N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra

Recent technical advances in CT have renewed interest in the development of CT angiography (CTA). CT angiography is a minimally invasive method of visualising the vascular system and is becoming an alternative to conventional arteriography in some situations. Spiral technology allows a volume of data to be obtained on a single breath-hold with no respiratory misregistration. Fast machines with second or subsecond acquisition times mean the images are obtained while there are high circulating levels of contrast medium giving peak vascular opacification from a peripheral intravenous injection. Accurate timing will ensure either the arterial or venous phase is imaged. Multiple overlapping axial images can be obtained from the data set with no increase in radiation dose to the patient and from these scans computer generated multiplanar and 3D images are obtained which can be viewed from numerous angles. CT angiography can be performed more quickly, less invasively and at reduced cost compared to conventional angiography.     

Depletion of striatal dopamine transporter does not affect psychostimulant-induced locomotor activity

The effect of neurotoxin-induced depletion of striatal dopamine transporter (DAT) binding sites on animals' responses to psychostimulants was investigated. Multiple 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH) injections but not a single METH injection to Swiss Webster mice resulted in > 60% depletion of striatal DAT. MPTP-induced depletion of DAT did not affect METH- and cocaine-stimulated locomotor activity compared with the response of control mice. Pre-exposure to either the neurotoxic or the single non-neurotoxic dose of METH resulted in a marked locomotor sensitization in response to METH or cocaine challenge injections. The present results indicate that > 60% loss in striatal DAT binding sites has no effect on animals' responses to psychostimulants, and suggest that neural systems other than striatal DAT may contribute to the induction of locomotor sensitization to METH and cocaine.     

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity.

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D?-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D? receptor agonist PD 168,077 or the selective D? receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D?, and D? receptors. These results suggest that D? receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens

Systemic nicotine enhances burst firing of dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens, mainly via stimulation of nicotinic acetylcholine receptors in the ventral tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excitatory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral tegmental area for the effects of nicotine on dopamine release in the nucleus accumbens using microdialysis, with one probe implanted in the ventral tegmental area for drug application and another in the ipsilateral nucleus accumbens for measuring dopamine, in awake rats. Systemic nicotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the ventral tegmental area increased dopamine output in the nucleus accumbens. Intrategmental infusion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumbal dopamine release; these effects were antagonized by concomitant infusion of a selective antagonist at N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively. Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegmental area did not affect basal dopamine levels, whereas infusion of 2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, starting 40 min before nicotine injection dose-dependently attenuated the nicotine-induced increase in accumbal dopamine release. Concurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucleus accumbens. These results indicate that the stimulatory action of nicotine on the mesolimbic dopamine system is to a considerable extent mediated via stimulation of N-methyl-D-aspartate receptors within the ventral tegmental area.     

Comparison of various N-methyl-D-aspartate receptor antagonists in a model of short-term memory and on overt behaviour

This study examined the effects on rat behaviour of antagonists acting at various sites on the N-methyl-D-aspartate (NMDA) receptor complex, i.e. the glutamate recognition site (CPP), ion channel (dizocilpine), glycine recognition site [(+)-HA-966] and the NR2B subunit-selective compound ifenprodil. Specifically, the effects of these agents were examined on working memory, assessed using the operant delayed match-to-position task (DMTP), and overt behaviour, assessed (a) in animals responding for food under a variable interval 20-s (VI20) schedule and (b) by spontaneous behaviour. Dizocilpine, CPP and (+)-HA-966 each reduced accuracy in the DMTP task independent of delay. At equivalent doses, changes in locomotor behaviour and VI20 responding were evident. In contrast, ifenprodil failed to impair accuracy in the DMTP task, even at doses that affected other performance measures and reduced VI20 responding. The relevance of these observations to neuroprotective and anticonvulsant doses of these compounds is considered.     

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.     

Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task

Involvement of amygdaloid N-methyl-D-aspartate (NMDA) receptors in memory processes was investigated. Rats with cannulas implanted in the basolateral amygdala were trained on a 1 trial step-through inhibitory avoidance task and tested for 24-hr retention. Pretraining infusion of 2-amino-5-phosphonovaleric acid (APV) into the amygdala, but not striatum or hippocampus, produced a dose-dependent retention deficit, which was attenuated by immediate posttraining intra-amygdala infusion of NMDA. Posttraining APV infusion also caused a dose- and time-dependent retention deficit. Pretest APV infusion had no effect on performance in the retention test. Further, pre- or posttraining infusion of 5.0 micrograms APV failed to affect acquisition and retention in the Morris water maze task. These findings suggest that amygdala NMDA receptors are normally activated by aversive training and play a critical role in memory formation for affective experience.     

D? dopamine receptor involvement in the rough-and-tumble play behavior of juvenile rats.

By using dorsal contacts and pinning to quantify play behavior in juvenile rats, it was found that the D? agonist, quinpirole, reduced both measures of play at doses greater than 0.05 mg/kg. Eticlopride, a D? antagonist, also reduced both measures of play and blocked the reduction caused by quinpirole. The effect of quinpirole on play was largely unaffected by concurrent administration of either a D? agonist (SKF 38393) or a D? antagonist (SCH 23390), suggesting that D? and D? receptors are functionally independent with respect to play behavior. Quinpirole also reduced overall activity, suggesting that the effects on play may not be selective to neural circuitry responsible for play behavior. Although low doses of quinpirole (0.001–0.03 mg/kg) had a tendency to increase pinning, this effect was not very robust. These data suggest that D? dopamine receptors may not have a major role in the control of play behavior in juvenile rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor

Release of the excitatory neurotransmitter glutamate and the excessive stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors is thought to be responsible for much of the neuronal death that occurs following focal hypoxia-ischemia in the central nervous system. Our laboratory has identified endogenous sulfated steroids that potentiate or inhibit NMDA-induced currents. Here we report that 3alpha-ol-5beta-pregnan-20-one hemisuccinate (3alpha5betaHS), a synthetic homologue of naturally occurring pregnanolone sulfate, inhibits NMDA-induced currents and cell death in primary cultures of rat hippocampal neurons. 3alpha5betaHS exhibits sedative, anticonvulsant, and analgesic properties consistent with an action at NMDA-type glutamate receptors. Intravenous administration of 3alpha5betaHS to rats (at a nonsedating dose) following focal cerebral ischemia induced by middle cerebral artery occlusion significantly reduces cortical and subcortical infarct size. The in vitro and in vivo neuroprotective effects of 3alpha5betaHS demonstrate that this steroid represents a new class of potentially useful therapeutic agents for the treatment of stroke and certain neurodegenerative diseases that involve over activation of NMDA receptors.     

Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat

The effect of a dopamine receptor antagonist on locomotor activity was examined during withdrawal from either self-administered or experimenter-administered cocaine. In the self-administration experiment, the locomotor response to a challenge injection of cis-flupenthixol was assessed in photocell cages at 4 h after the cessation of a 12-h cocaine self-administration session. Rats which had self-administered cocaine, and were challenged with cis-flupenthixol (0.05 mg/kg), were found to be hypoactive relative to controls. In the experimenter-administered cocaine experiment, animals were given eight IP injections of 15 mg/kg cocaine over a 9.5-h period, for a total of 120 mg/kg. At 4, 8, and 24 h (tested in three separate groups of rats) after cessation of the eight injections, the locomotor response to a challenge injection of saline or cis-flupenthixol was tested. Cocaine-treated animals displayed a dose-dependent, heightened sensitivity to the locomotor depressant effects of 0.05 mg/kg and 0.2 mg/kg cis-flupenthixol 4 h post-cocaine, whereas they did not show increased sensitivity to 0.05 mg/kg cis-flupenthixol 8 or 24 h post-cocaine. However, cocaine-treated animals displayed a mild hypoactivity 8 h post-cocaine. In a separate group of animals, a dose-response experiment was performed which indicated that a dose of cis-flupenthixol as high as 0.2 mg/kg was required to produce locomotor depression in cocaine-naive rats. The results of this study support clinical observations of dopamine antagonist-precipitated motor dysfunction in abstinent cocaine abusers, and lend further support to the hypothesis that alterations in dopaminergic neurotransmission consequent to prolonged cocaine exposure are partly responsible for some of the symptoms of cocaine withdrawal.     

Effects of GBR 12909 on locomotor activity and dopamine turnover in mice: comparison with apomorphine

31 patients with schizophrenic adolescent paranoid syndrome were treated by Leponex-Sandoz after the establishing of the therapeutic indications. We did not observe any considerable side effects. We observed the regression of positive symptoms at 19-day of the treatment and the regression of negative symptoms at 23-day of the therapy. We conclude that Leponex-Sandoz is effective and safe medication in the treatment of adolescent schizophrenic paranoid syndrome.     

Undernutrition by rearing in large litters delays the development of reflexive, locomotor, and memory processes in mice.

In 3 experiments with a total of 512 Swiss-Webster mice, the effects of early postnatal undernutrition on the ontogeny of several behavioral capacities of varying complexity were investigated. After birth, mouse pups in all experiments were reared in either normally nourished or undernourished conditions by maintaining litter sizes at 6 or 16, respectively. Exps I and II examined the development of adultlike patterns of swimming behaviors and spontaneous locomotor activity, respectively, as a function of litter size. The maturation of both behavior patterns was delayed by about 2 days in the 16-litter mice. In Exp III, normally-nourished and undernourished Ss received 25 trials in a shock–escape T-maze at 9, 11, and 13 days of age, followed by similar retention tests 24 hrs later. Although litter size had little effect on correct turns at each age during training, Ss reared in litters of 6 showed significant retention of prior training by 12 days of age, whereas comparable retention was not noted for the large litter mice until 14 days of age. Results suggest that nutritional deficits, imposed by rearing in large litters during the postnatal period of rapid CNS maturation, retard the development of behavioral capacities involving both unlearned and learned responses. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential involvement of cortical receptor mechanisms in working, short-term and long-term memory

Rats received, through bilaterally implanted indwelling cannulae, 0.5 microliter infusions of 6-cyano-7-nitroquinoxaline2,3-dione (CNQX) (0.5 microgram), D-2-amino-5-phophono pentanoic acid (AP5) (5.0 micrograms), muscimol (0.5 microgram), scopolamine (2.0 micrograms), SCH23390 (2.5 micrograms), saline or a vehicle into the CA1 region of the hippocampus, or into the antero-lateral prefrontal (PRE), posterior parietal (PP) and entorhinal cortex (EC). The infusions were given 6 min prior to one-trial step-down inhibitory avoidance training in order to measure their effect on working memory (WM), or immediately post-training in order to measure their effect on short-term (STM) and long-term memory (LTM), 1.5 and 24 h later, respectively. WM was inhibited by CNQX or muscimol given into any of the cortical areas, by SCH23390 given into CA1, PRE or PP, and by scopolamine given into PRE or EC. STM was unaffected by any of the treatments given into PRE, and was inhibited by CNQX or muscimol given into CA1, PP and EC and by scopolamine given into PP, and enhanced by SCH given into CA1. LTM was inhibited by CNQX, muscimol, scopolamine or SCH23390 given into PRE, by scopolamine given into PP, by SCH23390 given into the entorhinal cortex, and by AP5, CNQX, muscimol or scopolamine given into CA1. The results indicate a differential involvement of the various neurotransmitter systems in the three types of memory in the various brain areas, and a separation of the mechanisms and of the regions involved in each. In addition, some of the findings suggested links between WM and LTM processing in PRE, between WM and STM processing in EC and PP, and between all three types of memory in CA1.     

Dopaminergic modulation of kappa opioid-mediated ultrasonic vocalization, antinociception, and locomotor activity in the preweanling rat.

The purpose of this study was to determine whether dopamine (DA) systems modulate kappa opioid-mediated ultrasonic vocalizations (USVs), antinociception, and locomotion in young rats. Seventeen-day-old rats were injected with the kappa agonist U-50,488 (0.0-7.5 mg/kg) and saline, the D?-like receptor agonist R(-)-propylnorapomorphine (NPA; 0. 1 or 1.0 mg/kg), the indirect DA agonist cocaine (10 or 20 mg/kg), or the DA antagonist flupenthixol (0.25 or 0.5 mg/kg). USVs and locomotion were measured for 6 min, with antinociception being assessed with a tail-flick test. Kappa receptor stimulation produced analgesia and increased USVs and locomotion. U-50,488-induced analgesia was potentiated by NPA, whereas U-50,488-induced USVs were attenuated by both DA agonists. NPA and flupenthixol depressed U-50,488's locomotor effects. These results show that DA systems interact with kappa opioid systems to modulate USVs, antinociception, and locomotion in preweanling rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anisomycin disrupts a contextual memory following reactivation in a cocaine-induced locomotor activity paradigm.

In experiments examining the potential reconsolidation of drug-associated contextual memories, rats were given a single pairing of cocaine with a specific context, and the ability of the protein synthesis inhibitor anisomycin administered following a context-only memory retrieval trial to impair conditioned locomotor sensitization was tested. Rats receiving 150 mg/kg anisomycin immediately following a 5-min reexposure to the cocaine-conditioned context showed decreased activity compared with the vehicle control group in response to a low-dose cocaine challenge during a subsequent test for conditioned sensitization. This effect was not seen when anisomycin was administered following a 30-min reexposure to the context or when anisomycin was administered 25 min after a 5-min reexposure. These results are consistent with a growing literature suggesting that following retrieval, associative contextual memories may undergo a transient protein synthesis-dependent reconsolidation phase that normally serves to maintain memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An NK1 receptor antagonist affects the circadian regulation of locomotor activity in golden hamsters

The objective of this study was to evaluate the impact of a feeding supplementation program on the growth of undernourished children younger than 5 years in the city of Guariba, state of S?o Paulo, Brazil. The sample consisted of 469 malnourished children enrolled in a feeding supplementation program sponsored by the State Health Secretariat. The children were divided into four groups according to how long they had been enrolled in the program: in group 1, the children had been enrolled for up to 12 months; in group 2, from 12 to 24 months; in group 3 from 24 to 36 months; and in group 4 the children had been enrolled for more than 35 months. Percentiles for weight/age, height/age and weight/height were calculated for each child. To assess the impact of the program, reference curves for the anthropometric profile were constructed based on expected variations in population percentiles. The changes observed in each group were analyzed statistically (McNemar). Groups 1 and 2 presented weight recovery and gains in the weight/height ratios for the most severely malnourished children; in group 3, the weight/height ratio was maintained and there was a discrete tendency towards weight recovery, which was reversed in group 4, in which the weight was again low in relation to height. The feeding supplementation program temporarily minimized severe nutritional deficiencies but was not sufficient to recover and maintain normal growth.     

A differential involvement of the shell and core subterritories of the nucleus accumbens of the rats in memory processes.

The role of the core and the shell subterritories of the nucleus accumbens in conditioned freezing and spatial learning was investigated by means of selective N-methyl-D-aspartate lesions. Shell-lesioned rats showed reduced conditioned freezing to context and a tendency toward reduced freezing to the discrete stimulus compared with controls. However, lesions of the core did not modify the freezing response either to the context or to the discrete stimuli. Although spatial memory, as assessed by a water-maze paradigm, was not disrupted by the lesions, in a 4-arm baited, 4-arm unbaited radial-arm maze paradigm, the shell-lesioned rats showed selective deficits in working memory, but not in reference memory. In contrast, core-lesioned rats showed no memory deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alterations in locomotor activity during chronic cocaine administration: effect on dopamine receptors and interaction with opioids

Chronic cocaine administration can produce tolerance or sensitization to locomotor activating effects, depending on the treatment paradigm. The effects of chronic, continuous cocaine were measured on locomotor activity for 1 hr daily for 7 days. Cocaine produced significant increases in locomotor activity 4 hr after osmotic minipumps were implanted, and an even higher level of activity after 24 hr. This was likely a rapid sensitization to the locomotor activating effects of cocaine, because neither brain nor plasma levels of cocaine were significantly altered over the treatment period. By day 4, activity levels diminished, but remained significantly higher than in saline-treated animals. Twenty-four hr after pump removal, there were no changes in dopamine D1 or D2 receptor binding, or in dopamine-stimulation of adenylyl cyclase activity in either caudate putamen or nucleus accumbens of cocaine-treated animals. Chronic naltrexone produced a slight, nonsignificant decrease in locomotor activity and when combined with cocaine, produced the same pattern of activity as cocaine alone, but with slightly less stimulation on all days. Morphine produced a smaller increase in activity than cocaine that remained constant throughout the treatment week. Cocaine with morphine was additive, producing greater activity and less tolerance than cocaine alone. Thus, continuous cocaine administration produces a rapid sensitization that is lost over the course of the treatment period, yet does not produce any immediate alterations in dopamine receptors or regulation of adenylyl cyclase. The pattern of behavior is not altered by an opioid antagonist, while the sensitization period appears to be prolonged in the presence of an opioid agonist.     

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D3 versus D2 dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01-0.1 mg/kg), the preferential D2 agonist, bromocriptine (1-10 mg/kg) and the selective D3 agonists, 7-OH-DPAT (0.003-0.1 mg/kg), PD 128907 (0.1-3 mg/kg), (+)3PPP (0.3-3 mg/kg), quinelorane (0.0001-0.003 mg/kg) and quinpirole (0.003-0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D3 but not D2 responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D2/D3 dopamine antagonists, haloperidol (0.1-0.4 mg/kg) and tiapride (10-60 mg/kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission.