Transplantation of microencapsulated bovine chromaffin cells reduces lesion-induced rotational asymmetry in rats

Surrounding bovine chromaffin cells by a semipermeable membrane may protect the transplanted cells from a host immune response and shield them from the inflammatory process resulting from the surgical trauma. Encapsulation of the chromaffin cells was achieved by inter-facial adsorption of a polycation on a polyanionic colloid matrix in which the chromaffin cells were entrapped. Basal and potassium-evoked release of catecholamines from encapsulated bovine chromaffin cells was analyzed over a 4-week period in vitro. Norepinephrine and dopamine release remained constant over time whereas epinephrine release significantly decreased. The chromaffin cells also retained the capacity for depolarization-elicited catecholamine release 4 weeks following the encapsulation procedure. Morphological analysis revealed the presence of intact chromaffin cells with well-preserved secretory granules. Striatial implantation of chromaffin cell-loaded capsules significantly reduced apomorphine-induced rotation compared to empty polymer capsules in animals lesioned with 6-hydroxydopamne frr at least 4 weeks. Intact chromaffin cells expressing tyrosine hydroxylase and dopamine-β-hydroxylase were observed in all capsules implanted in the striatum for 4 weeks. The assessment of the clinical potential of transplanting encapsulated adrenal chromaffin cells of either allo- or xenogeneic origin for Parkinson's disease will require long-term behavioral studies. The present study suggests, however, that the polymer encapsulation procedure may offer an alternative to adrenal autografts as a source of dopaminergic tissue.     

Pharmacological interactions between serotonin and dopamine on behavior in the squirrel monkey

 The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT_2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions. Received: 9 July 1996 / Final version: 22 November 1996     

An efficient procedure for the regioselective synthesis of 10-methoxy-11-hydroxyaporphine from (R,S)-10,11-dihydroxyaporphine

A regioselective preparation of 10-methoxy-11-hydroxyaporphine (“Apocodeine,1b”) from (R,S)-10, 11-dihydroxyaporphine(apomorphine,1a) is described. The isopropylidene ketal ring of 10,11-(isopropylidenyldioxy) aporphine (2) obtained by the isopropylidenation of apomorphine, was regioselectively opened by the ten equivalent of trimethylaluminum to give 10-hydroxy-11-t-butyloxyaporphine (3). The free 10-hydroxyl position of 3 was methylated with methyl p-toluenesulfonate/NaH, and afforded 10-methoxy-11-t-butyloxyaporphine (4) in high yield. Selective debutylation gave the desired 10-methoxy-11-hydroxyaporphine (“apocodeine”,1b) in good yield.     

一次阿扑吗啡注射对大鼠视觉辨别学习和工作记忆的影响

目的探讨多巴胺受体激动剂 -阿扑吗啡对大鼠视觉辨别学习和工作记忆的影响。方法利用旋转T迷宫装置 ,通过食物强化 ,分别训练大鼠正常和逆反的视觉辨别学习任务。动物达到规定的标准次数后 ,腹腔注射 2mg/kg体重的阿扑吗啡 ,3 0分钟后观察药物对工作记忆的影响。 结果对于正常学习 ,阿扑吗啡注射组动物的正确次数与生理盐水对照组相比无显著性差异 ,且两组动物继续进行逆反学习训练 ,达到学习标准所需的总次数亦无显著性差异 ;对于逆反学习 ,阿扑吗啡注射组动物的正确次数较对照组显著降低。结论单独一次阿扑吗啡注射可能干扰大鼠逆反学习的工作记忆 ,但不影响正常学习的工作记忆和逆反学习的过程。     

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.     

Apomorphine-induced alterations in cortical EEG activity of rats

Summary EEG activity after activation of dopamine receptors of D-1 and/or D-2 type was studied by using telemetric recordings in rats. Apomorphine, a preferential D-2 agonist, produced a characteristic increase in the power of alpha-1 band (7.00–9.50 Hz) when given in doses mediating stereotypies (0.2 or 0.5 mg/kg s. c.). Low doses produced a general increase in the power of all of the bands except beta-2. In particular, delta activity was enhanced which seems to be in correspondence with the sedation observed after these doses (0.02 and 0.05 mg/kg). Haloperidol in a dose which is assumed to block both D-1 and D-2 receptors (0.1 mg/kg i. p.) completely antagonized the alpha-1 activation produced by apomorphine (0.5 mg/kg). A similar, although not complete inhibition of alpha-I activation was found after administration of a large dose of the selective D-1 antagonist SCH 23390 (0.2 mg/kg i. p.). The selective agonist at D-2 receptors quinpirole (1.0 mg/kg s. c.) produced a less pronounced activation of the power in the alpha-1 band than apomorphine.In general, there was found to be a good correlation between the activation of the alpha-1 activity and stereotyped behaviour. The results suggest that for the full expression of alpha-1 activation, a pronounced activation of D-2 receptors and at least a minimal activation of D-1 receptors, for instance by the endogenous dopamine, is necessary. Send offprint requests to K. Kuschinsky at the above address     

Modulation of MK-801 response by dopaminergic agents in mice

Various doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists, MK-801 (0.1–0.5 mg/kg) and ketamine (2.5–10 mg/kg), produced a dose-dependent increase in stereotypic behaviour in naive mice. MK-801 (0.1 mg/kg) and ketamine (2.5 mg/kg) potentiated the stereotypic response of apomorphine (0.1–0.5 mg/kg) in mice pretreated with reserpine (5 mg/kg, 24 h prior) and alpha-methyl-p-tyrosine (150 mg/kg, 1 h prior) but not in naive mice. SKF 38393, a D₁ dopamine agonist, enhanced whereas B-HT 920, a D₂ dopamine agonist, reduced the stereotypic response of MK-801 in naive mice. The response of MK-801 was blocked by pretreatment with haloperidol (0.5 mg/kg), molindone (2.5 mg/kg), clozapine (7.5 mg/kg) and SCH 23390 (0.1 mg/kg). The present data suggest involvement of endogenous DA transmission in the stimulant action of non-competitive NMDA antagonists in mice. Dopamine D₁ and D₂ receptor stimulation, respectively, exert opposing effects on the behavioural expression of MK-801 in mice.     

Chicks from a high and low feather pecking line of laying hens differ in apomorphine sensitivity

Proactive rodents show a larger behavioral response to apomorphine (APO) than reactive copers, suggesting a more sensitive DA system in proactive individuals. Previously, chicks from a high feather pecking (HFP) and low feather pecking line (LFP) have been suggested to display a proactive and reactive coping strategy, respectively. Therefore, at approximately 4 weeks of age, the behavior of 48 LFP and 48 HFP chicks in response to an APO injection was studied using an open field. Another objective of the present study was to determine whether behavioral variation (in an open field) between HFP and LFP birds, after APO injection, is also reflected by variation of D(1) and D(2) receptor densities in the brain. Receptor binding capacities were assessed by measuring specific binding of tritiated D(1) and D(2) receptor ligands in different regions of the brain of control HFP and LFP chicks. In the present study, it is shown that indeed HFP chicks display a more enhanced behavioral response to acute APO treatment (0.5 mg/kg BW) than LFP birds in an open field. This difference was not reflected by variation of D(1) and D(2) receptor densities in the brain between both lines.     

Effects of dopamine agonists on hypothalamic defensive attack in cats

The effects of methamphetamine (MAT) and apomorphine (APO), dopamine agonists, were studied in 16 cats to evaluate their effects on threshold for defensive attack behavior elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VMH). Directed attack and hissing were selected from elementary responses as constituting a defensive attack. Hissing threshold was measured in two situations, one with human provocation and the other without provocation. MAT administered systemically lowered the thresholds for all three types of responses in a dose-related manner (0.5, 1.0, and 3.0 mg/kg). The effects of 1.0 mg/kg of APO were almost identical to those observed with 0.5 or 1.0 mg/kg of MAT. These results suggest that MAT-induced aggressive behavior may be mediated by a dopamine-induced increase in the excitability of the VMH.     

Physostigmine and norepinephrine: Effects of injection into the amygdala on taste associations

The present investigation was conducted to determine whether norepinephrine or acetylcholine systems of the amygdala could be involved in two adaptive feeding behaviors in the rat: development of taste aversion and recovery from neophobia. In a taste aversion paradigm, a single bilateral injection of physostigmine directly into the amygdala at the onset of an apomorphine-induced illness experience produced a time-dependent attenuation in the development of taste aversion; in contrast, norepinephrine had no disruptive effects. In a neophobia paradigm, norepinephrine injected directly into the amygdala after a novel taste experience resulted in a time-dependent attenuation in recovery from neophobia; however, physostigmine produced no disruptive effects. Hence, acetylcholine appears to mediate taste-illness associations, while norepinephrine plays an important role in recovery from neophobia, i.e., taste-“learned safety” associations.