Dopamine receptors in the learning,memory and drug reward circuitry

As primary targets of a variety of abused drugs G-protein-coupled dopamine receptors in the brain play an important role in mediating the various drug-induced alterations in neural and psychological processes thought to underlie the transition from voluntary drug use to habitual and progressively compulsive drug-taking. This review considers the functional involvement of the five major dopamine receptor subtypes in drug reinforcement and reward and discusses the development of addiction as a series of learning transitions from initial goal-directed behaviour to pathological stimulus–response habits in which drug-seeking behaviours are automatically elicited and maintained by cues and stimuli associated with drug rewards.     

Synaptic plasticity and neuropathology: new approaches in drug discovery

Neuronal plasticity is now known to be very important in the adult, both in the formation of new synaptic connections and of new neurones (neurogenesis) and of glial cells. However, old age and stress can inhibit this plasticity and lead to cerebral atrophy. The time course of changes in neuronal plasticity involves, in the first milliseconds to seconds, changes in synaptic strength (long term potentialisation, LTP, or long term depression, LTD), then, over minutes to hours, changes in the number of synaptic connections (linked to changes in neurotrophic factors), and over weeks to months, to changes in neuronal reconfiguration. These changes in brain systems are particularly targeted in psychiatric disorders to the areas which are sensitive to stress and play roles in memory and emotion (hippocampus, amygdala and prefrontal cortex). The discovery and development of drugs modifying neuronal plasticity and neurotrophins production has been a priority for Servier research for the last ten years; Servier has a clinically effective antidepressant, tianeptine (Stablon), with a favourable side effect profile, but which does not inhibit the uptake of serotonin, or other monoamines. However, this drug can reverse the deleterious effects of stress on neuronal plasticity, thereby acting on the causes of psychiatric disorders. Furthermore, a new research area is being investigated - facilitation of AMPA receptors, favouring the production of neurotrophic factors.     

Synaptic signalling in cerebellar plasticity

A major goal of learning and memory research is to correlate the function of molecules with the behaviour of organisms. The beautiful laminar structure of the cerebellar cortex lends itself to the study of synaptic plasticity, because its clearly defined patterns of neurons and their synapses form circuits that have been implicated in simple motor behaviour paradigms. The best understood in terms of molecular mechanism is the parallel fibre-Purkinje cell synapse, where presynaptic long-term potentiation and postsynaptic long-term depression and potentiation finely tune cerebellar output. Our understanding of these forms of plasticity has mostly come from the electrophysiological and behavioural analysis of knockout mutant mice, but more recently the knock-in of synaptic molecules with mutated phosphorylation sites and binding domains has provided more detailed insights into the signalling events. The present review details the major forms of plasticity in the cerebellar cortex, with particular attention to the membrane trafficking and intracellular signalling responsible. This overview of the current literature suggests it will not be long before the involvement of the cerebellum in certain motor behaviours is fully explained in molecular terms.     

Synaptic plasticity and addiction

Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.     

Synaptic plasticity in learning and memory

Pavlovian conditioning has been considered as one of the principal experimental approaches to understanding such complex brain functions as learning and memory. Use-dependent alterations in synaptic efficacy are believed to form the basis for these functions. The algorithm of synapse modification proposed by D. Hebb as early as 1949 is the coincident activation of pre- and postsynaptic neurons. The present review considers the evolution of experimental protocols which were used to reveal the manifestations of Hebb-type plasticity in the synaptic inputs to neocortical and hippocampal neurons. Special attention is focused on long-term modifications of synaptic efficacy in the hippocampus as a possible neuronal mechanism of learning and the role of disinhibition in their development. The effects of various neuromodulators on hippocampal long-term potentiation are considered. It is suggested that along with their involvement in disinhibition processes these substances may control the Hebb-type plasticity through intracellular second messenger systems.     

Synaptic plasticity in an altered state

In this issue of Neuron, record from synaptically coupled pairs of CA3 neurons to closely examine the induction of synaptic depression at a small number of identified synapses. The authors provide convincing evidence that the activation history of a synapse determines both the ability of a synapse to depress and the mechanism of depression.     

Synaptic competition in developmental binocular plasticity

A mathematical model of the possible physiological and biochemical mechanisms responsible for the changes occurring during binocular development is proposed. The model is based on the mechanisms postulated for the occurrence of well known plastic processes, such as posttetanic potentiation, sensitization and heterosynaptic inhibition. Because all these processes are of presynaptic nature, we have postulated that the plastic processes occurring during development are of the same nature. The factors we have considered in our model are: the transmitter pool size, the mobilization or synthesis of the transmitter, the transmitter release by the physiological stimulus, the neuroendocrine and genetic activity. With this model we have simulated the following phenomena during ocular development: (1) normal binocular development; (2) monocular deprivation, including the effects of reversing the occluded eye; (3) binocular deprivation and recovery; and (4) effects of alternating deprivation on mature binocularity. The model also allows us to explain in a natural way the possible changes occurring during denervation or disuse.     

Synaptic plasticity in cortical systems.

Recent studies indicate that synapse addition and/or loss is associated with different types of learning. Other factors influencing synaptogenesis and synapse loss include neurotrophins, hormones, and the induction of long-term potentiation. An emerging view of synaptic plasticity suggests that local neurotrophin action and synaptically associated protein synthesis may promote synaptic remodelling and changes in receptor expression or activation.     

Brain reward circuitry: insights from unsensed incentives

The natural incentives that shape behavior reach the central circuitry of motivation trans-synaptically, via the five senses, whereas the laboratory rewards of intracranial stimulation or drug injections activate reward circuitry directly, bypassing peripheral sensory pathways. The unsensed incentives of brain stimulation and intracranial drug injections thus give us tools to identify reward circuit elements within the associational portions of the CNS. Such studies have implicated the mesolimbic dopamine system and several of its afferents and efferents in motivational function. Comparisons of natural and laboratory incentives suggest hypotheses as to why some habits become compulsive and give insights into the roles of reinforcement and of prediction of reinforcement in habit formation.     

Synaptic plasticity and nicotine addiction

Nicotine, the main addictive component of tobacco, activates and desensitizes nicotinic acetylcholine receptors (nAChRs). In that way, nicotine alters normal nicotinic cholinergic functions. Among the myriad of psychopharmacological effects that underlie the addiction process, nicotine influences nAChR participation in synaptic plasticity. This influence has particular importance in the mesocorticolimbic dopamine system, which serves during the reinforcement of rewarding behaviors.     

突触可塑性与脑疾病的神经发育基础

大脑神经回路高度有序的神经元活动是高级脑功能的基础,神经元之间的突触联结是神经回路的关键功能节点。神经突触根据神经元活动调整其传递效能的能力,亦即突触可塑性,被认为是神经回路发育和学习与记忆功能的基础。其异常则可能导致如抑郁症和阿尔茨海默病等精神、神经疾病。将介绍这两种疾病与突触可塑性的关系,聚焦于相关分子和细胞机制以及新的研究、治疗手段等进展。     

Synaptic plasticity in the mesolimbic dopamine system

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.     

Synaptic plasticity: regulated translation in dendrites

Synaptic activity can induce neurons to synthesize proteins important for cognition and brain development. Recent results suggest this activity-induced protein synthesis is partially mediated by regulated translation within neuronal dendrites.     

Synaptic transmission and plasticity in the amygdala

Numerous studies in both rats and humans indicate the importance of the amygdala in the acquisition and expression of learned fear. The identification of the amygdala as an essential neural substrate for fear conditioning has permitted neurophysiological examinations of synaptic processes in the amygdala that may mediate fear conditioning. One candidate cellular mechanism for fear conditioning is long-term potentiation (LTP), an enduring increase in synaptic transmission induced by high-frequency stimulation of excitatory afferents. At present, the mechanisms underlying the induction and expression of amygdaloid LTP are only beginning to be understood, and probably involve both theN-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subclasses of glutamate receptors. This article will examine recent studies of synaptic transmission and plasticity in the amygdala in an effort to understand the relationships of these processes to aversive learning and memory.