receptors. The regional distribution of [3H]quinpirole binding sites roughly paralleled the distribution of [3H]spiperone binding sites, with greatest densities present in the striatum, nucleus accumbens and olfactory tubercles.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Chronic treatment with SCH 23390 and haloperidol: effects on dopaminergic and serotonergic mechanisms in rat brain

Effects of chronic administration (18 days) with SCH 23390 (0.1 or 0.5 mg/kg/day s.c.) and haloperidol (1 mg/kg/day s.c.) on dopamine and serotonin synthesis and metabolism in discrete dopaminergic and serotonergic nuclei of rat brain were studied. Additionally, the effects of these treatments on dopamine D-1 and D-2 receptor characteristics in rat caudate-putamen were investigated. Chronic administration with both dose regimens of SCH 23390 decreased DA metabolism significantly (basal homovanillic acid concentrations) in nucleus caudatus. In another set of experiments dopamine synthesis (rate of accumulation of 3,4-dihydroxyphenylalanine after 3,4-dihydroxyphenylalanine-decarboxylase inhibition) was reduced significantly only in nucleus accumbens after the higher SCH 23390 dose regimen. In turn, chronic administration with haloperidol decreased basal dopamine metabolism and synthesis in nucleus caudatus and nucleus accumbens. Chronic haloperidol, but not SCH 23390, treatment induced a clear-cut increase in [3H]spiperone binding in caudate-putamen. Interestingly, neither SCH 23390 nor haloperidol treatments affected [3H]SCH 23390 binding in caudate-putamen. SCH 23390 and haloperidol had no significant effects on serotonin synthesis and metabolism in serotonergic and dopaminergic areas. In conclusion, the classical antipsychotic drug, haloperidol, clearly decreases dopamine turnover in nigrostriatal and mesolimbic dopaminergic systems. The D-1 antagonist, SCH 23390, also decreases dopaminergic activity in nigrostriatal and mesolimbic systems although DA synthesis and metabolism are affected to different degrees in nucleus caudatus and nucleus accumbens. Therefore, we suggest that if D-1 antagonists such as SCH 23390 show antipsychotic activity in clinical studies, they may not be free of extrapyramidal side-effects.     

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.     

金童颗粒治疗抽动秽语综合征模型小鼠的药效学研究

目的观察金童颗粒治疗实验性抽动秽语小鼠模型的药效学作用。方法采用苯丙胺腹腔注射及阿朴吗啡皮下注射方法建立拟抽动小鼠模型，将动物随机分为正常对照组、模型组、金童颗粒大、小剂量组和氟哌啶醇对照组，观察动物的自主活动和攀爬行为，检测动物脑纹状体内多巴胺及其代谢产物的含量。结果在苯丙胺模型中，金童颗粒组小鼠的自主活动和纹状体内多巴胺含量低于模型组（P〈0．05）；在阿朴吗啡模型中，金童颗粒组小鼠异常攀爬时间较模型组缩短（P〈0．05）。结论金童颗粒能够改善拟抽动模型小鼠异常增高的自主活动，降低其纹状体内多巴胺含量。     

Effects of thioridazine and its metabolites on dopaminergic function: drug metabolism as a determinant of the antidopaminergic actions of thioridazine

The antidopaminergic properties of thioridazine (THD) and its major metabolites were evaluated using in vitro and in vivo estimates of dopaminergic function. THD-2-sulfone was more potent than, and THD-2-sulfoxide equipotent to, THD in displacing [3]spiperone from rat striatal membranes and in inhibiting dopamine-stimulated cyclic adenosine 3',5'-monophosphate synthesis in rat striatal homogenates. Other major THD metabolites were relatively inactive. These in vitro data suggest that THD, THD-2-sulfone and THD-2-sulfoxide are potent dopamine receptor blocking agents. Intraperitoneally administered THD antagonized amphetamine-induced locomotion and also increased the concentration of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in terminals of the nigrostriatal dopamine system. Conversely, THD administered i.c.v. into conscious animals, did not antagonize amphetamine-induced locomotion nor increase brain regional concentrations of DOPAC or HVA. On the other hand, the i.c.v. administration of THD-2-sulfone and THD-2-sulfoxide dose-dependently inhibited amphetamine-induced locomotion and also increased the concentrations of HVA and/or DOPAC in the striatum and olfactory tubercles. These apparently discrepant in vitro and in vivo data suggest that the biotransformation of THD is a major determinant in those actions of THD attributed to a blockade of dopamine receptors in the central nervous system.     

Tachykinin gene expression in rat limbic nuclei: modulation by dopamine antagonists

The content and nature of the preprotachykinin (PPT; i.e., substance P/neurokinin A-encoding) messenger RNAs (mRNAs) present in rat brain striatum and limbic tissues were determined by RNA protection experiments. The rank order of PPT mRNA concentration was striatum greater than nucleus accumbens much greater than bed nucleus of the stria terminalis greater than hypothalamus, amygdala and septum. The proportion of beta-(full length) to gamma-(minus exon 4) PPT mRNA was invariant (40/60) among the tissues tested. Because these brain regions receive prominent dopaminergic innervations, the effects of repeated treatment with dopamine antagonists (antipsychotic drugs) on PPT gene expression were assessed. The prototypical dopamine antagonists haloperidol and chlorpromazine decreased striatal PPT mRNA, had no effect on PPT mRNA in the nucleus accumbens or bed nucleus of the stria terminalis, and increased septal PPT mRNA levels. In contrast, the atypical antipsychotic drugs clozapine and l-sulpiride did not alter striatal or septal PPT mRNA, but increased PPT mRNA content in the nucleus accumbens and bed nucleus. The correlation between the effects of typical and atypical antipsychotic drugs on rat striatal and limbic PPT gene expression and their clinical side effects and therapeutic efficacy is discussed.     

Effect of nialamide on the metabolism of dopamine injected into the nucleus accumbens of old rats

We have reported previously that after nialamide pretreatment there is an age-related difference in the stimulation of locomotor activity produced by the injection of dopamine bilaterally into the nucleus accumbens. Thus, the stimulation of locomotor activity produced by dopamine in old rats was significantly less than that of young and mature rats. The purpose of the present study was to determine whether nialamide was an effective inhibitor of the metabolism of dopamine after dopamine was injected into the nucleus accumbens of old rats. When we measured the concentration of injected dopamine in the limbic forebrain (nucleus accumbens and olfactory tubercle) of young (6 months), mature (15 months) and old (26 months) rats pretreated with nialamide, the amount of dopamine that was present was significantly less in old rats than in young or mature rats. Consistent with this observation, the concentrations of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid were higher in nialamide-pretreated old rats than in young and mature rats, suggesting that there was a smaller inhibition of the metabolism of dopamine in the limbic forebrain of old rats after nialamide pretreatment. In support of this hypothesis, nialamide (25-100 mg/kg i.p.), which inhibited monoamine oxidase activity in limbic forebrain homogenates of old, mature and young rats, was a less effective inhibitor of this enzyme in the old rats. These results suggest that the reduced locomotor activity response of old rats to the intra-accumbens injections of dopamine after nialamide pretreatment may be due to the reduced ability of nialamide to inhibit monoamine oxidase (and dopamine metabolism) in these animals.     

Endogenous opioids in dopaminergic cell body regions modulate amphetamine-induced increases in extracellular dopamine levels in the terminal regions

Opioid antagonists attenuate behavioral effects of amphetamine and amphetamine-induced increases in extracellular dopamine levels in nucleus accumbens and striatum of rats but do not alter those effects of cocaine. This study was performed to determine 1) if the effect of opioid antagonists on the dopamine response to amphetamine is mediated in either the terminal or cell body region of the nigrostriatal and mesolimbic pathways, and 2) if the enkephalinase inhibitor thiorphan, which slows degradation of endogenous opioid peptides, increases the dopamine response to amphetamine but not to cocaine. Microdialysis probes were placed either into a dopaminergic terminal region or into both a terminal and cell body region of rats. Naloxone methiodide (1.0 microM), a lipophobic opioid antagonist, was administered into either the terminal or cell body region by reverse dialysis, whereas extracellular dopamine was collected in the terminal region. Increases in extracellular dopamine in nucleus accumbens and striatum caused by amphetamine (0.1-6.4 mg/kg, s.c.) were reduced significantly (28-39%) by naloxone methiodide administered into either substantia nigra or ventral tegmentum but not into terminal regions. Thiorphan (10 microM) administered into substantia nigra increased significantly the dopamine response to amphetamine in the ipsilateral striatum by as much as 42% but did not affect the dopamine response to cocaine (3.0-56 mg/kg, i.p.). These results suggest that amphetamine promotes release of endogenous opioids, which, through actions in the ventral tegmentum and substantia nigra, contribute to amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and striatum.     

Antipsychotic-like profile of thioperamide, a selective H3-receptor antagonist in mice

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.     

Dopamine D(3) receptors modulate evoked dopamine release from slices of rat nucleus accumbens via muscarinic receptors, but not from the striatum

It is not clear whether dopamine D(3) receptor contributes to the regional difference in dopamine antagonist-induced increase in the evoked dopamine release from the nucleus accumbens and striatum. We investigated the regional differences in augmentation of electrically evoked dopamine release induced by preferential dopamine D(2) or D(3) receptor antagonists from slices of the rat striatum and nucleus accumbens. Haloperidol, a preferential dopamine D(2) receptor antagonist, enhanced the evoked dopamine release from both the striatum and nucleus accumbens. Preferential dopamine D(3) antagonists, cis-(+)-(1S, 2R)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin HCl [(+)-UH232] and 5,6-dimethoxy-2-(di-n-propylamine)indan (U-99194A) resulted in a greater increase in the evoked dopamine released from the nucleus accumbens compared with that from the striatum. Moreover, U-99194A attenuated the quinpirole-induced reduction of evoked dopamine release from the nucleus accumbens but not from the striatum. When slices were superfused with pirenzepine, a muscarinic receptor antagonist, the increase in the evoked dopamine release by (+)-UH232 or U-99194A was reduced in the nucleus accumbens to the same level as that in the striatum. Our results indicate that the preferential D(3) receptor antagonists-induced increase in evoked dopamine release is probably mediated by the cholinergic system in the nucleus accumbens, which contains more postsynaptic dopamine D(3) receptors than the striatum.     

Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens

The purpose of this investigation was to determine if striatal or nucleus accumbens dopamine (DA) release, ACh release or DA receptor function were altered by acute and chronic haloperidol or clozapine treatment in a manner consistent with the reported pharmacological effects of each drug on A9 and A10 DA cell bodies and projection areas, when experiments were performed without a drug-free, or washout, period after drug treatment. The release of neurotransmitters reported here was evaluated using a slice-superfusion assay system. Transmitter release was induced either by an electrical field (for DA and ACh) or by application of either amphetamine or amfonelic acid (DA only). Dopaminergic receptor function was assessed by inhibiting electrically stimulated ACh release with in vitro TL-99 (a dopaminergic agonist) and by reversing that inhibition with in vitro neuroleptics or with ex vivo experimental paradigms (the in vitro analysis of transmitter release subsequent to in vivo drug administration). These data suggest that although there are differences between haloperidol and clozapine, there is no difference between the degree of postsynaptic DA receptor blockade produced that can be attributed to the duration of neuroleptic treatment. Chronic clozapine (20 mg/kg x 21 days) reversed TL-99-induced inhibition of ACh release in the nucleus accumbens only, whereas chronic haloperidol (0.5 mg/kg x 21 days) produced a similar reversal in both brain areas. One possible explanation for the lack of effect of chronic clozapine treatment in the striatum is that carrier-mediated (amphetamine-stimulated) DA release is enhanced in the striatum but not in the nucleus accumbens, suggesting that the potential DA receptor block in the striatum may be compromised by enhanced striatal DA levels. Acute haloperidol (0.5 mg/kg) was found to increase electrically stimulated ACh release in the striatum and DA release in the nucleus accumbens. Tolerance developed in the striatum, but not the nucleus accumbens, with repeated administration. However, acute clozapine had no effect on ACh release in either area, but it was found to enhance DA release in the striatum, an effect to which tolerance developed with chronic administration. Further, comparison of these data with data obtained using haloperidol and clozapine in vitro suggests that it is unlikely that these effects are due to residual drug still present in these tissues at the time of experimentation. These data are discussed with regard to electrophysiological and pharmacological differences observed between clozapine and haloperidol on the activity of A9 and A10 DA cells after chronic neuroleptic treatment.     

Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes

Glutamic acid and excitatory amino acids specific for the glutamate receptor subtypes were microinjected into the A10 region of the rat. Glutamate produced an increase in motor behavior that was antagonized by pretreatment with the dopamine D2 receptor antagonist, haloperidol. This motor stimulant effect was produced by kainate, but not by N-methyl-D-aspartate (NMDA) or quisqualic acid. By using in vivo dialysis it was found that dopamine release in the nucleus accumbens and locomotor activity were enhanced by glutamate injection into the A10 region. Whereas glutamate was found to increase the postmortem concentration of dopamine metabolites in the medial prefrontal cortex, nucleus accumbens and A10 region, NMDA selectively increased dopamine metabolism in the prefrontal cortex, and kainate produced increases in the nucleus accumbens and A10 region. When glutamate and the NMDA receptor antagonist, 3-[(+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) were coadministered, CPP selectively abolished the effect of glutamate on medial prefrontal cortical dopamine metabolites. A physiological role for the NMDA receptor modulation of A10 dopamine neurons was shown by intra-A10 pretreatment with CPP antagonism of mild footshock-induced increase in dopamine metabolites in the prefrontal cortex. These data argue that glutamate is a regulatory transmitter of A10 dopamine neurons, and that the NMDA receptor subtype modulates neurons projecting to the prefrontal cortex whereas the kainate subtype modulates mesoaccumbens neurons.     

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.     

Behavioral and neurochemical effects of acute and daily cocaine administration in rats

Daily cocaine injection into rodents produces a progressive increase in the motor stimulant effect of acute cocaine administration. In this study it was found that daily cocaine injection (15 mg/kg i.p. x 3 days) produced an enhanced motor stimulant response to acute cocaine injection. The behavioral augmentation was linear with regards to dose in horizontal activity and behavioral intensity rating, but was biphasic in vertical activity. Augmented vertical, but not horizontal, activity in response to acute cocaine was found to persist for 2 weeks after the last daily injection of cocaine. Acute injection of cocaine was found to significantly decrease the level of dopamine (DA) metabolites in the nucleus accumbens, striatum and A10 DA region. In rats pretreated with daily injections of cocaine (15 mg/kg i.p. x 3 days), an acute challenge of cocaine 14 days after the last daily injection produced a more consistent decrease in DA metabolites in the nucleus accumbens, striatum and prefrontal cortex compared to daily saline-pretreated rats. In contrast, daily cocaine treatment abolished the decrease in DA metabolites produced in the A10 region by an acute cocaine challenge. Acute injection with cocaine was found to significantly depress dopa accumulation in the A10 region, nucleus accumbens and striatum. This effect was abolished in the A10 region in rats pretreated 14 days previously with daily injections of cocaine (7.5, 15.0 or 30 mg/kg i.p. x 3 days), but remained intact in the nucleus accumbens and striatum, except after daily pretreatment with the highest dose of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine

Behavioral and neurochemical effects of haloperidol (D2-dopamine antagonist) and SCH-23390 (D1-dopamine antagonist) were examined in unlesioned rats and in rats lesioned with 6-hydroxy-dopamine (6-OHDA) as adults or as neonates. In unlesioned rats, chronic haloperidol treatment (15 days) resulted in an increase in D2-dopamine receptor density, as measured with [3H]spiperone, in the nucleus accumbens and in the caudate-putamen. Rats treated as adults with 6-OHDA responded to chronic haloperidol similarly to controls. However, adult rats treated with 6-OHDA as neonates did not exhibit an increase in [3H]spiperone binding in response to chronic haloperidol treatment. Control and adult 6-OHDA-treated rats given haloperidol exhibited a profound akinesia. In contrast, rats that received 6-OHDA as neonates and were tested as adults did not display a significant behavioral response to haloperidol at doses as high as 2 mg/kg. Results similar to those for haloperidol were also found for SCH-23390. Chronic treatment (15 days) with this D1-dopamine antagonist increased [3H]SCH-23390 binding in the nucleus accumbens and caudate-putamen in unlesioned rats as well as in adult 6-OHDA-treated rats. However, after neonatal 6-OHDA treatment, an elevation in [3H]SCH-23390 binding did not occur after chronic SCH-23390 treatment. SCH-23390 produced akinesia similar to that produced by haloperidol in unlesioned and in adult 6-OHDA-treated rats. In contrast, rats lesioned with 6-OHDA as neonates and tested as adults did not exhibit a significant behavioral response to SCH-23390 under our test conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine

The prescribed use of methylphenidate (Ritalin) in the treatment of attention deficit hyperactivity disorder has risen dramatically in recent years. The relative roles of dopamine, norepinephrine, and serotonin in the therapeutic action of these drugs was assessed by comparing the responses of extracellular nucleus accumbens dopamine and serotonin and hippocampus norepinephrine to the acute administration of low methylphenidate and amphetamine doses. The comparative neurochemical profiles in response to methylphenidate and amphetamine suggest that the norepinephrine effects may play an important role in the therapeutic effects of low doses of psychostimulants. In addition, to assess possible long-term consequences of prolonged exposure to this drug, we examined whether changes in the locomotor response occurred with repeated administration of these stimulant doses. Threshold doses of methylphenidate (0.5-1.0 mg/kg) or amphetamine (0.1-0.25 mg/kg) were administered twice daily, and then animals were tested in response to 2.5 mg/kg methylphenidate or 0.5 mg/kg amphetamine. Our results provide evidence that low-dose stimulant administration can result in the development of behavioral sensitization, which is evident in the subsequent behavioral response to the drug. The relevance of these data to the therapeutic uses of these drugs is discussed within the context of the many variables that can affect the behavioral and neurochemical responses to stimulants.     

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.