Seminars in Neuroscience最新文献

Progress is being made in identifying molecular and cellular adaptations induced in specific brain regions by long-term opiate exposure and in relating these adaptations to specific aspects of opiate addiction. In the locus coeruleus, the major noradrenergic nucleus in brain which plays an important role in physical opiate dependence and withdrawal, upregulation of the cAMP pathway in response to chronic opiate administration has been shown to be one important mechanism involved. In the mesolimbic dopamine system, which plays an important role in the reinforcing effects of opiates after short- and long-term exposure, some similar and some different types of opiate-induced adaptations have been identified. As an increasingly complete understanding of opiate action is obtained, this knowledge will provide the framework for the development of novel therapeutic agents to treat opiate addiction.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are brain imaging techniques that enable the investigation of human neurochemistryin vivo.They can be used to measure receptor parameters (B_max,K_d, binding potential and volume of distribution) and indices (ratio methods) as well as receptor occupancy by drugs. In this article, we review the characteristics of the available ligands for studying brain opioid receptors and the results of studies carried out to date. The possibilities and limitations of using current tools to investigate opioid receptors in human addiction are also discussed.

Primary sensory cortex in the adult is modified by learning. The primary auditory cortex is retuned when a tone is paired with a behaviorally relevant reinforcer. Frequency receptive fields are shifted toward or to the frequency of the signal stimulus, yielding enhanced processing and representation of important frequencies. Receptive field plasticity constitutes “physiological memory” because, like much memory, it is associative, highly specific, rapidly-induced, and retained indefinitely, at least for months. The basal forebrain cholinergic system may be a substrate because its paired activation is sufficient to induce receptive field plasticity in the absence of actual behavioral learning experiences.

Over recent years, we have come to the surprising realization that sensory cortex is highly plastic in functional organization, even in adult brains. Much of the evidence for this conclusion comes from studies of the effects of peripheral deafferentation or sensory experience on the somatotopy of primary somatosensory cortex (area 3b) of monkeys. Local modifications in cortical representations occur rapidly after sensory loss or more gradually during altered sensory experience. These changes depend on reductions in lateral inhibition and other dynamic adjustments in sensory networks, as well as Hebbian-like modifications of synaptic strengths. Activity-dependent alterations in the expression of neurotransmitters and modulators may also play a role. After major deactivations, such as those produced by amputation or section of dorsal column afferents, cortex regains responsiveness over a much longer time period as a result, at least in part, from the growth of new connections.

Opioid tolerance and physical dependence are undesirable consequences of chronic opioid use or misuse. Evidence from rodents, using a variety of modes of drug coadministration, reveals that drugs with glutamatergic antagonist activity at the competitive, noncompetitive, or glycine binding sites of the NMDA receptor complex or inhibitors of certain forms of nitric oxide synthase (NOS) can attenuate the development of morphine tolerance and in some cases reverse established tolerance or dependence. Some of these drugs modulate tolerance and dependence without affecting morphine's analgesic effects, suggesting that they prevent neuronal plasticity associated with adaptive changes mediated by the NMDA/NO cascade. Drugs that have a favorable preclinical safety margin are providing leads for new drugs for clinical evaluation.

Seconds after a cutaneous deafferentation is induced in adult animals, a complex process of plastic reorganization is triggered in the subcortical and cortical structures that form the somatosensory system. This process, which leads to the immediate unmasking of novel neuronal sensory responses, continues to evolve for many weeks and months until most of the neuronal tissue deprived of its original afferent input gains responsiveness to surrounding skin territories. Here, I propose that the existence of dynamic and distributed sensory representations throughout the somatosensory system offers the substrate for the occurrence of immediate plastic remapping of the body surface following either a peripheral injury or a change in sensory experience.

Neurons in adult visual cortex can generate new receptive fields (RFs) when small retinal injuries remove their normal feedforward signals, a clear sign of plasticity. The activation of new RFs leads to a striking topographic map reorganization around the deafferentated cortical region. It appears that the lesion down-regulates GABAergic inhibition and uncovers the normally subthreshold signals from remote areas. The newly activated individual neurons and their assemblies show surprisingly normal response patterns, indicating that these large-scale alterations in the cortical map may contribute to, rather than disrupt, visual perception. Thus, weighing a variety of synaptic inputs based on the nature of the current drive and history of prior stimulation, the adult visual cortex is capable of showing considerable “plasticity” while maintaining the overall stability of its functional organization. In the mammalian visual system, however, the involvement of experience-dependent plasticity in this process is, as reviewed here, a matter of debate.

After years of failures in managing heroin addiction by both supportive and punitive abstinence-based treatment modalities or incarceration, with or without initial short-term detoxification using an opioid agonist, research into the potential use of primarily mu opioid receptor directed agonist (or use of a partial agonist) in the chronic maintenance treatment of long-term opiate (primarily heroin) addiction was performed and such treatments have been developed. Of these treatments, chronic “maintenance” with the long-acting, orally effective, synthetic opioid methadone has been shown to be both highly effective and very safe. The extent of its effectiveness is directly related to its appropriate use in maintenance treatment, combining the use ofproperdoses of methadone (60 to 120 mg/day in most patients) with adjunctive treatment, including counseling and access to medical, behavioral, and psychiatric care. More recently, a second long-acting opioid,l-α-acetylmethadol (LAAM) has been approved for chronic maintenance of opiate addiction. This agent has also been shown to be safe and effective when used in appropriate doses and with adjunctive treatment as needed by each individual. A third agent, a partial agonist (or mixed agonist–antagonist) buprenorphine, is currently under rigorous study in the United States and is already being used in other parts of the world in the chronic maintenance treatment of opiate addiction. Other novel approaches such as using a kappa opioid receptor agonist, like the natural opioid receptor peptide dynorphin A, or a synthetic peptide or heterocyclic congener thereof, are now under study. This paper presents a historical review of the development, the pharmacokinetic and pharmacodynamic properties of each agent, their neurobiological effects and safety, and efficacy in treatment. A formulation of the rationale for use of these and other opioid agonist-like compounds which might be developed in the future for the treatment of opioid addiction will be discussed.

It is now clear that the motor cortex of adult mammals is capable of widespread functional reorganization. After specific types of motor skill training, the cortical representations of the movements used to perform the task expand, invading adjacent motor representations. After peripheral nerve injury, representations of unaffected muscles expand, invading those of the denervated muscles. After focal cortical injury, representations in the uninjured, adjacent cortical tissue undergo widespread alterations. Specific changes are dependent upon the use of the affected limb during the postinjury period. It now appears likely that motor map alterability results from changes in synaptic efficacy of intrinsic horizontal connections within motor cortex. Taken together, these studies suggest that the neurophysiological circuitry underlying muscle and movement maps within primary motor cortex is continually remodeled throughout an individual's life. The functional organization of motor cortex is constantly reshaped by behavioral demands for the learning of new motor skills.

Plasticity in somatic sensory cortex refers to the ability of cells to change their response to sensory inputs. Typically changes depend upon activity-induced modifications of synaptic strength. Increasing or decreasing synaptic strength is orchestrated through changes in transmitter release from axon terminals, in glutamate receptor properties, in postsynaptic cell depolarization, and in calcium activation of a cascade of intracellular events. Synaptic changes in cortex are facilitated by the level of cortical excitability and modulatory transmitters that create the background for activity arriving over sensory pathways. Ongoing activity initiated by peripheral receptors creates the patterns of activity in cortex that map the activity-dependent representation of the body onto cortex.