NMDA glutamate but not dopamine antagonists blocks drug-induced reinstatement of morphine place preference

The effects of dopaminergic and glutamatergic antagonists on the drug-induced reinstatement of a previously extinguished morphine conditioned place preference (CPP) in mice were evaluated. Following extinction of a place preference induced by morphine (40 mg/kg), a non-contingent injection of the dopaminergic antagonists SCH 23390 (0.125, 0.5 mg/kg), raclopride (0.3, 1.2 mg/kg), haloperidol (0.1, 0.2 mg/kg) and the dopamine (DA) release inhibitor CGS 10746B (1, 10 mg/kg) or glutamatergic NMDA antagonists memantine (10, 20, 40 mg/kg) and MK-801 (0.1, 0.2, 0.3 mg/kg) alone or with 10 mg/kg morphine was given. Neither the dopaminergic nor the glutamatergic antagonists alone reinstated the place preference. Dopamine antagonists failed to block the morphine-induced reinstatement of place preference while memantine and MK-801 blocked it with intermediate and high doses. These results suggest that drug-induced reinstatement of place preference may be largely independent of dopamine and more closely related to glutamatergic neurotransmission.     

Differences between nicotine and cocaine-induced conditioned place preferences

In previous studies, we found differences between nicotine and cocaine-induced changes in the levels of neurotransmitters in various brain areas, which suggested differences in their reward - preference mechanisms. The present study was based on the idea that drug preference is modulated by a number of different factors, among them several neurotransmitters and their receptors, and antagonists of specific receptors will influence preference. We also assumed that the factors (components of reward mechanisms) involved are different in the case of different drugs. We compared the inhibition of nicotine preference with cocaine preference. We assayed preference as conditioned place preference (CPP) and measured CPP inhibition by receptor subtype antagonists using mice. In general, induced CPP of cocaine was stronger than of nicotine as shown by more time spent in the nonpreferred area after conditioning with cocaine. We measured inhibition by four antagonists: mecamylamine, atropine, SCH23390, and phentolamine: antagonists respectively of nicotinic, and muscarinic acetylcholine, dopamine D1, and α noradrenergic receptors. The inhibition by the antagonists of cocaine CPP was lower in most instances than that of nicotine CPP. Atropine and SCH23390 inhibited nicotine and cocaine CPP approximately to the same degree, while the inhibition by mecamylamine and phentolamine of nicotine CPP was 100%; that of cocaine was 20% and 0, respectively. We conclude that several receptor systems and transmitters play a role in drug preference, some represent essential elements or circuits, some may be only required partially or their role can be partially substituted. The composition of such systems is different for different drugs - in the present study, some of the components influencing CPP are different for nicotine as opposed to cocaine.     

Morphine and methadone have different effects on calcium channel currents in neuroblastoma cells

Using patch-clamp technique, cellular calcium channel currents were studied on nine mouse neuroblastoma N1E115 cells. Both morphine and methadone decreased the T-type calcium currents in dose-dependent fashion. These effects were partially blocked by naloxane. On L-type calcium currents, morphine showed no effect. However, methadone inhibited the L-calcium currents in dose-dependent fashion. This effect was not antagonised by naloxone. Hence, the action of methadone on L-calcium channel is probably not associated with μ receptors.     

Effects of excitotoxic lesions of the central or basolateral nucleus of the amygdala on naloxone-precipitated withdrawal-induced conditioned place aversion in morphine-dependent rats

We examined the effects of discrete, bilateral excitotoxic lesions of the central or basolateral nucleus of the amygdala on naloxone-precipitated withdrawal-induced conditioned place aversion in morphine-dependent rats. Lesions of the central nucleus significantly attenuated the conditioned place aversion, while lesions of the basolateral nucleus had little effect. These results suggest that the central nucleus of the amygdala, rather than the basolateral nucleus, plays a crucial role in the negative affective component of morphine abstinence.     

Selectivity of the protective effects of dihydropyridine calcium channel antagonists against the ethanol withdrawal syndrome

Four dihydropyridine calcium channel antagonists were compared for their ability to protect against the hyperexcitability produced in mice by withdrawal from chronic ethanol treatment and to protect against seizures due to bicuculline or pentylenetetrazol. Comparison was also made of their effects on locomotor activity, body temperature and motor co-ordination, and with the corresponding effects of the benzodiazepine, diazepam. Nitrendipine, nimodipine, nicardipine (at 50 and 10 mg/kg) and isradipine (at 10 and 4 mg/kg) decreased the withdrawal hyperexcitability, but showed no anticonvulsant action against either bicuculline or pentylenetetrazol. Diazepam (1.5 and 4 mg/kg) both protected against the withdrawal signs and decreased seizure incidence after bicuculline and pentylenetetrazol, although the latter effects were of shorter duration than those on the withdrawal signs. The four dihydropyridines decreased spontaneous locomotor activity, an effect which lasted up to 6 h. Only isradipine and diazepam had any ataxic actions at the doses tested. All the dihydropyridines had hypothermic actions, considerably shorter in duration than effects on withdrawal hyperexcitability, with little evidence of dose dependence, except for nicardipine, which had a larger, dose-related, hypothermic action. Of the four compounds, isradipine was more potent in terms of dose, but not any more selective for effectiveness against the withdrawal signs, than the other three dihydropyridines, and nicardipine was slightly less effective in protecting against the withdrawal signs. The results indicate that the anticonvulsant effects of the dihydropyridines were selective for ethanol withdrawal hyperexcitability, whereas diazepam showed no such selectivity.     

舒必利消除小鼠对吗啡的条件性位置偏爱

目的对阿片类成瘾觅药行为的药物干预的可能性进行探索。方法将４０只雄性昆明种小鼠随机分为盐水组、吗啡组（９ｍｇ／ｋｇ，皮下注射）、舒必利（２０ｍｇ／ｋｇ，皮下注射）＋吗啡组、舒必利（３０ｍｇ／ｋｇ，皮下注射）＋吗啡组，每组１０只，观察多巴胺Ｄ２受体拮抗剂舒必利对吗啡所致小鼠条件性位置偏爱的效应。结果吗啡组在相应的箱体中停留的时间较对侧显著延长（Ｐ＜０．０１）。盐水组、舒必利２０ｍｇ／ｋｇ＋吗啡组、舒必利３０ｍｇ／ｋｇ＋吗啡组与吗啡组之间比较，显示吗啡组在其相应的箱体中停留的时间显著增加（Ｐ＜０．０５），而其它组无显著增加。结论提示预先给予舒必利能消除吗啡产生的条件性位置偏爱。     

Glutamate in the parabrachial nucleus of rats during conditioned taste aversion

Brain microdialysis combined with HPLC and spectroscopic detection was used to monitor extracellular glutamate in the parabrachial nucleus (PBN) of rats during acquisition of a conditioned taste aversion (CTA). Microdialysis fractions taken every 20 min were used to assess the effects of presentation of the conditioned stimulus alone (CS, consumption of 0.1% saccharin), the unconditioned stimulus alone (US, intraperitoneal injection of 0.15 M LiCl, 2% b.w. induced malaise after water drinking) as well as that of CS-US pairing. After 15 min of saccharin drinking, the glutamate concentration in the eluate (20 microl/20 min) reached 80% above the baseline but returned to the basal value in the next fraction. LiCl alone (applied 1 h after 15 min drinking of water) increased glutamate only following some delay, i.e. in the second and third post-lithium fraction by 90 and 67%, respectively. However, when LiCl was injected 1 h after the onset of saccharin intake, the glutamate concentration rose significantly (by 95%) already in the first post-LiCl fraction and by 120% in the second one. It appears, therefore, that the 'saccharin trace' facilitates the effect of lithium on extracellular concentration of glutamate in PBN during acquisition of CTA.     

The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats

It has been reported that N-methyl-D-aspartate (NMDA) receptor is implicated in drug addiction and antagonists of the NMDA receptor complex can inhibit the development and expression of conditioned place preference (CPP) induced by several addictive drugs, implying that this class of compounds might be considered as candidate for the treatment of substance abuse. To explore this possibility, it is important to evaluate whether the inhibitory effect of NMDA receptor antagonists would be confined to behaviors produced by drugs of abuse only, but not by natural reinforcers. According to the quantitative changes of NMDA receptor subunits, including NR1, NR2A, and NR2B, induced by diverse types of reinforcers, we chose NR2B subunit as the target of research. Experimental results showed that (1) an augmented expression of NR2B subunit was revealed by Western blotting in the nucleus accumbens (NAc) and the hippocampus in rats with CPP induced by morphine, but not by natural rewards such as food, novel environment and social interaction. (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction. Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse.     

Chronic cadmium exposure attenuates the conditioned reinforcing properties of morphine and fentanyl

Adult male rats were exposed ad libitum for 40 days to 100 ppm cadmium chloride through their diet, or an identical diet with no added cadmium. Conditioned place preference (CPP) was conducted in a 2-chamber apparatus in which all drugs were paired with the least-preferred side as determined on a pre-test. In Experiment 1, control and cadmium-exposed rats received 0, 0.6, 1.25, 2.5, or 5 mg/kg morphine sulfate (i.p.) for 4 days, and vehicle only for 4 days. Control animals showed a preference for the drug-paired side at 1.25, 2.5, and 5 mg/kg while the cadmium-exposed rats showed a preference at 5 mg/kg only. In Experiment 2, rats were implanted with cannulae into the lateral ventricles and 0, 2, or 5 μg morphine sulfate was administered intracerebroventricularly (i.c.v.). An attenuation by cadmium again was observed, as control animals showed a place preference at 2 and 5 μg and cadmium-exposed animals showed preference at 5 μg only. In Experiment 3, increasing doses of the μ-opioid receptor agonist fentanyl (0, 0.0004, 0.004, and 0.04 mg/kg) were systemically administered (s.c.) and rats tested for CPP. While cadmium animals showed place preference only at 0.04 mg/kg, control animals showed preference at 0.0004, 0.004, and 0.04 mg/kg. These findings are discussed within the framework of metal-induced disturbance of neurochemical function and/or associative processing, and the implications that such disturbances may have for drug seeking and taking.     

Pimozide prevents the development of conditioned place preferences induced by rewarding locus coeruleus stimulation

Electrical stimulation in the vicinity of the cell bodies of the locus coeruleus (LC) has been shown to support self-stimulation behaviors in rats. In the present study, a Conditioned Place Test, sensitive to both rewarding and aversive qualities of brain stimulation, was employed to determine (a) whether rewarding locus coeruleus stimulation would result in place preferences and (b) if so, whether dopamine receptor antagonism would affect the development of such place preferences. Animals were pretreated with pimozide (0.0, 0.5 or 1.0 mg/kg) prior to exposure to two distinctive environments only one of which was paired with locus coeruleus stimulation. Rats that received vehicle injections prior to stimulation/place pairings developed strong preferences for the stimulation-paired environment while those animals pretreated with 0.5 mg/kg pimozide showed no reliable shift in preference from baseline performance. Additionally, animals injected with the 1.0 mg/kg dose of pimozide exhibited mild place aversions to the stimulation-paired environment. It is hypothesized that dopamine neurotransmission is important for the rewarding effects of locus coeruleus stimulation without which such stimulation appears to be aversive.     

钙拮抗剂防治蛛网膜下腔出血后的迟发性脑血管痉挛的观察

目的 :观察钙拮抗剂对蛛网膜下腔出血后迟发性脑血管痉挛 (DCVS)的疗效。方法 :对 66例蛛网膜下腔出血 (SAH)患者将其分为钙拮抗剂治疗组 ( 32例 )和常规治疗对照组 ( 34例 )。结果 :32例治疗组中发生DCVS的 5例 ,34例对照组中发生DCVS2 1例 (P <0 0 5) ;死亡人数治疗组 4例 ,对照组 7例 ,无显著差异 (P >0 0 5)。结论 :钙拮抗剂在DCVS的防治中有显著疗效。     

强迫游泳和糖皮质激素促进小鼠对吗啡的条件性位置偏爱

目的　探讨应激和糖皮质激素在发生药物依赖行为中的作用机制。方法　 (1)将 30只雄性昆明品系小鼠随机分为盐水组、糖皮质激素组 (2 0mg- 1 ·kg- 1 ,皮下注射 )、强迫游泳组 (2 5℃强迫游泳 10min) ,每组 10只 ,观察 3种措施对小鼠条件性位置偏爱形成的影响 ;将 30只雄性昆明品系小鼠先进行吗啡条件性位置偏爱实验 ,再随机分为盐水组、糖皮质激组和强迫游泳组 ,每组 10只 ,处理条件同前 ,持续 6天 ,观察 3种措施对小鼠条件性位置偏爱消退的影响。结果　 (1)强迫游泳组和糖皮质激素组在吗啡搭配箱体中停留时间 [分别为 (9 6± 1 0 )min ,(9 4± 1 3)min]均分别高于盐水组[(7 3± 0 8)min];t1 =4 5 6 ,P1 <0 0 1;t2 =4 5 8,P2 <0 0 1,而强迫游泳组和糖皮质激素组之间差异无显著性 (t=0 41,P >0 0 5 ) ;(2 )经过 6天消退期后 ,强迫游泳组和糖皮质激素组在吗啡搭配箱体中停留时间 [分别为 (7 6± 1 1)min ,(7 4± 0 8)min]亦均分别高于盐水组 [(7 3± 1 0 )min];t1 =4 15 ,P1 <0 0 1;t2 =3 38,P2 <0 0 1。结论　强迫游泳和注射糖皮质激素均能促进小鼠对吗啡的条件性位置偏爱 ,并能延缓条件性位置偏爱的消退。     

Assessment of rewarding and reinforcing properties of biperiden in conditioned place preference in rats

Biperiden is one of the most commonly abused anticholinergic drugs. This study assessed its motivational effects in the acquisition of conditioned place preference in rats. Biperiden neither produced place conditioning itself nor enhanced the rewarding effect of morphine. Furthermore, biperiden in combination with haloperidol also did not affect place preference. These findings suggest that biperiden seems devoid of abuse potential properties at least at the doses used.     

Hippocampal lesion effects on conditioned taste aversion and pituitary-adrenal activity in rats

A series of experiments examined the effects of hippocampal lesions on conditioned taste aversion (CTA) and pituitary-adrenal activity. Experiment 1 examined recovery from a conditioned taste aversion under conditions of free extinction. Hippocampal and unoperated rats recovered from the aversion at the same rate. Further, this experiment showed that the suppression in drinking in both groups produced by lithium chloride (LiCl) injection was a conditioned taste aversion (was dependent upon the contingent pairing of the taste stimulus with LiCl) and not enhanced neophobia. In Experiment 2 there were no behavioral effects of the lesion in a forced extinction CTA paradigm. In addition, hippocampal lesions failed to alter pituitary-adrenal responsiveness to LiCl. In the same experiment, pituitary-adrenal responsiveness of hippocampectomized rats, when re-exposed to the taste paired earlier with LiCl, was altered. Hippocampal lesions eliminated the elevation in corticosterone shown by unoperated control and neocortical-lesioned rats. The third experiment replicated this finding showing again that hippocampal-lesioned rats failed to show the forced extinction elevation in corticosterone when re-exposed to the aversive taste (Experiment 3). These data were integrated with other reports of behavioral and pituitary-adrenal alterations in hippocampal-lesioned rats.     

Calcium channel antagonists for the treatment of bipolar disorder

Calcium channel antagonists (CCAs) have many clinical applications, including their possible use in the treatment of bipolar disorder. Two justifications for this last application are some overlap in physiological activities of CCAs with those of lithium, and a possible association between bipolar disorder and calcium dysregulation. While the data from earlier studies support the use of verapamil in treating bipolar mania, more recent better-controlled trials have not. This paper reviews the available body of data regarding CCAs in the treatment of bipolar disorder, concluding there is presently limited support for their efficacy.     

Effects of insular cortex lesions on conditioned taste aversion and latent inhibition in the rat

The present study tested the hypothesis that lesions of the insular cortex of the rat retard the acquisition of conditioned taste aversions (CTAs) because of an impairment in the detection of the novelty of taste stimuli. Demonstrating the expected latent inhibition effect, nonlesioned control subjects acquired CTAs more rapidly when the conditioned stimulus (0.15% sodium saccharin) was novel rather than familiar (achieved by pre-exposure to the to-be-conditioned taste cue). However, rats with insular cortex lesions acquired taste aversions at the same slow rate regardless of whether the saccharin was novel or familiar. The pattern of behavioural deficits obtained cannot be interpreted as disruptions of taste detection or stimulus intensity, but is consistent with the view that insular cortex lesions disrupt taste neophobia, a dysfunction that consequently retards CTA acquisition because of a latent inhibition-like effect.     

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

Neurokinins, such as substance P (SP), modulate the reflex regulation of cardiovascular and respiratory function in the CNS, particularly in the nucleus tractus solitarius (NTS). There is considerable evidence of the action of SP in the NTS, but the precise effects have not yet been determined. Voltage-dependent Ca2+ channels (VDCCs) serve as crucial mediators of membrane excitability and Ca2+ -dependent functions such as neurotransmitter release, enzyme activity and gene expression. The purpose of this study was to investigate the effects of neurokinins on VDCCs currents (ICa) in the NTS using patch-clamp recording methods. In 142 of 282 neurons, an application of [Sar(9), Met(O(2)11]-substance P (SSP, NK(1) receptor agonist) caused facilitation of L-type I(Ba). Intracellular dialysis of the Galpha(q/11)-protein antibody attenuated the SSP-induced facilitation of I(Ba). In addition, phospholipase C (PLC) inhibitor, protein kinase C (PKC) inhibitor and PKC activator attenuated the SSP-induced the facilitation of I(Ba). In contrast, in 115 of 282 neurons, an application of SSP caused inhibition of N- and P/Q-types I(Ba). Intracellular dialysis of the Gbetagamma-protein antibody attenuated the SSP-induced inhibition of I(Ba). These results indicate that NK(1) receptor facilitates L-type VDCCs via Galpha(q/11)-protein involving PKC in NTS. On the other hand, NK(1) receptor inhibits N- and P/Q-types VDCCs via Galpha(q/11)-protein betagamma subunits in NTS.     

Differential effects of a dihydropyridine calcium channel antagonist on the components of ethanol tolerance

The dihydropyridine calcium channel antagonist, nimodipine, was found to decrease the extent of tolerance that developed to the ataxic action of ethanol in experimental designs in which the tolerance was not context-specific, when ethanol was given by liquid diet. When ethanol was given by injection, so that cues were present for the effects of ethanol during the chronic treatment, tolerance to the ataxic actions of ethanol was unaffected. Nimodipine, however, decreased the tolerance to the hypothermic actions of ethanol, when the ethanol was given by injection. When the rats were given practice sessions on the motor task while under the influence of the ethanol, during the chronic treatment, nimodipine did not affect tolerance to the ataxic actions of ethanol. When nimodipine was given before the motor task learning and ethanol after the practice sessions, the tolerance to the ataxic effect of ethanol was increased. A similar schedule of drug treatment with the NMDA antagonist CGP37849 given before the practice sessions, and ethanol afterwards, resulted in decreased tolerance to ethanol. It is suggested that these changes in ethanol tolerance may be explained by dual actions of nimodipine in, firstly, decreasing the form of tolerance to ethanol that is not dependent on contextual cues and, secondarily, in increasing the learning of a motor task.     

Anticonvulsant effects of dihydropyridine Ca2+ antagonists in electrocortical shock seizures

The dihydropyridine calcium antagonists nimodipine (NMD), PN200-110, and nicardipine were compared with phenytoin (PHT) as potential anticonvulsants in electrocortical shock (ECS)-induced seizures in the white New Zealand rabbit. Before treatment, seizure duration ranged from 43.8 +/- 5.1 to 49.6 +/- 5.2 s with an ECS stimulus of 10-V, 100-Hz, 0.1-ms pulses for 5 s. Each drug was administered into the right internal intracarotid artery 2 min before the ECS. A cumulative nimodipine dose of 440 micrograms/kg decreased seizure discharge to 6.6 +/- 5.0 s (p less than 0.001), whereas a total dose of 1.0 mg/kg PN200-110 was required to achieve a similar effect. Nicardipine was ineffective. A cumulative dose of 7 mg/kg phenytoin was required to suppress seizure discharge. These results indicate that Ca2+ channels modulated by dihydropyridines play a facilitating role in ECS-induced seizures. We propose that the anticonvulsant effects of nimodipine and PN200-110 are due to inhibition of neuronal calcium L-channels. Dihydropyridine Ca2+ antagonists that penetrate the blood-brain barrier (BBB) and bind to neuronal tissue may emerge as a novel class of anticonvulsants.