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The “addicted” spine

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How is the COVID-19 pandemic changing our use of illegal drugs? An overview of ongoing research

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Try out PMC Labs and tell us what you think. Learn More. Medium Spiny Neurons MSNs of the Nucleus Accumbens Nacc show a reduced number of dendritic spines and a decrease in TH-positive terminals upon withdrawal from opiates, cannabinoids and alcohol. In addition, long-thin spines seems preferentially affected raising the possibility that cellular learning of these neurons may be selectively hampered. These findings suggest that dendritic spines are affected by drugs widely abused by humans and provide yet another example of drug-induced aberrant neural plasticity with marked reflections on the physiology of synapses, system structural organization, and neuronal circuitry remodeling. While other investigators and even Golgi himself, disregarded spines as artifacts, Gray unambiguously showed that spines were sites of synaptic contact. It is now clear that dendritic spines are the main postsynaptic compartments of excitatory synapses in the brain with peculiar and distinctive morphological features. Dendritic spines are heterogeneous in size and shape but, mostly mature ones, consist of a bulbous head and a thinner neck that connects the spine to the dendritic shaft Wilson et al. This morphological configuration is particularly important for synaptic efficacy. In particular, dimensions of the spine head Kirov and Harris, ; Holtmaat and Svoboda, , rather than the neck, realistically reflect the observed differences in synaptic strength Harris and Stevens, At the ultrastructural level, the spine head is characterized by an electron-dense matrix of receptors and supporting proteins collectively known as the postsynaptic density PSD; Yamauchi, This complex assembly, made of hundreds of distinct proteins Moon et al. Spine development is a dynamic process which includes transition from small dendritic formations to large spines and vice versa, through a series of sophisticated structural refinements Calabrese et al. The continuous and rapid change in shape of dendritic spines is essential for short and long term plasticity Kasai et al. A pioneering classification was proposed by Peters and Kaiserman-Abramof , where they distinguished three categories: stubby, thin, and mushroom spines. However, it was necessary to introduce the dendritic filopodia in this classification. In some cases, following establishment of contact with an afferent fiber, these transient structures can become a spine Ziv and Smith, ; Fiala et al. On the other hand, some author prefers to distinguish mature spines into two broad categories: large and small considering the head size Kasai et al. The confocal microscope is able to detect sufficient details of the Golgi-Cox-stained neurons. Inset shows details of different morphologies. Image is color-coded. Reconstructed with filament tracer algorithm Imaris 7. Terminals of DA containing neurons from the ventral tegmentum VTA are jumbled in a dense network of connections in many forebrain regions. Accordingly, the Nacc plays a central role in the integration of cortical and mesencephalic afferent systems. Cell body and different portions of dendrites of MSNs, are targeted by various inputs. Mainly the soma and most proximal dendrites receive recurrent collaterals from other MSN Groves, , while cortical and DAergic afferents synapse onto spines located more distally on the dendrite. Similar innervation architecture is also observed in pyramidal neurons in the cortex Sesack and Pickel, , hippocampus Totterdell and Smith, and magnocellualar neurons of basolateral amygdala Johnson et al. In this configuration, DAergic terminals make a symmetric synapse with the neck whereas cortical terminals form an asymmetric contact in the spine head Bouyer et al. The significance of this heterosynaptic formation is not very clear but it seems to suggest that DA Pascoli et al. This aspect is particularly important because, despite their distinct targets, all addictive drugs commonly abused by humans evoke variations on DA concentrations within the Nacc Di Chiara and Imperato, and it may have a role in spine density, morphology and synaptic strength. Because of this particular synaptic configuration, even modest changes in the number of dendritic spines, can have major effects on the entire neuronal pathway. Accordingly, conditions of lowered DA tone such as morphine withdrawal has been associated with spine loss Spiga et al. Similarly, cannabis-dependent subjects undergo spine pruning in the shell of the Nacc Spiga et al. Synaptic triad in the Nucleus Accumbens. Tyrosine Hydroxylase-positive terminals green are forming a putative contact with the neck of a spine on a second order dendritic trunk red , while the head of the same spine is reached by a Golgi-Cox impregnated fiber blue from an adjacent neuron. The number and shape of dendritic spines, during pathological events, are extremely variable. A broad variety of psychiatric diseases and neurological disorders are accompanied by patterns of spine disruption Huttenlocher, ; Fiala et al. Schizophrenia, for example, is commonly associated with fewer spines and synapses in many brain areas and neuronal types Garey et al. Likewise, neural events related to chronic drug intake are linked to long-lasting drug-induced whole cell plasticity Miller et al. Four functionally connected structures of the brain: medial PFC, Nacc, lateral hypothalamus and the mesencephalic VTA, represent the neuroanatomical substrate of the so-called reward pathway Koob, ; Melis et al. This fundamental system of regulation of complex behavior, influences rudimentary functions like food intake Wise, , sexual behavior Robbins and Everitt, , sensory perception Berridge and Robinson, , emotions LeDoux, , intellectual evaluations and processes of memory and learning Robbins and Everitt, ; Hyman et al. Addictive drugs, for example, can release 2—10 times the amount of DA Di Chiara and Imperato, that natural rewards do and they do it more quickly and more reliably. Accordingly, addiction can be considered an example of experience-dependent plasticity Robinson and Kolb, Drug-induced structural plasticity of dendritic spines was first described by Kunz et al. While chronic administration of ethanol Zhou et al. Indeed, a direct comparison among different substances is not easy because researchers use a wide variety of doses and ways of drug administration, producing, very often, divergent results on neuron morphology, during different phases of treatment with the same substance. In particular, the withdrawal syndrome after chronic drug administration seems to be a crucial point of the addictive process that is manifested by the induction of rapid changes in dendritic spine density and morphology and is thus experimentally appealing to gain insights when the drug is not on-board, to avoid possible confounds. Accordingly, we observed radical changes on spine density in accumbal MSNs during the early phases of abstinence of various drugs of abuse Spiga et al. In fact, spontaneous and naloxone-induced morphine withdrawal, after 14 days of escalating chronic morphine administration, selectively alters spine density in the MSN second order dendrites of the NAcc shell Spiga et al. Similar results we found when rats were subjected to a chronic treatment with two different cannabinoid agonists Delta 9 -tetrahydrocannabinol and CP 55 and withdrawn spontaneously and pharmacologically with the CB1 antagonist SRA. Confocal analysis of Golgi-Cox-stained MSNs of the NAcc revealed a decrease in spine density in the shell, but not in the core only during withdrawal both spontaneous and pharmacologically-precipitated Spiga et al. Interestingly, 3 weeks of daily cocaine administration did not seem to alter spine density in the core subregion of the Nacc Shen et al. Further, increases were seen in the whole Nacc Lee et al. However, there are no clear indications how and whether and if these additional spines participate in the network activity but see Heck et al. These experiments cast doubt and urge caution on the notion that chronic cocaine or morphine treatments are unequivocally accompanied by an increase or a decrease of dendritic spines density in the NAcc, but suggest that the withdrawal itself might be the time-window in which to observe unequivocally the reported functional and morphological changes. Indeed, chronic treatment per se without exact dosing, regimen, degree of tolerance etc. On the other hand, it should be considered that withdrawal, after not during chronic drug intake, is one of the most powerful factor negative reinforcement driving dependence Koob and Volkow, On the contrary, repeated exposure of drugs of abuse drug on-board likely alters the brain, but adaptive mechanisms intervened over the course of treatment may hide objective observations, potentially misleading judgement and spoiling conclusions Kosten and George, because, mainly due to the wide variety of drugs, diverse treatment regimens, ample dosing, different pharmacokinetic properties, and various degrees of adaptive mechanisms such as tolerance, sensitization and others. One possible explanation for these conflicting results, is provided by the particular nature of dendritic spines, relationships with afferents and their dynamic nature in changing size, shape and function Kasai et al. For example, in the striatum the loss of DA terminals, in animal models of Parkinson disease Schintu et al. Remodeling in size and morphology of dendritic spines seems to be important at least as much as their changes in density on behavioral plasticity Grutzendler et al. In drug addiction Dumitriu et al. Two spine types seem to be particularly involved in excitatory synaptic activity: long thin and mushroom. Although long thin spines can change their volume even independently from synaptic activity, reflecting a native instability of these structures Yasumatsu et al. During the course of cocaine treatment, spines shift from small to large Shen et al. On the contrary, thin spines shift toward smaller size in response to cocaine withdrawal with the addition of new thin spines Dumitriu et al. Therefore, the stabilization of heads enlargement of potentiated spines is associated with recruitment of additional AMPA-type glutamate receptors Nusser et al. In line with an active remodeling theory, by the introduction of a new staining method combining Golgi-Cox impregnation with immunofluorescence Spiga et al. At the same time, PSD and tyrosine hydroxilase but not DA transporters immunoreactivity were similarly reduced in association with ethanol withdrawal. These results show a close relationship between morphology and function of spines and reiterate on the trophic role of DA on spines in addictive states Melis et al. On the other hand, long thin spines, in MSNs, could be strategically used as elements highly modifiable to support important modulatory roles in synaptic transmission Jones, This raises the possibility that long lasting changes in synapse formation and synaptic organization induced by drugs of abuse, may interact and hinder those produced by experience in the reward pathway. These drug-paired memories and the drug withdrawal-associated aversive feeling have been suggested to contribute to the high rate of relapse among addicts Nestler, ; Hyman et al. This wrong aberrant learning mechanism should be strongly related to synapse formation, changes in efficacy of synaptic transmission and morphology, modulated by DA tone in different cell types and brain regions. The resulting changes in neuronal connectivity are likely to contribute to hamper cognitive functions such as decision making and emotional rigidity typical of addicts. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Neuroanat v. Front Neuroanat. Published online Oct 2. Author information Article notes Copyright and License information Disclaimer. Received Aug 4; Accepted Sep The use, distribution and reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Keywords: spines, long thin, learning, dopamine, nucleus accumbens. Classification Spine development is a dynamic process which includes transition from small dendritic formations to large spines and vice versa, through a series of sophisticated structural refinements Calabrese et al. Open in a separate window. Figure 1. Figure 2. Abnormal spine plasticity and addiction The number and shape of dendritic spines, during pathological events, are extremely variable. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Berridge K. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Dopamine neuron systems in the brain: an update. Trends Neurosci. Neurobiology of an addiction memory. Neural Transm. Do thin spines learn to be mushroom spines that remember? Chemical and structural analysis of the relation between cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum. Local protein synthesis, actin dynamics and LTP consolidation. AMPA receptor trafficking at excitatory synapses. Neuron 40 , — Nicotine sensitization increases dendritic length and spine density in the nucleus accumbens and cingulate cortex. Estructura de los centros nerviosos de las aves. Development and regulation of dendritic spine synapses. 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Psychiatry 65 , — Negative reinforcement via motivational withdrawal is the driving force behind the transition to addiction. Psychopharmacology Berl , — Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Psychiatry 57 , 65—73 Nicotine stimulates dendritic arborization in motor cortex and improves concurrent motor skill but impairs subsequent motor learning. Synapse 55 , — Electron microscopy of synaptic contacts on dendritic spines of the cerebral cortex. Nature , — A theory of the functional organization of the neostriatum and the neostriatal control of voluntary movement. Long-term dendritic spine stability in the adult cortex. Dendritic spines of rat cerebellar Purkinje cells: serial electron microscopy with reference to their biophysical characteristics. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. 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Neuron 44 , — Total recall-the memory of addiction. Cellular basis of memory for addiction. Dialogues Clin. Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase Neuroscience , 19—22 Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 1 , — Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. Neuropsychopharmacology 39 , — Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature , 71—75 The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Dopamine D1 and N-methyl-d-aspartate receptors and extracellular signal-regulated kinase mediate neuronal morphological changes induced by repeated cocaine administration. Neuroscience , 48—60 Morphological alterations in hippocampus after long-term alcohol consumption in mice. Drug addiction and the memory systems of the brain. Neurobehavioural mechanisms of reward and motivation. Limbic-striatal memory systems and drug addiction. Reduced striatal spine size in schizophrenia: a postmortem ultrastructural study. Neuroreport 7 , — Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 39 , — Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus and neocortex of adult rats. 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