F-FECNT: Validation as PET dopamine transporter ligand in parkinsonism

The positron emission tomography (PET) tracer 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)-nortropane (¹⁸F-FECNT) is a highly specific ligand for dopamine transporter (DAT) that yields higher peak striatum-to-cerebellum ratios and offers more favorable kinetics than most ¹⁸F-radiolabeled DAT ligands currently available. The goal of this study is to validate the use of ¹⁸F-FECNT as a PET radiotracer to assess the degree of striatal dopamine terminals denervation and midbrain dopaminergic cell loss in MPTP-treated parkinsonian monkeys. Three rhesus monkeys received weekly injections of MPTP (0.2–0.5 mg/kg) for 21 weeks, which resulted in the progressive development of a moderate level of parkinsonism. We carried out ¹⁸F-FECNT PET at baseline (twice; 10 weeks apart) and at week 21 post-MPTP injections. Postmortem stereological cell counts of dopaminergic neurons in the ventral midbrain, and intensity measurements of DAT and tyrosine hydroxylase (TH) immunoreactivity in the striatum were performed and correlated with striatal and ventral midbrain PET data. Three additional monkeys were used as controls for midbrain dopaminergic cell counts, and striatal DAT or TH immunoreactivity measurements. The correlation and coefficient of variance between ¹⁸F-FECNT test–retest specific uptake ratios were 0.99 (R²) and 2.65%, respectively. The ¹⁸F-FECNT binding potential of the ventral midbrain and striatal regions was tightly correlated with postmortem stereological cell counts of nigral dopaminergic neurons (R² = 0.91), and striatal DAT (R² = 0.83) or TH (R² = 0.88) immunoreactivity intensity measurements. These findings demonstrate that ¹⁸F-FECNT is a highly sensitive PET imaging ligand to quantify both striatal dopamine denervation and midbrain dopaminergic cell loss associated with parkinsonism.     

Serum brain-derived neurotrophic factor predicts responses to escitalopram in chronic posttraumatic stress disorder

Introduction

Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats.

Objectives

This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response.

Methods

Medically healthy male subjects (N = 16) with chronic PTSD completed a 12 week open-label trial of flexible dose (5–20 mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12.

Results

PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r = 0.58, p = 0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial.

Conclusions

PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects.     

Effect of adolescent exposure to MDMA and cocaine on acquisition and reinstatement of morphine-induce CPP

It is well known that an elevated percentage of ecstasy users also consume cocaine. Recently, it has been reported that a high frequency of heroin smokers first consumed heroin under the effects of ecstasy with the hope of reducing the stimulant effects of the latter drug. The aim of the present study was to evaluate the effect of exposure to MDMA and cocaine during adolescence on morphine-induced conditioned place preference (CPP) and reinstatement in adulthood. In the first experiment, adolescent mice were exposed to six injections of MDMA and three weeks later their response to the reinforcing properties of 40 mg/kg of morphine was evaluated using the CPP paradigm. All the treatment groups developed the same magnitude of morphine-induced preference and, after CPP was extinguished, it was restored in all the groups with a priming dose of 10 mg/kg of morphine. Only mice that had been treated with 10 or 20 mg/kg of MDMA had their morphine-induced preference reinstated after receiving only 5 mg/kg of morphine. In the second experiment, adolescent mice were similarly treated with six administrations of cocaine (25 mg/kg) or cocaine plus MDMA (5, 10 or 20 mg/kg), and their response to morphine-induce CPP was evaluated three weeks later. Similarly to the first experiment, all the groups developed a preference for the morphine-paired compartment, but this preference was not reinstated with a priming dose of 10 mg/kg of morphine following extinction, as was the case among the control animals. These results lead us to hypothesize that periadolescent MDMA exposure alters responsiveness to the rewarding properties of morphine, highlighting MDMA as a gateway drug whose use may increase the likelihood of dependence on other drugs.     

Diet and chronic haloperidol effects on rat midbrain dopamine neurons

The effects of dietary glucose (chow containing 0%, 10%, 20%, or 40% glucose, w/w) on chronic haloperidol-induced changes in dopamine (DA) neuronal activity were tested. Rats were treated daily by oral gavage for 21 days with either water or 0.5 mg/kg haloperidol, then anesthetized for in vivo electrophysiological recording. The numbers of spontaneously active DA neurons in the substantia nigra (A9) and ventral tegmental area (A10) regions of the midbrain were estimated with the cells-per-track sampling method. In rats fed standard chow, haloperidol significantly reduced the number of active neurons in both regions compared to water controls. In water controls there were no differences in DA cells per track between rats fed standard chow or chow containing 10% or 20% glucose, whereas these glucose diets significantly attenuated the effects of chronic haloperidol on DA cells per track. The 40% glucose diet itself nonsignificantly reduced cells per track and, in turn, nonsignificantly attenuated the effects of haloperidol. The results demonstrate that dietary glucose content can alter haloperidol-induced changes in the activity of midbrain DA neurons.     

Suppressing calcium/calmodulin-dependent protein kinase II activity in the ventral tegmental area enhances the acute behavioural response to cocaine but attenuates the initiation of cocaine-induced behavioural sensitization in rats

In the present experiments we administered an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist (CNQX), N-methyl-D-aspartate (NMDA) receptor antagonist (AP-5), or l-type calcium channel blocker (diltiazem) directly into the ventral tegmental area (VTA) before each of four daily systemic cocaine injections in order to assess their influence on the initiation phase of behavioural sensitization. Results indicated that pretreatment with CNQX or AP-5 impaired the initiation of cocaine-induced behavioural sensitization. Intra-VTA administration of diltiazem significantly increased the behavioural activation induced by an acute cocaine injection, but impaired the development of cocaine-induced behavioural sensitization. Because AMPA and NMDA receptors, as well as l-type calcium channels are calcium permeable, we also investigated the role of the calcium-activated second messenger calcium/calmodulin-dependent protein kinase II (CaM-KII). Similar to the results obtained with diltiazem, administration of the CaM-KII inhibitor KN-93 into the VTA enhanced the acute behavioural response to cocaine but prevented the augmentation of cocaine-induced behavioural hyperactivity following repeated injections. Consistent with this finding, the behavioural hyperactivity produced by cocaine was markedly enhanced among homozygous alpha-CaM-KII knockout mice but the initiation of behavioural sensitization to cocaine was attenuated relative to wild-type mice. Separate experiments performed in rats demonstrated an increase in total protein levels of CaM-KII in the VTA 24 h after the last of seven daily injections of cocaine. Taken together, these results indicate that blocking l-type calcium channels or impairing CaM-KII activity in the VTA augments the acute behavioural hyperactivity induced by cocaine. The present findings also suggest that increased calcium influx through AMPA receptors, NMDA receptors and l-type calcium channels on dopaminergic neurons in the VTA contributes significantly to the initiation of behavioural sensitization by amplifying calcium signalling through CaM-KII.     

Electrophysiological profile of the new atypical neuroleptic, sertindole, on midbrain dopamine neurones in rats: acute and repeated treatment.

Sertindole (Lundbeck code No. Lu 23-174) (1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] ethyl]-2-imidazolidinone) is a new potential neuroleptic compound. After 3 weeks of treatment sertindole shows an extreme selectivity to inhibit the number of spontaneously active dopaminergic (DA) neurones in ventral tegmental area (VTA) while leaving the number of active DA neurones in substantia nigra pars compacta (SNC) unaffected. Acute injection of apomorphine or baclofen reverse the inhibition of activity seen after repeated treatment with sertindole. This suggests that sertindole induces a depolarization inactivation of the DA neurones. The depolarization inactivation is reversible since normal activity of DA neurones is found in both SNC and VTA after two weeks withdrawal from repeated treatment with a low dose with sertindole. One or two weeks administration of a high dose of sertindole induced only minor effects on the DA neurones in VTA; i.e., in order to obtain the depolarization inactivation sertindole requires 3 weeks of treatment as has also been reported for other neuroleptics. Three weeks of treatment with clozapine induces a selective inhibition of the active DA neurones in VTA but at much higher doses than seen with sertindole, while haloperidol induces a non-selective decrease of spontaneously active DA neurones in both areas. In acute electrophysiological experiments intravenous (i.v.) administration of sertindole--in contrast to both clozapine and haloperidol--neither reverse d-amphetamine- nor apomorphine-induced inhibition of the firing frequencies of DA neurones in SNC or in VTA. In addition, sertindole does not--even in high doses--increase the firing frequency of DA neurones in SNC or VTA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity by the novel selective dopamine D3-receptor partial agonist FAUC 329 predominantly in the nucleus accumbens of mice

We previously synthesised a novel dopamine (DA) partial agonist FAUC 329 with high affinity and selectivity for the DA D(3) receptor. This is the first in vivo study to investigate the protective effects of FAUC 329 in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Adult male C57bl/6 mice were injected with FAUC 329 (0, 0.1, 0.5, 0.75, or 1 mg/kg) 30 min before MPTP (2 x 30 mg/kg, 4 hr apart). One week later, accumbal and striatal tissue was processed for DA and metabolite HPLC determination as well as immunohistochemical analysis of DA transporter positive neurons in the substantia nigra pars compacta and ventral tegmental area was carried out. FAUC 329 showed a significant attenuation of MPTP-induced DA reduction in the nucleus accumbens (0.5, 0.75 and 1 mg/kg) in a dose-dependent manner. FAUC 329 (0.75 mg/kg) partly protected against DA depletion in the dorsal striatum as well as protected against loss of DA transporter immunoreactivity in the substantia nigra pars compacta. The highest dose of FAUC 329 (1 mg/kg), however, showed a non-significant tendency to augment the MPTP-induced striatal DA reduction. The protective effect of FAUC 329 against MPTP-induced DA depletion was most pronounced in the nucleus accumbens and appears to be linked to the preferential abundance of D(3) receptors in this region. Targeting the mesolimbic DA system may have implications for improvement of impaired motor behaviour and particularly non-motor functions related to the nucleus accumbens.     

Cocaine self-administration alters the locomotor response to microinjection of bicuculline into the ventral tegmental area of rats

Several studies indicate that repeated administration of cocaine can alter GABA(A) receptor function, particularly in the mesolimbic pathway. The purpose of the present study was to assess the effect of cocaine self-administration on GABA(A) receptor activity in the ventral tegmental area (VTA), measured by bicuculline-induced rotational behavior. In order to test whether the hypothesized alteration in GABA(A) receptor function persisted during withdrawal, rats were tested when drug-nai;ve and at two time points after cocaine self-administration. Eighteen rats were implanted with intrajugular catheters and unilateral guide shafts aimed at the VTA. Microinjection of the GABA(A) receptor antagonist bicuculline (10, 25 and 50 ng) produced a dose-dependent turning behavior in a direction ipsilateral to the side of the injection. A subset of six rats was given up to 2 weeks exposure to intravenous cocaine by self-administration and was tested for bicuculline-induced rotations early in withdrawal (24 h) and again at a late withdrawal time point (between 11 and 14 days after the last cocaine session). Cocaine self-administration reduced sensitivity to bicuculline-induced rotations at the early but not at the late withdrawal point, when compared to sensitivity in drug-naive animals. A separate control study that was conducted in seven rats determined that repeated injections of bicuculline in the cocaine self-administration animals was not the cause of the decrease in behavioral response to bicuculline at the early withdrawal time point. These results suggest that exposure to cocaine via self-administration reduces the function of GABA(A) receptors in the ventral midbrain, but this reduction in receptor sensitivity did not persist beyond 10 days of withdrawal from cocaine.     

Mesolimbic dopamine projection modulates amygdala-evoked EPSP in nucleus accumbens neurons: an in vivo study

In urethane anesthetized rats, excitatory postsynaptic potential (EPSP) recorded intracellularly from nucleus accumbens neurons following stimulation of the amygdala was attenuated by repetitive stimulation of the ventral tegmental area (VTA). VTA stimulation also depolarized the resting membrane potential of accumbens neurons. Attenuation of the EPSP and membrane depolarization were frequently dissociated but both were blocked by haloperidol, a dopamine antagonist.     

Deep brain stimulation electrode insertion and depression: Patterns of activity and modulation by analgesics

Background

An initial antidepressant effect when using deep brain stimulation (DBS) of the subcallosal area of the cingulate cortex (Cg25) to treat resistant depression that could be the result of electrode insertion has been described. We previously showed that electrode insertion into the infralimbic cortex (ILC; the Cg25 rodent correlate) provokes a temporally limited antidepressant-like effect that is counteracted by non-steroidal anti-inflammatory drugs, such as those routinely used for pain relief.