Further studies on the modulation of regional brain neurotensin concentrations by antipsychotic drugs: focus on haloperidol and BMY 14802.

Acute and chronic treatment with the antipsychotic drug haloperidol or the potential antipsychotic BMY 14802 produce increases in regional neurotensin concentrations which are similar with respect to regional specificity (nucleus accumbens and caudate), time course, magnitude of increase and precedence by an increase in proneurotensin mRNA. The present study characterizes further the effects of haloperidol and BMY 14802 on regional brain neurotensin concentrations and compares certain of their effects to those of sulpiride. Neurotensin concentrations in discrete brain regions of adult, male, Sprague-Dawley rats were determined by radioimmunoassay. Both acute and chronic treatment with BMY 14802 produced significant decreases in the concentration of neurotensin in the frontal cortex. When administered concomitantly, low doses of haloperidol and BMY 14802 produced additive increases in neurotensin content in the nucleus accumbens and caudate. Increases in neurotensin content resulting from concomitant treatment, or with doses which produce maximal effects individually, were not greater than those produced by either drug alone. Concomitant administration of SCH 23390 and sulpiride attenuated the neurotensin increases observed after treatment with sulpiride. Increases in neurotensin concentrations produced by haloperidol and BMY 14802 were not antagonized by SCH 23390. These findings support the hypothesis that haloperidol and BMY 14802 modulate regional neurotensin concentrations through a common or similar mechanism which is distinct from that of sulpiride.     

Increase of neurotensin content elicited by neuroleptics in nucleus accumbens

The content of neurotensin immunoreactive material (neurotensin-IR) of nucleus accumbens increases 16 hr after a single injection of 2 mg/kg i.p. of haloperidol; this increase persists for 8 hr or longer. Repeated injections of 2 mg/kg/day of haloperidol i.p. cause a gradual and progressive increase of neurotensin-IR. From 0.32 pmol/mg of protein, it increases to 0.57 pmol/mg (1 week) to 0.62 pmol/mg (2 weeks) and reaches 0.68 pmol/mg (3 weeks). A significant increase of neurotensin-IR content of nucleus accumbens is obtained with 0.5 mg/kg i.p. daily for 2 weeks. Maximal responses are obtained with 1 mg/kg/day in 3 weeks. The striatal neurotensin-IR content of rats injected for 2 weeks with 1 mg/kg/day of haloperidol is also increased. In these rats, the neurotensin-IR content of preoptic area hypothalamus, septum and amygdala failed to increase. The increase of neurotensin-IR material of nucleus accumbens was elicited also by chloropromazine (6 mg/kg), trifluoroperazine (2 mg/kg) and pimozide (1.5 mg/kg) while promazine (10 mg/kg) and promethazine (25 mg/kg) were ineffective. The increase of neurotensin-IR content caused by haloperidol chloropromazine, trifluoroperazine and pimozide in accumbens and striatum suggests a modulation of neurotensin metabolism, synthesis or utilization directly or indirectly through dopaminergic synapses.     

Effects of subcutaneous and intracerebroventricular administration of the sigma receptor ligand 1,3-Di-o-tolylguanidine on body temperature in the rat: interactions with BMY 14802 and rimcazole.

The current study investigated the effects of the acute s.c. and i.c.v. administration of 1,3-di-o-tolylguanidine (DTG) on body temperature in rats. The effects of putative sigma receptor antagonists BMY 14802 and rimcazole on DTG-induced changes in body temperature also were evaluated. The acute s.c. administration of DTG (10.0 and 20.0 mg/kg) produced hypothermia but no observable behavioral effects. Similarly, the acute i.c.v. administration of DTG (12.0-100.0 micrograms/rat) produced hypothermia, but ataxia occurred after this route of administration. The s.c. administration of BMY 14802 alone (25.0 mg/kg) decreased body temperature and enhanced the DTG-induced hypothermia, whereas the administration of rimcazole (25.0 mg/kg) neither altered body temperature nor affected the hypothermia produced by DTG. Neither BMY 14802 nor rimcazole produced any behavioral effects when administered alone. The inability of the putative sigma receptor antagonists BMY 14802 and rimcazole to antagonize DTG-induced hypothermia suggests that either these compounds at the dose used have little sigma receptor antagonist activity, or that the DTG-induced hypothermia is not due to specific interactions with sigma receptors.     

Neuromedin N mimics the actions of neurotensin in the ventral tegmental area but not in the nucleus accumbens

Neuromedin N (NN) is a hexapeptide recently isolated from porcine spinal cord that shares a four-amino acid homology with the C-terminus of the biologically active tridecapeptide neurotensin (NT). Microinjection with NT into the ventral tegmental area or nucleus accumbens of rats has been shown to increase locomotor activity and dopamine (DA) metabolism in some limbic areas or to inhibit the motor stimulant effect of intra-accumbens administration of DA, respectively. In this study the effects of microinjected NN were compared with those of NT. After injection into the ventral tegmental area, NN was shown to be more potent than NT at increasing spontaneous motor activity and to produce an increase in DA metabolism in the nucleus accumbens, prefrontal cortex, diagonal band of Broca and septum. However, when injected into the nucleus accumbens, NN was markedly less potent than NT at inhibiting DA-induced behavioral hyperactivity. In addition to DA-related effects, i.c.v. injection with NT causes hypothermia, and i.c.v. administration with NN was without effect on colonic temperature. These data demonstrate that NN has a behavioral profile distinct from that of NT.     

Developmental regulation of expression of the D3 dopamine receptor in rat nucleus accumbens and islands of Calleja

The dopamine D3 receptor (D3R) belongs to the D2 subfamily and is expressed in the rat brain in targets of the mesolimbic dopaminergic system. Little is known about its normal development and control by dopaminergic innervation. We studied developmental expression of D3R in the rat nucleus accumbens (NAC) and islands of Calleja (ISC). At postnatal day (P) 7, D3 binding sites and mRNA were low in both areas. By P14, D3R and mRNA concentrations were close to adult levels in the ISC, whereas, in the NAC, binding increased until 3 months after birth. Cellular concentrations of D3 mRNA in the ISC increased with age in conjunction with a decrease in the number of D3 positive cells. In the NAC, the number of positive cells increased, whereas cellular levels of expression remained unchanged. Neonatal 6-hydroxydopamine lesion caused age-dependent changes in D3R expression. D3 binding sites did not change at P7 or P14, but there was a reduction in the number of D3 mRNA positive neurons accompanied by an increase in cellular levels of D3 mRNA at P14, suggesting that changes occurred in a subset of neurons. Up-regulation of D3 binding sites in NAC and ISC occurred 1 month after the lesion (P35) concomitant with a decrease in cellular levels of D3 mRNA and the number of D3 mRNA positive cells. At 3 months (P90) after the lesion, an increase in D3 mRNA occurred with no change in D3 binding sites. D3R shows region-specific dynamics in receptor/mRNA expression during development and is sensitive to loss of dopamine in early postnatal development.     

Electrophysiological effects of BMY 14802, a new potential antipsychotic drug, on midbrain dopamine neurons in the rat: acute and chronic studies

The present experiments compared the ability of a new potential antipsychotic drug, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol), to alter the electrophysiological activity of midbrain dopamine (DA) neurons in the rat substantia nigra (A9) and ventral tegmental area (A10). Intravenous administration of BMY 14802 reversed the rate-suppressant effects of the DA agonist apomorphine on both A9 and A10 DA neurons; however, this reversal occurred at significantly lower doses in A10 than in A9. These effects of BMY 14802 appeared not to be mediated by DA receptors because, unlike the established antipsychotic drugs haloperidol and clozapine, BMY 14802 pretreatment failed to block apomorphine-induced suppression of A10 DA cells. Repeated s.c. administration (28 days) of BMY 14802 (2.5-10.0 mg/kg) reduced the number of spontaneously active A10 DA cells recorded per electrode track without affecting the number of A9 DA cells. This inactivation of A10 DA neurons was only partially reversed by the administration of apomorphine. Thus, it is uncertain as to whether this effect was produced by depolarization block as occurs during repeated administration of known antipsychotic drugs. These findings indicate that BMY 14802 influences DA neurotransmission by a nondopaminergic (perhaps sigma opioid) mechanism. The more potent effect of BMY 14802 on A10 DA neurons suggests that this novel compound may exert antipsychotic effects without producing significant extrapyramidal side effects.     

Effect of methamphetamine on neurotensin concentrations in rat brain regions

High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immunoreactivity (NTLI) concentrations of the substantia nigra and striatum in rats after a single or multiple drug doses; smaller but significant increases of 30 to 50% were observed in the hypothalamus and hippocampus after multiple, but not single, METH administrations whereas no measurable changes were detected in the NTLI levels of the periaqueductal gray area or the amygdala. These METH-induced increases in NTLI concentrations were attenuated by coadministration of haloperidol in the substantia nigra, hypothalamus and hippocampus, indicating a possible involvement of dopamine receptors in these tissues. In the striatum haloperidol alone produced significant increases in NTLI levels; these increases were additive with those induced by METH treatment demonstrating that the neurotensin pathways associated with the striatum are regulated differently from that of the other brain areas examined. The implications of these findings to the relationship between dopamine and neurotensin transmitter systems are discussed.     

Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens

The rewarding effects of cocaine are mediated primarily by the mesoaccumbens dopamine (DA) system, which projects from A10 DA cell bodies within the ventral tegmental area to the nucleus accumbens (NAc). This pathway is also intricately involved in the locomotor stimulating effect of cocaine and the progressive increases (sensitization) in this behavior observed after repeated administration of cocaine and other psychomotor stimulants. By using single-cell electrophysiological recording and microiontophoretic techniques, we demonstrated previously that repeated cocaine administration (10 mg/kg i.p., twice daily, 14 days) renders impulse-regulating somatodendritic A10 DA autoreceptors subsensitive, thereby increasing impulse flow within the mesoaccumbens DA system. In striking contrast, inhibitory responses of NAc neurons to iontophoretic DA were significantly increased in cocaine-treated rats tested 16 to 24 hr after the last cocaine injection. In the present study, iontophoretic application of selective D1 (SKF 38393) and D2 (quinpirole) DA receptor agonists was utilized to determine the extent to which each of these DA receptor subtypes is altered by repeated cocaine administration. After 2 weeks of twice daily cocaine (10 mg/kg i.p.) injections, significant increases in the inhibitory responses of NAc neurons to SKF 38393, but not quinpirole, were observed. In addition, this D1 receptor sensitization was still evident when animals were tested either 7 days or 1 month after the final cocaine injection. After 2 months of withdrawal from cocaine treatment, D1 receptor sensitivity in the NAc had returned to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

大鼠帕金森综合征模型脑内黑质、尾状核及中缝核的超微结构变化(英文)

目的观察大鼠帕金森综合征模型脑内黑质、尾状核及中缝核神经元超微结构变化,为阐述该病的发病机制及筛选有效药物,提供实验依据。方法选用健康成年Wistar大鼠12只,雌雄不限,按随机法选9只为实验组(注射盐酸哌替啶),3只为正常对照组(注射等量生理盐水)。应用透射电镜观察经美兰块染的中脑黑质、脑桥中缝部及尾状核部。结果上述核团神经元的超微结构均发生病理性改变,神经细胞核膜皱缩,核膜凹凸不整,并有局部断裂;线粒体变性,基质浓度降低及空泡化;粗面内质网和高尔基复合体囊腔扩张变性;大量初级溶酶体及脂褐素集聚;出现了髓样体和多泡体等变性结构。结论黑质、尾状核及中缝核神经元超微结构的病理性变化从而导致纹状体-黑质-纹状体锥体外路系环路功能障碍,是引发帕金森综合征的结构基础。     

Effects of the 5-hydroxytryptamine receptor antagonist, BMY 7378, on 5-hydroxytryptamine neurotransmission: electrophysiological studies in the rat central nervous system

In the present electrophysiological studies, the effects of the putative 5-hydroxytryptamine (5-HT) receptor antagonist, BMY 7378, on the response of dorsal raphe nucleus 5-HT neurons and of CA3 dorsal hippocampus pyramidal neurons to 5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in chloral hydrate-anesthetized rats. The effectiveness of microiontophoretically applied 5-HT and 8-OH-DPAT in suppressing the firing activity of both neuronal populations was assessed before and during the microiontophoretic application of BMY 7378. BMY 7378 reduced the effectiveness of 8-OH-DPAT, but not that of 5-HT, in depressing 5-HT neuron firing rate, whereas that of both agonists was reduced by concurrent application of BMY 7378 in the hippocampus. To assess whether endogenous 5-HT also could be antagonized, the response of pyramidal neurons to electrical activation of the 5-HT pathway was determined before and after i.v. BMY 7378. Low doses enhanced the efficacy of the stimulation, whereas higher doses decreased it. The latter finding suggests that BMY 7378 antagonizes the effect of endogenous 5-HT. Three procedures were used to investigate the enhancing effect of BMY 7378 on 5-HT synaptic transmission: 1) administration of BMY 7378 after terminal 5-HT autoreceptor blockade by methiothepin: methiothepin abolished the enhancing effect of BMY 7378; 2) blockade of the effect of RU 24969, a terminal 5-HT autoreceptor agonist: pretreatment with methiothepin, but not with BMY 7378, blocked the effect of RU 24969 on 5-HT synaptic transmission; and 3) administration of BMY 7378 during a reduced level of activation of terminal 5-HT autoreceptors, obtained by lowering the stimulation frequency from 1 to 0.5 Hz: the enhancing effect of BMY 7378 was reduced when the stimulation was delivered at 0.5 Hz. It is concluded that BMY 7378 is an effective antagonist of 5-HT1A receptors in vivo and that the mechanism of its enhancing effect on 5-HT transmission at low doses, although still undetermined, is not due to a competitive interaction at the terminal 5-HT autoreceptor.     

Adenoviral overexpression of interleukin-1 receptor antagonist protein increases beta-cell replication in rat pancreatic islets

The naturally occurring inhibitor of interleukin-1 (IL-1) action, interleukin-1 receptor antagonist protein (IRAP), binds to the type 1 IL-1 receptor but does not initiate IL-1 signal transduction. In this study, we have determined the effects of IL-1beta and IRAP overexpression on adult beta-cell replication and viability. IL-1beta reduced dramatically beta-cell replication in adult rat islets both at 5.5 mM (control: 0.29+/-0.04%; IL-1beta: 0.02+/-0.02%, P<0.05) and 22.2 mM glucose (control: 0.84+/-0.2%; IL-1beta: 0.05+/-0.05%, P<0.05). This effect was completely prevented in islets overexpressing IRAP after adenoviral gene transfer at 5.5 mM (Ad-IL-1Ra+IL-1beta: 0.84+/-0.1%, P<0.05) and 22.2 mM glucose (Ad-IL-1Ra+IL-1beta: 1.22+/-0.2%, P<0.05). Moreover, overexpression of IRAP increased glucose-stimulated beta-cell replication in the absence of IL-1beta exposure (Ad-IL-1Ra: 1.59+/-0.5%, P<0.05). beta-Cell death (TUNEL technique) was increased in IL-1beta-exposed islets but not in Ad-IL-1Ra-infected islets (control: 0.82+/-0.2%; control+IL-1beta: 1.77+/-0.2; IRAP: 0.61+/-0.2%; IRAP+IL-1beta: 0.86+/-0.1%, P<0.05). Comparable results were obtained by flow cytometry. To determine the effect of IRAP overexpression on beta-cell replication in vivo, Ad-IL-1Ra-transduced islets were transplanted into streptozotocin diabetic rats. beta-Cell replication was significantly increased in IRAP-overexpressing islet grafts (0.98+/-0.3%, P<0.05) compared to normal pancreas (0.35+/-0.02%), but not in control islet grafts (0.50+/-0.1%). This study shows that in addition to the effects of IL-1beta on beta-cell viability, this cytokine exerts a deleterious action on beta-cell replication, which can be prevented by IRAP overexpression, and provides support for the potential use of IRAP as a therapeutic tool.     

In vivo electrochemical demonstration of the presynaptic actions of phencyclidine in rat caudate nucleus

In vivo electrochemical recordings, coupled with local application of drugs from micropipettes, were used to determine the presynaptic effects of phencyclidine (PCP) on dopamine-containing nerve terminals in the intact rat striatum. Local application of PCP did not elicit an observable increase in extracellular levels of the monoamine neurotransmitters. However, pretreatment with PCP significantly potentiated the potassium-evoked release of monoamines. Nomifensine, a potent catecholamine reuptake blocker, produced effects that were analogous with PCP. Local pretreatment with PCP was also found to potentiate the electrochemical signal detected after pressure ejection of dopamine directly into the caudate nucleus. Finally, electrophysiological studies showed that locally applied PCP and nomifensine solutions had similar potencies in depressing the spontaneous firing of striatal neurons. Taken together, these data suggest that the major presynaptic action of PCP in the rat caudate nucleus is inhibition of the reuptake, and not alteration of release, of the monoamine neurotransmitters.     

Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats

We studied the effect of opiates acting preferentially on mu receptors, like morphine, methadone and fentanyl (mu agonists) and on kappa receptors, like U50,488, bremazocine and tifluadom (kappa agonists) on the release of dopamine (DA) and of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, from the nucleus accumbens and from the dorsal caudate of freely moving rats using brain dialysis coupled to high-performance liquid chromatography with electrochemical detection. Spontaneous behavior was videotaped and analyzed by estimating the percentage of time spent by the animals in performing certain specific behavioral items. Mu agonists stimulated DA-release and metabolism in the accumbens at lower doses than in the caudate. Maximal stimulation of DA release did not exceed 100% except after high doses of methadone (10 mg/kg) which stimulated DA release in the accumbens by more than 300%, possibly as a result of hypoxia. Stimulation of DA release was associated to stimulation of behavior at low doses and to a biphasic inhibitory-stimulatory syndrome after higher doses of the opiates. Pretreatment with low doses of naloxone (0.1 mg/kg s.c.) or with the irreversible mu antagonist beta-funaltrexamine (10 nmol i.c.v.) increased the ED50 for the stimulation of DA release by the three opiates. In contrast with mu agonists, agonists of kappa receptors like U50,488, bremazocine and tifluadom decreased DA release in the accumbens and in the caudate and reduced motor activity. These effects were antagonized only by rather high doses of naloxone (2.5 mg/kg s.c.) and were not affected by pretreatment with beta-funaltrexamine (10 nmol i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated cocaine treatment decreases whole-cell calcium current in rat nucleus accumbens neurons

Dopamine D1 receptors within the nucleus accumbens (NAc) are intricately involved in the rewarding effects of cocaine and in withdrawal symptoms after cessation of repeated cocaine administration. These receptors couple to a variety of ion channels to modulate neuronal excitability. Using whole-cell recordings from dissociated adult rat NAc medium spiny neurons (MSNs), we show that, as in dorsal striatal MSNs, D1 receptor stimulation suppresses N- and P/Q-type Ca(2+) currents (I(Ca)) by activating a cAMP/protein kinase A/protein phosphatase (PP) signaling system, presumably leading to channel dephosphorylation. We also report that during withdrawal from repeated cocaine administration, basal I(Ca) density is decreased by 30%. Pharmacological isolation of specific I(Ca) components indicates that N- and R-type, but not P/Q- or L-type, currents are significantly reduced by repeated cocaine treatment. Inhibiting PP activity with okadaic acid enhances I(Ca) in cocaine withdrawn, but not control, NAc neurons, suggesting an increase in constitutive PP activity. This suggestion was supported by a significant decrease in the ability of D1 receptor stimulation and direct activation of cAMP signaling to suppress I(Ca) in cocaine-withdrawn NAc neurons. Chronic cocaine-induced reduction of I(Ca) in NAc MSNs will globally impact Ca(2+)-dependent processes, including synaptic plasticity, transmitter release, and intracellular signaling cascades that regulate membrane excitability. Along with our previously reported reduction in whole-cell Na(+) currents during cocaine withdrawal, these findings further emphasize the important role of whole-cell plasticity in reducing information processing during cocaine withdrawal.     

Acupuncture stimulates the release of serotonin, but not dopamine, in the rat nucleus accumbens

Acupuncture has been introduced as one of the available therapies widely used in alternative medicine, but it has not achieved widespread acceptance with scientific evidence. Furthermore there are still many unanswered questions about the basic mechanisms of acupuncture. To investigate the neuropharmacological mechanisms of oriental acupuncture, we studied the acupuncture-induced changes of in vivo monoamine release in the rat brain. A microdialysis guide cannula was implanted into the nucleus accumbens (ACC), which plays an important role in the brain reward system. Acupuncture treatment at the unilateral or bilateral Shenshu (bladder urinary channel 23) acupoints, located on the both sides of the spinous processes on the lower back, was carried out for 60 min in freely moving rats, and the dopamine (DA) and serotonin (5-HT) contents of the microdialysates in the ACC were measured simultaneously. In rats subjected to acupuncture at bilateral Shenshu acupoints, increases of 5-HT release in the ACC were observed at 20 min of acupuncture treatment and continued until 40 min after acupuncture was ended. Acupuncture at a unilateral Shenshu acupoint increased the release of 5-HT at 20 min compared with that in the sham-control group. Five-HT release returned to the baseline level at 120 min. The effects of acupuncture at bilateral Shenshu acupoints on the release of 5-HT in the ACC were greater than that of unilateral acupuncture treatment. In contrast, DA release in the ACC was not changed following acupuncture treatment. Effective acupuncture increased and prolonged the activity of serotonergic neurons in the reward system pathway of the brain. This suggests that oriental acupuncture therapy may be effective for the treatment of emotional disorders, drug abuse and alcoholism.     

Dysregulation of dopamine transporter trafficking and function after abstinence from cocaine self-administration in rats: evidence for differential regulation in caudate putamen and nucleus accumbens

The profound alterations produced by cocaine on dopamine (DA) neurotransmission raise the possibility that dopamine transporter (DAT)-expressing neurons may modify DA transport in response to repeated cocaine exposure to maintain the appropriate efficiency of DA clearance. In this study, we determined the changes in molecular mechanisms of DAT regulation in rats with a history of repeated cocaine self-administration followed by 3 weeks of abstinence. Using ex vivo caudate putamen (CPu) and nucleus accumbens (NAcc) synaptosomal preparations, we found that DA uptake was significantly higher in the CPu and NAcc of cocaine-experienced animals compared with yoked saline animals. Surface distribution, p-Ser phosphorylation, and protein phosphatase 2A catalytic subunit (PP2Ac) interaction of DAT were all altered in the CPu. Maximal velocity (V(max)) values were elevated both in the CPu and NAcc of cocaine-experienced rats compared with saline controls. Although there was no change in the apparent affinity for DA in the CPu, increased DA affinity was evident in the NAcc. Consistent with elevated DAT activity in cocaine-experienced animals, a higher level of surface DAT, DAT-PP2Ac association, and decreased serine phosphorylation of DAT were observed in the CPu, but not in the NAcc. These results, for the first time, suggest that chronic cocaine self-administration followed by abstinence leads to persisting alterations in normal DAT trafficking and catalytic regulatory cascades in the CPu and NAcc in a brain region-specific manner.     

Signal valence in the nucleus accumbens to pain onset and offset

Pain and relief are at opposite ends of the reward–aversion continuum. Studying them provides an opportunity to evaluate dynamic changes in brain activity in reward–aversion pathways as measured by functional magnetic resonance imaging (fMRI). Of particular interest is the nucleus accumbens (NAc), a brain substrate known to be involved in reward–aversion processing, whose activation valence has been observed to be opposite in response to reward or aversive stimuli. Here we have used pain onset (aversive) and pain offset (rewarding) involving a prolonged stimulus applied to the dorsum of the hand in 10 male subjects over 120 s to study the NAc fMRI response. The results show a negative signal change with pain onset and a positive signal change with pain offset in the NAc contralateral to the stimulus. The study supports the idea that the NAc fMRI signal may provide a useful marker for the effects of pain and analgesia in healthy volunteers.     

MRI atrophy of the caudate nucleus and slower walking speed in the elderly

Cerebral white matter lesions are associated with poorer motor performances in the elderly, but the role of gray matter atrophy remains largely unknown. We investigated the cross-sectional relation between brain regional gray matter volumes and walking speed over 6m in the 3C-Dijon study, a large population-based study of community-dwelling persons aged 65 years and over (N=1623). Regional gray matter volumes were obtained using an automated anatomical labeling parcellation method. Multivariable analyses were performed using a semi-Bayes approach. After adjustment for potential confounders, persons who walked slower had a smaller volume of basal ganglia (regression coefficient [β]=0.054, standard error [SE]=0.028, p=0.05). In more detailed analyses, the volume of the caudate nucleus had a preponderant role on this association (β=0.049, SE=0.019, p=0.009), and walking speed decreased progressively with the volume of the caudate nucleus (p for linear trend<0.001). These results underline the role of gray matter subcortical structures, in particular of the caudate nucleus, in the age-related decline of motor performances among community-dwelling elderly subjects.     

Role of nucleus accumbens in neuropathic pain: Linked multi-scale evidence in the rat transitioning to neuropathic pain

Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury [SNI]). We observed interrelated changes: (1) In resting-state functional magnetic resonance imaging (fMRI), functional connectivity of the NAc to dorsal striatum and cortex was reduced 28 days (but not 5 days) after SNI; (2) Contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28 days after SNI; (3) In SNI (but not sham), covariance of gene expression was upregulated at 5 days and settled to a new state at 28 days; and (4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior.