Flunarizine induces a transient loss of tyrosine hydroxylase immunoreactivity in nigrostriatal neurons

Neurotoxic effects of flunarizine (Fz), a selective calcium channel blocker, on the nigrostriatal dopamine system was investigated. Systemic injections of Fz to mice resulted in a transient loss of tyrosine hydroxylase (TH) immunoreactive nigrostriatal neurons without cell loss. TH immunoreactivity in these neurons was greatly reduced as rapidly as one day after drug administration (regardless of dosage used) and thereafter recovered in both dose- and time-dependent manners. Such a novel neurotoxic action of Fz may constitute a morphological substrate for reversible drug-induced parkinsonian signs described in recent clinical case reports.     

Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice,drug discrimination procedure

The discriminative stimulus properties of (+)-lysergic acid diethylamide (LSD) and lisuride hydrogen maleate (LHM), were compared in a three-choice, water reinforced (FR 20) situation in which rats were required to press one lever following LSD (0.08 mg/kg), a second lever following LHM (0.04 mg/kg), and a third lever following saline. Reliable drug-appropriate responding was established in 72 sessions. Dose-response tests with LSD and LHM indicated that, as dose increased, the per cent of responding on the lever associated with the particular training drug also increased; little or no cross-transfer occurred between LSD and LHM. In generalization tests, the serotonin (5-HT) agonist quipazine substituted for LSD but not LHM while the dopamine (DA) agonist apomorphine mimicked LHM but not LSD; an unrelated compound, pentylenetetrazol (PTZ), produced responding on the saline-appropriate lever. In combination tests, 5-HT antagonists (e.g., BC-105 and low doses of pirenperone) blocked responding on the LSD lever while DA antagonists (e.g., haloperidol and much higher doses of pirenperone) blocked LHM-appropriate responding. These data suggest that the three-lever (D-D-N) procedure is similar to, but can be more sensitive than the two-lever (D-N) procedure (because it can differentiate between LSD and LHM); they therefore at least partially support the hypothesis that three-choice discriminations can be conceptualized as two separate, two-choice (D-N) discriminations (Jarbe and Swedberg 1982). The results also confirm suggestion that the stimulus effects of LSD and LHM are mediated by different mechanisms; the primary action of LSD is serotonergic (5-HT₂), while that of LHM is dopaminergic (White 1986).Some of these data were presented at the meeting of the Society of Neuroscience, Toronto, 1988 (Satellite Session of the Society for the Stimulus Properties of Drugs). They were also submitted (in somewhat different form) to the Graduate School of the University of South Carolina in partial fulfillment of the requirements for an MA degree (in Experimental Psychology)     

Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate occaine from saline. In substitution tests, the stimulus effects of 10mg/kg of this substance generalized tod-amphetamine (0.25–1.0 mg/kg) and the selective D₂ against LY-171555 (0.05–0.25 mg/kg); but not to the D₁ agonist SKF-38393 (5.0–15.0 mg/kg); in combination tests, the D₁ antagonist Sch-23390 (0.0625–0.5 mg/kg) significantly blocked, and the D₂ antagonist spiperone (0.25–0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D₁ or D₂ receptor activation; for example, the stimulus properties of this substance might involve both D₁ and D₂ receptor activation.Some of these results were presented at the meeting of the Society for Neuroscience, Toronto, 1988     

舒必利治疗精神分裂症患者脑脊液HVA含量的对照研究

为了探讨精神分裂症患者治疗期间多巴胺的变化,我们选择舒必利治疗组20例,非舒必利治疗组10例作为病例组;15例非精神病患者作为对照组;检测脑脊液中多巴胺代谢产物高香草酸的含量;结果显示两组无显著性差异。精神分裂症患者治疗后舒必利组高香草酸含量升高,非舒必利组则降低,进一步分析显示舒必利治疗组非显效者较显效者治疗后高香草酸显著升高。提示机体对药物阻滞多巴胺受体后代偿反应的强弱与疗效有一定关系。     

Amphetamine sensitivity in open-field activity vs. the prepulse inhibition paradigm

Amphetamine-induced mesolimbic dopamine release has been reported to reduce prepulse inhibition of the acoustic startle response. In addition, it is well known that mesolimbic dopamine stimulation leads to hyperactivity. The present study was undertaken to explore the possibility that one or the other measure may be a more sensitive in vivo indicator of dopamine release in the nucleus accumbens by determining if the amphetamine dose-response curves for these two behavioral measures were different. The data indicate that the dose-response curves obtained for the different behavioral measures are identical. These data are consistent with the idea that the same dopamine terminal field supports both prepulse inhibition of the acoustic startle response and dopamine-stimulated hyperactivity.     

Enhanced stimulus-reward learning by intra-amygdala administration of a D3 dopamine receptor agonist

The amygdala is considered to be a critical neural substrate underlying the formation of stimulus-reward associations, and is known to receive substantial innervation from dopaminergic neurons located within the ventral mesencephalon. However, relat- ively little is known about the function of the mesoamygdaloid dopamine projection in stimulus-reward learning. Recently, we have found post-session intra-amygdala microinjections of d-amphetamine to enhance appetitive Pavlovian conditioning as assessed in a discriminative approach task. In the present study, we have examined the effects of dopamine receptor agonists possessing relative selectivity for the D₁, D₂ and D₃ receptor subtypes in order to examine more fully the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Thus, subjects were trained to associate an initially neutral stimulus (CS⁺) with 10% sucrose reward (US). A second, control stimulus (CS⁻) was also presented but never paired with sucrose reward. In order to measure specifically the conditioned response to CS⁺/CS⁻ presentation, responding during CS and US presentations was measured separately. Immediately following each training session, subjects received bilateral intra-amygdala infusion of 0.1, 1 or 10 nmol/side of SKF-38393, quinpirole or 7-OH-DPAT. Infusions of SKF-38393 or quinpirole were without effect on CS⁺ approach. However, post-session intra-amygdala infusions of 7-OH-DPAT enhanced selectively CS⁺ approach in a dose-dependent fashion. No dose of any drug affected CS⁻approach, US behaviours, or measures of extraneous behaviour. Subsequent acquisition of a novel conditioned instrumental response was also unaffected. Thus, the present data indicate a selective involvement of the D₃ dopamine receptor subtype in the modulation of stimulus-reward learning by the mesoamygdaloid dopamine projection. Received: 12 December 1996 / Final version: 9 April 1997     

Tolerance-like attenuation to contingent and noncontingent cocaine-induced elevation of extracellular dopamine in the ventral striatum following 7 days of withdrawal from chronic treatment

Time-dependent changes in mesolimbic dopamine (DA) function are believed to play a role in behavioral sensitization and drug craving experienced during withdrawal from chronic cocaine administration. The present study utilized intravenous (IV) cocaine self-administration coupled with intracranial microdialysis in rats to investigate time dependent changes during withdrawal from chronic cocaine exposure. Following 2 weeks of IV cocaine self-administration, rats were allowed contingent access to cocaine at 1 and 7 days of withdrawal while extracellular levels of DA were measured from the ventral striatum. A second group of animals received yoked, noncontingent cocaine for 2 weeks and were then administered noncontingent cocaine on days 1 and 7 of withdrawal. In addition, a third group of animals received 2 weeks of yoked saline followed by noncontingent cocaine 1 day after withdrawal. There were no significant differences between groups for the overall cocaine dosage or temporal pattern of infusions on days 1 and 7 of withdrawal. Basal extracellular DA concentrations did not differ between any treatment groups at either withdrawal time. Extracellular DA levels were increased throughout the session on both days; however, the increases at day 7 were significantly less than day 1 for both contingent and noncontingent conditions. DA overflow on day 1 did not differ between animals receiving chronic yoked cocaine or saline. These results suggest that tolerance-like attenuation to the DA-elevating effects of cocaine is not apparent early in withdrawal, but does develop by later time points. DA release in the ventral striatum may not be directly related to cocaine self-administration following withdrawal, since DA levels were attenuated after 7 days of withdrawal while responding for cocaine was unaltered.     

[H](+)S 14297: A novel, selective radioligand at cloned human dopamine D3 receptors

The selective dopamine D₃ receptor antagonist [³H](+)S 14297 ((+)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3b)dihydro,2,3-furane]), labelled to high specific activity (145 Ci/mmol), bound to cloned human dopamine D₃ receptors but displayed negligible binding to cloned human D₂ receptors. [³H](+)S 14297 exhibited rapid association and dissociation, high affinity saturable binding (K_d = 7.0 nM) and a competition binding profile highly correlated with that of [¹²⁵I]iodosulpride (r = 0.98).     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.