Monoaminergic Modulation of Motor Cortex Function

Elaboration of appropriate responses to behavioral situations rests on the ability of selecting appropriate motor outcomes in accordance to specific environmental inputs. To this end, the primary motor cortex (M1) is a key structure for the control of voluntary movements and motor skills learning. Subcortical loops regulate the activity of the motor cortex and thus contribute to the selection of appropriate motor plans. Monoamines are key mediators of arousal, attention and motivation. Their firing pattern enables a direct encoding of different states thus promoting or repressing the selection of actions adapted to the behavioral context. Monoaminergic modulation of motor systems has been extensively studied in subcortical circuits. Despite evidence of converging projections of multiple neurotransmitters systems in the motor cortex pointing to a direct modulation of local circuits, their contribution to the execution and learning of motor skills is still poorly understood. Monoaminergic dysregulation leads to impaired plasticity and motor function in several neurological and psychiatric conditions, thus it is critical to better understand how monoamines modulate neural activity in the motor cortex. This review aims to provide an update of our current understanding on the monoaminergic modulation of the motor cortex with an emphasis on motor skill learning and execution under physiological conditions

Basolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits.

In the development of addiction, drug seeking becomes habitual and controlled by drug-associated cues, and the neural locus of control over behaviour shifts from the ventral to the dorsolateral striatum. The neural mechanisms underlying this functional transition from recreational drug use to drug-seeking habits are unknown. Here we combined functional disconnections and electrophysiological recordings of the amygdalo-striatal networks in rats trained to seek cocaine to demonstrate that functional shifts within the striatum are driven by transitions from the basolateral (BLA) to the central (CeN) amygdala. Thus, while the recruitment of dorsolateral striatum dopamine-dependent control over cocaine seeking is triggered by the BLA, its long-term maintenance depends instead on the CeN. These data demonstrate that limbic cortical areas both tune the function of cognitive territories of the striatum and thereby underpin maladaptive cocaine-seeking habits.This work was supported by the Fondation pour la Recherche Médicale (FRM), the United Kingdom Medical Research Council (MRC) Grant 9536855 to BJE, the AXA research fund to ABR, an INSERM Avenir and an Agence Nationale de la Recherche (ANR) grant ANR12 SAMA00201 to DB. Research was conducted within both the MRC/Wellcome Trust Behavioral and Clinical Neuroscience Institute of Cambridge and the Inserm team “Psychobiology of Compulsive Disorders”, University of Poitiers.This is the final version of the article. It was first available from NPG via http://dx.doi.org/10.1038/ncomms1008

Integrated dopaminergic neuronal model with reduced intracellular processes and inhibitory autoreceptors

Dopamine (DA) is an important neurotransmitter for multiple brain functions, and dysfunctions of the dopaminergic system are implicated in neurological and neuropsychiatric disorders. Although the dopaminergic system has been studied at multiple levels, an integrated and efficient computational model that bridges from molecular to neuronal circuit level is still lacking. In this study, the authors aim to develop a realistic yet efficient computational model of a dopaminergic pre‐synaptic terminal. They first systematically perturb the variables/substrates of an established computational model of DA synthesis, release and uptake, and based on their relative dynamical timescales and steady‐state changes, approximate and reduce the model into two versions: one for simulating hourly timescale, and another for millisecond timescale. They show that the original and reduced models exhibit rather similar steady and perturbed states, whereas the reduced models are more computationally efficient and illuminate the underlying key mechanisms. They then incorporate the reduced fast model into a spiking neuronal model that can realistically simulate the spiking behaviour of dopaminergic neurons. In addition, they successfully include autoreceptor‐mediated inhibitory current explicitly in the neuronal model. This integrated computational model provides the first step toward an efficient computational platform for realistic multiscale simulation of dopaminergic systems in in silico neuropharmacology

Cortical choline transporter function measured in vivo using choline-sensitive microelectrodes: clearance of endogenous and exogenous choline and effects of removal of cholinergic terminals

The capacity of the high-affinity choline transporter (CHT) to import choline into presynaptic terminals is essential for acetylcholine synthesis. Ceramic-based microelectrodes, coated at recording sites with choline oxidase to detect extracellular choline concentration changes, were attached to multibarrel glass micropipettes and implanted into the rat frontoparietal cortex. Pressure ejections of hemicholinium-3 (HC-3), a selective CHT blocker, dose-dependently reduced the uptake rate of exogenous choline as well as that of choline generated in response to terminal depolarization. Following the removal of CHTs, choline signal recordings confirmed that the demonstration of potassium-induced choline signals and HC-3-induced decreases in choline clearance require the presence of cholinergic terminals. The results obtained from lesioned animals also confirmed the selectivity of the effects of HC-3 on choline clearance in intact animals. Residual cortical choline clearance correlated significantly with CHT-immunoreactivity in lesioned and intact animals. Finally, synaptosomal choline uptake assays were conducted under conditions reflecting in vivo basal extracellular choline concentrations. Results from these assays confirmed the capacity of CHTs measured in vivo and indicated that diffusion of substrate away from the electrode did not confound the in vivo findings. Collectively, these results indicate that increases in extracellular choline concentrations, irrespective of source, are rapidly cleared by CHTs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65847/1/j.1471-4159.2006.03766.x.pd

Striatal Dopamine Transmission Is Subtly Modified in Human A53Tα-Synuclein Overexpressing Mice

Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD). Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA) signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs) were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction

Age-dependent effects of low-dose nicotine treatment on cocaine-induced behavioral plasticity in rats

Epidemiological evidence of early adolescent tobacco use, prior to that of marijuana and other illicit drugs, has led to the hypothesis that nicotine is a “gateway” drug that sensitizes reward pathways to the addictive effects of other psychostimulants. To test this hypothesis, we have compared the effect of a brief, low-dose nicotine pretreatment of adolescent and adult rats on subsequent locomotor response to acute and chronic cocaine. Adolescents, aged postnatal day (P) 28, and adults, aged P86, were given four daily injections of saline or nicotine (0.06 mg/kg, i.v.). At P32 and P90, rats were given acute injections of cocaine (0, 0.4 or 1.0 mg/kg, i.v.) and monitored for locomotor activity in either a habituated or novel test environment. To examine cocaine sensitization, rats were treated for 3 days with saline or cocaine (0.4 mg/kg, i.v.), and, after 1 day of withdrawal, were given a challenge dose of cocaine (0.4 mg/kg, i.v.). Nicotine pretreatment did not affect acute, drug-induced locomotor activity at either age. However, age differences in cocaine response were observed, with adolescent animals showing enhanced locomotor activity in the novel environment. Adolescent controls did not exhibit cocaine-induced locomotor sensitization, whereas adults did. Nicotine pretreatment during adolescence promoted the development and expression of a sensitized response to repeated cocaine exposure similar to that observed in saline-pretreated adult controls. These findings show that brief pretreatment with nicotine, in a low dose comparable to that inhaled in 2–4 cigarettes, enhances cocaine-induced behavioral plasticity in adolescent rats

Role of Kv1 Potassium Channels in Regulating Dopamine Release and Presynaptic D2 Receptor Function

Dopamine (DA) release in the CNS is critical for motor control and motivated behaviors. Dysfunction of its regulation is thought to be implicated in drug abuse and in diseases such as schizophrenia and Parkinson's. Although various potassium channels located in the somatodendritic compartment of DA neurons such as G-protein-gated inward rectifying potassium channels (GIRK) have been shown to regulate cell firing and DA release, little is presently known about the role of potassium channels localized in the axon terminals of these neurons. Here we used fast-scan cyclic voltammetry to study electrically-evoked DA release in rat dorsal striatal brain slices. We find that although G-protein-gated inward rectifying (GIRK) and ATP-gated (KATP) potassium channels play only a minor role, voltage-gated potassium channels of the Kv1 family play a major role in regulating DA release. The use of Kv subtype-selective blockers confirmed a role for Kv1.2, 1.3 and 1.6, but not Kv1.1, 3.1, 3.2, 3.4 and 4.2. Interestingly, Kv1 blockers also reduced the ability of quinpirole, a D2 receptor agonist, to inhibit evoked DA overflow, thus suggesting that Kv1 channels also regulate presynaptic D2 receptor function. Our work identifies Kv1 potassium channels as key regulators of DA release in the striatum

Contrôle de la libération et de l'élimination de la dopamine par la recapture et les autorécepteurs (études par électrochimie in vivo dans le striatum)

Nous avons étudié deux mécanismes contrôlant la dopamine extracellulaire : l'autorégulation et la recapture par son transporteur (DAT). L'efflux de dopamine évoqué par des stimulations électriques a été enregistré dans le striatum et le noyau accumbens par ampérométrie continue chez la souris anesthésiée. Nous avons montré in vivo que le DAT est le seul mécanisme d'élimination de la dopamine, et qu'il permet la reconstitution du stock de dopamine libérable. Les neurones dopaminergiques présentent une activité tonique à 4 Hz, et une activité phasique en bouffées à 15 Hz. Chez l'animal normal, seules les bouffées entraînent une accumulation de la dopamine extracellulaire. Chez les souris sans DAT, la dopamine s'accumule aussi lors de l'activité tonique. L'expression différentielle des activités tonique et phasique, en termes de dopamine extracellulaire, dépend donc du DAT. Nous avons montré que la recapture limite la distance de diffusion de la dopamine à 7(micron)m. La dopamine extracellulaire agit sur des autorécepteurs D2 présynaptiques qui inhibent sa propre libération. Nous avons précisé le décours temporel de cette inhibition (maximum à 0,2 s et durée de 0,6 s) et nous avons montré que l'activation des autorécepteurs nécessite l'accumulation de dopamine extracellulaire. Ces caractéristiques sont typiques des récepteurs couplés aux protéines G. L'autoinhibition limite le taux de dopamine extracellulaire durant une bouffée et la quantité de dopamine libérée par un potentiel d'action suivant une bouffée. Toutefoi_s, par rapport à la recapture, l'autorégulation ne joue qu'un rôle secondaire de régulateur fin. L'autorégulation est diminuée en absence du DAT, et non l'inverse. De plus, des altérations postsynaptiques de la transmission dopaminergique n'induisent pas d'adaptation présynaptique. Il semble donc que seule une atteinte directe de la recapture altère de façon majeure l'expression de la transmission dopaminergique en termes de dopamine extracellulaire.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

D 2 dopamine modulation of corticoaccumbens synaptic responses changes during adolescence

International audienc