Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally-lesioned rat

Morphine has been reported to increase extracellular levels of dopamine in the brain of intact rats and to potentiate turning induced by amphetamine in nigrally-lesioned rats. The present study tested the hypothesis that there is a causal relationship between these two effects of morphine. We tested morphine alone, amphetamine alone, and the combination in separate groups of nigrally-lesioned rats for effects on turning and, by microdialysis, on extracellular dopamine levels. Morphine (3.0 or 10 mg/kg) did not produce significant turning but amphetamine (1.0 mg/kg) did. The lower dose, but not the higher dose, of morphine potentiated amphetamine-induced turning. Amphetamine, but not morphine, produced increases in extracellular dopamine levels. In contrast to what occurred with turning, 10 mg/kg but not 3.0 mg/kg morphine potentiated amphetamine-induced increases in extracellular dopamine levels. These results show that the potentiation of amphetamine-induced turning by morphine in nigrally-lesioned rats is not due to the potentiation of dopamine release in the intact striatum.     

Systemic morphine-induced Fos protein in the rat striatum and nucleus accumbens is regulated by mu opioid receptors in the substantia nigra and ventral tegmental area

To characterize how systemic morphine induces Fos protein in dorsomedial striatum and nucleus accumbens (NAc), we examined the role of receptors in striatum, substantia nigra (SN), and ventral tegmental area (VTA). Morphine injected into medial SN or into VTA of awake rats induced Fos in neurons in ipsilateral dorsomedial striatum and NAc. Morphine injected into lateral SN induced Fos in dorsolateral striatum and globus pallidus. The morphine infusions produced contralateral turning that was most prominent after lateral SN injections. Intranigral injections of [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a mu opioid receptor agonist, and of bicuculline, a GABAA receptor antagonist, induced Fos in ipsilateral striatum. Fos induction in dorsomedial striatum produced by systemic administration of morphine was blocked by (1) SN and VTA injections of the mu1 opioid antagonist naloxonazine and (2) striatal injections of either MK 801, an NMDA glutamate receptor antagonist, or SCH 23390, a D1 dopamine receptor antagonist. Fos induction in dorsomedial striatum and NAc after systemic administration of morphine seems to be mediated by dopamine neurons in medial SN and VTA that project to medial striatum and NAc, respectively. Systemic morphine is proposed to act on mu opioid receptors located on GABAergic interneurons in medial SN and VTA. Inhibition of these GABA interneurons disinhibits medial SN and VTA dopamine neurons, producing dopamine release in medial striatum and NAc. This activates D1 dopamine receptors and coupled with the coactivation of NMDA receptors possibly from cortical glutamate input induces Fos in striatal and NAc neurons. The modulation of target gene expression by Fos could influence addictive behavioral responses to opiates.     

Inhibitory and facilitatory effects of cue onset and offset

Phencyclidine (PCP) and phencyclidine-like drugs (TCP, dexoxadrol, MK-801, and SKF 10,047) were evaluated for their ability to induce rotational behavior in rats with unilateral 6-OHDA lesions of the medial forebrain bundle and for their ability to alter striatal dopamine (DA) overflow with microdialysis procedures. All of the compounds tested produced rotational behavior ipsilateral to the lesion, suggesting that they were enhancing extracellular dopamine in the intact striatum. The microdialysis studies, however, did not support this contention. There appeared to be a complete dissociation between the ability of the five compounds to produce ipsilateral rotations and their ability to enhance extracellular dopamine levels in the striatum. PCP was the only compound able to elicit significant increases in striatal dopamine overflow following i.p. injections and also produce dramatic rotational behavior. MK-801 was the most potent compound in enhancing rotational output while it had no effect at all on striatal dopamine overflow. Dexoxadrol also produced significant rotational output without having any effect on extracellular levels of dopamine following i.p. injections. TCP and SKF 10,047, at doses which produced significant rotational behavior, only elevated dopamine 16% and 12%, respectively, at peak effect. It is most parsimonious to conclude that the effects of PCP-like drugs on nigro-striatal function are mediated through their ability to act as indirect NMDA receptor antagonists and not through their ability to alter striatal dopamine activity.     

Mu opioid agonists potentiate amphetamine- and cocaine-induced rotational behavior in the rat

Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.     

Behavioural and neurochemical sensitization of morphine-withdrawn rats to quinpirole

The sensitivity of dopamine D2-like receptors in morphine-withdrawn rats was studied using the selective agonist quinpirole. Morphine was administered twice daily increasing the daily dose from 20 to 50 mg/kg during 7 days. Twenty-four hours after the last morphine administration the rats were given quinpirole (0.01-1 mg/kg) and their behavior was assessed. Withdrawal from repeated morphine treatment enhanced yawning behavior and penile erections induced by small doses (0.01-0.1 mg/kg) as well as the intensity of stereotypy induced by a large dose (1.0 mg/kg) of quinpirole. In the morphine-withdrawn rats the dose of 1 mg/kg of quinpirole caused less yawning than in the control rats, whereas the number of erections induced by this dose was enhanced as compared with the control animals. In the control rats, the striatal and limbic concentrations of dopamine metabolites, 3,4-dihydroxphenylacetic acid (DOPAC), and homovanillic acid (HVA), were not clearly affected by the smallest dose of quinpirole. However, the small dose of quinpirole (0.01 mg/kg) significantly reduced the levels of DOPAC and HVA in the striatum and limbic forebrain of the rats withdrawn from morphine either for 24 or 48 h. These findings indicate that withdrawal from repeated morphine treatment enhances the sensitivity of dopamine D2-like receptors.     

Chronic exposure to morphine does not alter the neural tissues subserving its acute rewarding properties: Apparent tolerance is overshadowing.

Drug-naive, but not morphine-dependent, rats preferred places paired with morphine (2 mg/kg) over unfamiliar neutral places. Both drug-naive and morphine-dependent rats preferred places paired with higher doses of morphine (20 mg/kg) over unfamiliar places. Lesions of the tegmental pedunculopontine nucleus (TPP) blocked the conditioned place preferences produced by both 2 and 20 mg/kg morphine in drug-naive rats but not the preferences produced by 20 mg/kg morphine in dependent rats. When morphine-dependent animals received withdrawal-alleviating doses of morphine (20 mg/kg) 3.5 hrs before pairing one environment with 2 mg/kg morphine, they showed morphine-conditioned place preferences that were abolished by TPP lesions. The apparent behavioral tolerance to the TPP-mediated rewarding effects may have resulted from overshadowing by separate withdrawal-related motivational mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Different effects of opiate withdrawal on dopamine turnover, uptake, and release in the striatum and nucleus accumbens

The purpose of these experiments was to further characterize changes in dopaminergic function that follow withdrawal from chronic opiate treatment. Withdrawal after treatment to a maximum dose of 120 mg/kg of morphine did not alter dopamine concentrations in the substantia nigra, ventral tegmental area, striatum, or nucleus accumbens; but did decrease concentrations of DOPAC and the ratio of DOPAC to dopamine in the lateral striatum and nucleus accumbens. Uptake of tritiated dopamine was diminished for withdrawn slices obtained from the striatum with no effect observed for tissue from the nucleus accumbens. Deficits of in vitro release of tritiated dopamine also occurred following withdrawal, with the nucleus accumbens being sensitive to dependence produced by a lower dose of morphine. In conclusion, opiate withdrawal produces a complex pattern of effects on dopaminergic function that is specific for the striatum and nucleus accumbens.     

Sex differences in ethanol-induced dopamine release in nucleus accumbens and in ethanol consumption in rats

In vivo microdialysis was used to examine changes in nucleus accumbens and striatal dopamine, dihydrophenylacetic acid (DOPAC), and homovanillic acid (HVA) following acute administration of ethanol (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) in male and female Long-Evans rats. Following dialysis, rats were trained to bar-press for oral ethanol reinforcement. In nucleus accumbens, females showed significant increases in extracellular dopamine following 0.25 or 0.5 g/kg ethanol, but did not show significant increases over baseline at the higher doses. Males showed slight increases in dopamine at the lower doses and decreased dopamine at 2.0 g/kg. In striatum, both sexes showed increased dopamine at the lower doses and decreased dopamine at 2.0 g/kg. There were slight increases in nucleus accumbens DOPAC and HVA at some doses in both sexes, but no changes in striatal metabolite levels. In addition to showing increased responsiveness to ethanol-induced mesolimbic dopamine stimulation, females consumed more ethanol than males during behavioral testing. The pattern of both greater ethanol-induced nucleus accumbens dopamine release and greater ethanol consumption in females supports the hypothesis that ethanol reward is mediated, at least in part, by the mesolimbic dopamine system.     

Surface structure of human mucin using X-ray photoelectron spectroscopy

The stimulating effect of antiparkinsonian drugs, talipexole and bromocriptine, on the striatal postsynaptic dopamine receptors were studied by measuring contralateral rotational behavior in rats. The nigro-striatal dopamine system of rats was degenerated by unilateral injection of 6-hydroxydopamine (6-OHDA, 8 micrograms/rat) into substantia nigra. By subcutaneous administration, talipexole at 0.16 mg/kg and bromocriptine at 10.24 mg/kg induced significantly increased rotational behavior to the contralateral direction to the lesioned side. The onset of the effect was 30 min for talipexole and 90 min for bromocriptine. By intragastric administration, talipexole at 0.4 mg/kg and bromocriptine at 20.48 mg/kg significantly increased the rotational behavior, and the onset of the effect was 60 min for talipexole and 180 min for bromocriptine. Rotational behavior induced by talipexole was suppressed by a D2 antagonist, sulpiride (40 mg/kg, s.c.), but not by a D1 antagonist, SCH23390 (1 mg/kg, s.c.). In contrast, rotational behavior induced by bromocriptine was suppressed by both sulpiride and SCH23390. These results indicated that when the nigrostriatal dopaminergic functions are disrupted, talipexole stimulates the striatal postsynaptic dopamine receptors at much lower doses than bromocriptine. Also it was indicated that the stimulating effect of talipexole is solely mediated by dopamine D2 receptors, whereas the effect of bromocriptine is mediated by both D1 and D2 receptors.     

The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain

The importance of extrapyramidal and mesolimbic function for circling behaviour was investigated by placing 6-hydroxydopamine (6-OHDA) and electrolesions in the cell bodies, axons and terminals of each system. Circling behaviour was weak when 6-OHDA was placed at the centre of the substantia nigra (SN), but the characteristic contralateral/ipsilateral turning to apomorphine/amphetamine were recorded. Circling was more marked when 6-OHDA was placed anterior to the SN but was generally absent following injections posterior to the SN. However, 6-OHDA placed in the medial forebrain bundle in the lateral hypothalamus resulted in intense contralateral/ipsilateral turning to apomorphine/amphetamine. Generally, the intensity of circling responses was related to the degree of striatal dopamine (DA) depletion but the more effective lesions also caused reductions in mesolimbic DA content. However, circling was not observed following any 6-OHDA injection into the mesolimbic DA system and it is concluded that mesolimbic DA function is not essential for the initiation of circling. In contrast to the 6-OHDA lesions, rats circled ipsilateral to both apomorphine and amphetamine when the SN was damaged by electrocoagulation to cause marked depletion of striatal dopamine. Lesser depletions of striatal dopamine after electrocoagulation in different regions of the medial forebrain bundle were associated with a lower intensity of ipsilateral circling to both drugs. In general, the differences between 6-OHDA and electrolesions could not be explained by additional damage to ascending noradrenaline or 5-hydroxytryptamine pathways. Lower doses of apomorphine were effective in the 6-OHDA circling rats, and the ipsilateral striatum of such rats was more sensitive to directly applied DA. Higher doses of apomorphine were required to produce circling after chronic electrolesions which rendered the ipsilateral striatum insensitive to DA. The contralateral circling to apomorphine after 6-OHDA lesions was abolished by chronic but not by acute electrolesion of the SN. It is suggested that electrolesions of the SN cause different effects to 6-OHDA because they destroy neuronal pathways in addition to the dopaminergic nigrostriatal tract. These appear to be required for the expression of circling behaviour caused by stimulation of the denervated striatum. Whereas 6-OHDA lesions result in super-sensitivity of the denervated strital DA receptors, electrolesions may cause a hypo-sensitivity of the same receptor sites.     

Antigen-specific immunoglobulin-A prevents increased airway responsiveness and lung eosinophilia after airway challenge in sensitized mice

The aim of this study was to examine the role of dopamine neurotransmission in the effects of morphine in the learned helplessness paradigm in rats, a generally recognized model of depression. In this model, rats first exposed to inescapable shocks (stressed rats) exhibited an escape deficit in a subsequent shuttle-box test performed 48 h later for 3 consecutive days. The numbers of escape failures and intertrial crossings (motor activity during each intertrial interval) were recorded. Morphine was injected twice daily for 5 days (6 mg/kg/day, s.c.), and haloperidol, a preferential D2-dopamine receptor antagonist, was injected i.p. 15 min before each shuttle-box session. At the highest dose tested (150 microg/kg) haloperidol mimicked the behavioral deficit produced by inescapable shocks. A 37.5 microg/kg dose of haloperidol, which was ineffective by itself, reversed the morphine-induced improvement of escape behavior in previously stressed rats and the morphine-induced increase in intertrial activity in both stressed and nonstressed animals. These results support roles (a) for a dysregulation of dopaminergic neuronal activity in the expression of escape deficit subsequent to an inescapable aversive situation, and (b) for a dopaminergic mediation in the effects of morphine in the learned helplessness paradigm.     

Polarization of chemokine receptors to the leading edge during lymphocyte chemotaxis

To further clarify the interaction between opioid and dopaminergic systems, the effects of simultaneous administration of morphine hydrochloride (1.25 or 2.5 mg/kg) and haloperidol (0.1 mg/kg) on aggressive behavior of male mice were explored. Isolated male mice (experimental animals) were confronted in a neutral area with anosmic, group-housed consepecifics (standard opponents) 30 min after injection of both compounds, and aggression was evaluated by estimation of times allocated to 11 different behavioral categories. In the first experiment (which functioned as a pilot study), the two doses of morphine were explored. In the second one, incorporating a more complete experimental design, only the lowest morphine dose was used and the animals were preselected by a previous aggression test. In attack behavior, morphine added to haloperidol counteracted, at least partially, the antiaggressive effect of the neuroleptic. In contrast, the impairing effects of haloperidol on motor activity were increased by the addition of morphine. These results show that the behavioral effects of dopaminergic antagonists are modulated by opioid influences and that opiates and dopaminergic agents interact in a different manner on motor and on aggressive behaviors.     

Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior

Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.     

Sensitization to the rewarding effects of the specific dopamine uptake inhibitor GBR12783

The conditioned place preference (CPP) induced by increasing doses (1.25-40 mg/kg) of cocaine or the specific dopamine uptake inhibitor GBR12783 was investigated in rats previously treated with cocaine (10 or 20 mg/kg), GBR12783 (10 mg/kg) or morphine (10 mg/kg) for 15 days. In solvent-pretreated rats, cocaine- and GBR12783-induced CPPs were biphasic, with the highest scores observed at 20 mg/kg. Prior exposure to GBR12783 sensitized the rats to the rewarding effects of low doses of either GBR12783 or cocaine. Pretreatment with cocaine 20 mg/kg, but not 10 mg/kg, sensitized the rats to its own rewarding effects. Furthermore, it was less efficient than GBR12783 in sensitizing the animals to the rewarding effects of both drugs. These data confirm the major role of dopamine uptake inhibition in the sensitization process. On the other hand, the magnitude of CPP induced by a high dose of both drugs (20 mg/kg) was decreased after pretreatment with either GBR12783 or cocaine, reaching the lower scores observed at 40 mg/kg. This decrease was unrelated to altered anxiety level but was associated with sensitization to stereotypies. Morphine pretreatment modified neither the CPP induced by high doses of cocaine or GBR12783 nor cocaine- or GBR12783-induced stereotypies. However, prior exposure to morphine sensitized the rats to the rewarding effects of cocaine (2.5 mg/kg) but not to those of GBR12783, suggesting that other mechanisms working in concert with dopamine may facilitate the rewarding effect of cocaine without affecting that of GBR12783.     

Interaction between recovery from behavioral asymmetries induced by hemivibrissotomy in the rat and the effects of apomorphine and amphetamine.

Spontaneous and drug-induced turning behavior and thigmotactic scanning were tested either acutely (4–6 hr) or chronically (9 days) after unilateral removal of vibrissae in rats. Rats that were tested acutely scanned more with the intact vibrissae side. This asymmetry was reduced in rats that were tested chronically, indicating behavioral recovery. The indirect dopamine agonist amphetamine induced a reversed asymmetry after 9 days because the animals then scanned more with the side lacking the vibrissae. Postsynaptic doses of apomorphine administered to acutely tested rats induced more scanning with, and more turning toward, the intact vibrissae side. A negative correlation was found in the chronically tested rats between the asymmetry in spontaneous scanning and the asymmetry after apomorphine. Nonrecovered rats showed indications of a reversal after apomorphine. The results are discussed in relation to mechanisms of neural plasticity in the basal ganglia, such as receptor supersensitivity and changes in nigrostriatal afferents. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of repeated nicotine pre-treatment on mesoprefrontal dopaminergic and behavioral responses to acute footshock stress

The effects of acute and repeated nicotine administration on the stress response of rat mesoprefrontal dopaminergic pathways were examined. Rats were given daily injections of nicotine (0.15 or 0.60 mg/kg, s.c., freebase) or saline for 4 days, then challenged with either nicotine or saline. A regimen of inescapable electrical footshocks or no footshocks was then administered. Thirty minutes after final injection, rats were sacrificed, brains removed and dopamine (DA) and its metabolite dihydroxy-O-phenylacetic acid (DOPAC) were extracted from medial prefrontal cortex (mPFC), nucleus accumbens septi (NAS) and dorsolateral striatum and quantified by high performance liquid chromatography with electrochemical detection. Acute administration of low dose nicotine (0.15 mg/kg) produced an increase in DA utilization (increased DOPAC/DA ratio) in mPFC and NAS, but not striatum. High dose nicotine (0.60 mg/kg) produced activation in NAS, but not mPFC or striatum. Repeated low dose nicotine pre-treatment produced tolerance to the effects of nicotine challenge in the mPFC, and reduced its effects in NAS. Footshock stress preferentially increased DA utilization in mPFC and associated footshock stress-induced immobility responses, and these were reduced by low, but not high, dose repeated nicotine pre-treatment. Further, a single dose of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MCA) 30 min prior to nicotine challenge dose-dependently blocked the reduction of mesoprefrontal DA stress responsivity and immobility responses produced by repeated nicotine pre-treatment. These results indicate that: (1) there are dose-dependent differential effects of acute and repeated nicotine pre-exposure on regional DA utilization; (2) low, but not high, dose repeated nicotine reduces both the mesoprefrontal DA and behavioral effects of acute footshock stress; and (3) these effects of repeated nicotine may depend on mecamylamine-sensitive nAChR stimulation. These results may have relevance to acute stress and nicotine dependence, particularly in schizophrenic disorders, which have high prevalence rates of co-morbid nicotine dependence, stress-induced symptom exacerbation and prefrontal cortical dysfunction.     

Prior morphine exposure enhances ibogaine antagonism of morphine-induced dopamine release in rats

The present study examines the effect of prior morphine exposure on ibogaine antagonism of morphine-induced dopamine release. Female Sprague-Dawley rats were pretreated once a day for 2 days with morphine (20 mg/kg, i.p.) or saline and given a low dose of ibogaine (10 mg/kg, i.p.) or saline 5 hr after the last morphine or saline injection. Nineteen hours later, rats (awake and freely moving) were challenged with morphine (5 mg/kg, i.p.), and dopamine and its metabolites were monitored in the striatum and nucleus accumbens using in vivo microdialysis. Neither saline pretreatment, morphine pretreatment, nor ibogaine alone altered morphine-induced increases in extracellular dopamine and dopamine metabolites in either structure. However, when morphine pretreatment was combined with ibogaine, the morphine-induced elevation of dopamine, but not of metabolites, was completely blocked. These data suggest that prior morphine exposure enhances an opioid antagonist action of ibogaine on dopaminergic systems and that prior drug exposure may be a clinically significant determinant of ibogaine efficacy and/or potency in the treatment of opioid addiction.     

Role of (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors in amelioration of conditioned fear stress in rats: association with mesolimbic dopaminergic systems

Rats exhibited a marked suppression of motility when they were re-placed in the same environment as that in which they had previously received an electric footshock. We examined the behavioral and neurochemical effects of (+)-N-allylnormetazocine hydrochloride ((+)-SKF-10,047) and (+)-pentazocine, putative sigma 1 receptor ligands, on this psychological-stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently attenuated the conditioned fear stress, whereas (+)-pentazocine failed to do so even at a higher dose (32 mg/kg). In rats showing the conditioned fear stress, dopamine turnover (i.e., the ratio of dopamine metabolites/dopamine contents) was decreased in the nucleus accumbens and was increased in the medial prefrontal cortex, but remained unchanged in the striatum. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently reversed the decreased dopamine turnover in the nucleus accumbens without changing the increased dopamine turnover in the medial prefrontal cortex. (+)-Pentazocine (32 mg/kg) did not affect the stress-induced changes in dopamine turnover in these brain regions. Thus, the decreased dopamine turnover in the nucleus accumbens appears to be involved in the conditioned fear stress. These results suggest that (+)-SKF-10,047 ameliorates the conditioned fear stress by reversing the psychological stress-induced dysfunction in the mesolimbic dopaminergic systems, and that the (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors may play in important role in this stress response.     

Ketamine increases the striatal N-[11C]methylspiperone binding in vivo: positron emission tomography study using conscious rhesus monkey

A system for positron emission tomography study of conscious monkeys was newly developed. By use of this system in combination with a microdialysis technique, the effect of ketamine on the binding and release of dopamine was investigated. The administration of ketamine (5 mg/kg) caused sedation accompanied by psychotic symptoms such as nystagmus and stereotyped movements of extremities. During this psychotomimetic period produced by ketamine, a significant increase in the accumulation of the dopamine D2 receptor ligand N-[11C]methylspiperone was observed in the striatum compared with the level in the conscious state, while no significant change was observed in the frontal cortex and cerebellum. In contrast to the use of ketamine as the anesthetic, pentobarbital (25 mg/kg), which produced deeper anesthesia but no psychotic symptoms, caused a decrease in the accumulation of N-[11C]methylspiperone in the striatum. Kinetic analysis, conducted by a graphical method, revealed that the value of the association constant (K3) for N-[11C]methylspiperone binding in the striatum was increased to approximately 130% by ketamine and decreased to approximately 70% by pentobarbital compared with the control values. Furthermore, the release of dopamine from the striatum measured by microdialysis was not affected by ketamine anesthesia. These results indicate that ketamine facilitates striatal dopaminergic neurotransmission through increasing the binding activity of dopamine D2 receptors in the striatum, and suggest that these changes may be related to the psychotomimetic behavioral symptoms of this drug.     

Ibogaine-like effects of noribogaine in rats

Ibogaine is a naturally occurring alkaloid that has been claimed to be effective in treating addiction to opioids and stimulants; a single dose is claimed to be effective for 6 months. Analogously, studies in rats have demonstrated prolonged (one or more days) effects of ibogaine on morphine and cocaine self-administration even though ibogaine is mostly eliminated from the body in several hours. These observations have suggested that a metabolite may mediate some of the effects of ibogaine. Recently, noribogaine was identified as a metabolite of ibogaine. Accordingly, the present study sought to determine, in rats, whether noribogaine had pharmacological effects mimicking those of ibogaine. Noribogaine (40 mg/kg) was found to decrease morphine and cocaine self-administration, reduce the locomotor stimulant effect of morphine, and decrease extracellular levels of dopamine in the nucleus accumbens and striatum. All of these effects were similar to effects previously observed with ibogaine (40 mg/kg); however, noribogaine did not induce any ibogaine-like tremors. The results suggest that noribogaine may be a mediator of ibogaine's putative anti-addictive effects.