By Q. Narkam. Montana Tech.
For example buy metoclopramide 10mg without prescription gastritis nexium, distinct dependence that result from tobacco use. Cigarette smoking binding sites on the receptor have been identified for barbi- rapidly delivers nicotine into the bloodstream. The convergence of actions fers from cocaine and opiates in that it is powerfully rein- of ethanol, barbiturates, and benzodiazepines on a single forcing in the absence of subjective euphoria. In addition, these agents nicotinic acetylcholine receptors (nAChRs). Nicotinic all produce cross-tolerance, thus permitting the use of ben- AChRs are ligand-gated cation channels located both pre- zodiazepines in ethanol detoxification protocols. Presynaptic nAChRs fa- Not all GABAA receptors are ethanol sensitive. The reinforcing effects of receptor complexes are heteropentamers comprised of com- nicotine depend on an intact mesolimbic dopamine system; binations of the various members of five distinct subunit nicotine-induced increases in locomotor behavior are also families. The subunit combinations vary in different cell blocked by destruction of mesolimbic dopamine nerve ter- types, leading to differences in the sensitivity of GABAA minals or cell bodies (22). Moreover, nicotine increases do- receptors to ethanol in different brain regions. Other actions of ethanol that are possibly relevant be involved in both nicotine-induced dopamine release and to its psychotropic effects include potentiation of the action reinforcement and in nicotine-induced locomotor activa- of serotonin at 5-HT3 receptors, which, like NMDA recep- tion (24,25). Systemic nicotine self-administration is dis- tors, are excitatory, cation-selective ion channels. Nicotine may also have some ability to stimu- effects of ethanol are partly explained by its ability to activate late dopamine release in the NAc, however, mediated by mesocorticolimbic dopamine circuitry (15), with enhanced presynaptic nAChRs located on dopamine terminals within release of dopamine in the NAc. Nicotinic AChRs on VTA dopamine neurons are this effect is mediated by disinhibition of dopamine neurons normally activated by cholinergic innervation from the at the level of the VTA or whether it occurs at the level of laterodorsal tegmental nucleus or the pedunculopontine nu- the NAc, nor is it known whether it is caused primarily by cleus. Finally, it is not know to what degree opioid, peptide system. Not only dopamine antagonists, but also serotonin, and other systems play a role in ethanol-mediated opiate antagonists, block nicotine-induced behaviors and reinforcement. Thus, for example, not only GABA recep- self-administration (26,27). These findings suggest a role A for endogenous opioid systems in the reinforcing effects of tor antagonists but also opiate antagonists, decrease ethanol nicotine, and raise the possibility that such antagonists may self-administration and ethanol-related behavioral effects in be of use in the treatment of nicotine addiction. The opiate antagonist naltrexone reduces ethanol self-administration in animals; moreover, naltrex- Cannabinoids one and other opioid receptor antagonists reduce ethanol consumption, relapse to active drinking, and craving clini- -9-Tetrahydrocannabinol (THC)is the major psychoac- cally (19,20). THC produces ef- Chapter 96: Molecular and Cellular Biology of Addiction 1371 fects in humans that range from mild relaxation, euphoria, contrast, hallucinogens, such as LSD, act at 5-HT2 seroto- analgesia, and hunger to panic attacks. THC MECHANISMS OF LONG-LIVED DRUG increases mesolimbic dopamine transmission in the NAc EFFECTS shell, probably via a -opioid receptor-mediated mecha- Homeostasis Versus Associative Learning nism because -receptor antagonists prevent the THC- induced dopamine increases in the brain mesolimbic area Diverse behaviors, symptoms, and signs of substance use (30). Cannabinoids have also been reported to inhibit exci- disorders coexist clinically, but depending on the drug and tatory glutamatergic neurotransmission in the substantia on the stage of the disorder, these may involve multiple nigra pars reticulata (31). THC binds to two cannabinoid receptors denoted CB1 Heuristically, the types of molecular mechanisms involved and CB2. Of the two, only the CB1 receptor is expressed in the long-lived effects of addictive drugs may be divided in the central nervous system, with high levels in the basal into two major classes: homeostatic adaptations and associa- ganglia and limbic system (32). These adaptations tend to dampen drug effects, thus receptor. The Despite ongoing debates about the addictiveness of can- adapted state of neurons or neural systems may be un- nabinoids in humans, there appear to be many compulsive masked on drug cessation, leading to the production of marijuana users. Withdrawal symptoms typically are not withdrawal symptoms, as illustrated in the following. Ho- reported with termination of long-term marijuana use, but meostatic adaptations typically occur within reversible withdrawal symptoms have been demonstrated in a labora- bounds, and with removal of the drug, tend to dissipate tory setting after four days of marijuana smoking (33). Relapse often occurs on re-exposure to cues with THC, a selective cannabinoid receptor antagonist pro- associated with drug use, consistent with an important role duced withdrawal symptoms that included head shakes, fa- for associative learning (36). Although homeostatic mecha- cial tremors, tongue rolling, biting, wet dog shakes, and nisms are thought to represent reversible global alterations ptosis (34).
An array of tent with these interpretations effective metoclopramide 10 mg gastritis pain remedy, postmortem observations in- shorter basilar dendrites spread in a radial fashion at the dicate that cortical thickness in the dPFC may be reduced base of the cell body. Both the apical and basilar dendrites by 3% to 12% in subjects with schizophrenia (34–37), al- are coated with short protrusions or spines, which represent though these changes do not always achieve statistical signif- the principal targets of most excitatory synaptic inputs to icance. In addition, some (38–40), but not all (41), in vivo pyramidal neurons. Because dendritic spines are actively proton spectroscopy studies indicate that N-acetyl aspartate formed or resorbed in response to changes in presynaptic (NAA), a putative marker of neuronal and/or axonal integ- inputs, dendritic spines provide a good estimate of the num- rity, is reduced in this brain region. Interestingly, the magni- ber of excitatory synapses that pyramidal cells receive (52). In addition to receiving one excitatory during working memory tasks, raising the possibility that input, some dendritic spines also receive a synapse with a neuronal abnormality in the dPFC could account for dis- the features suggestive of an inhibitory input. Inhibitory tributed functional disturbances in the working memory terminals also synapse on the dendritic shafts, cell body, and network (40). Typically, pyramidal Other lines of evidence suggest that these changes may cells receive about 2,000 inhibitory synapses on dendritic reflect disturbances in the synaptic connectivity of the dPFC shafts, 200 on the cell soma, and 20 on the axon initial in schizophrenia. For example, the presence of decreased segment (53). Schematic drawing illustrating the characteristic morphologic features of pyrami- dal neurons in different cortical layers. Note that the laminar location of the cell soma tends to be associated with the major projection target of the principal axon. The axons of pyramidal cells typically give rise to intrinsic primate neocortex (55), and are comprised of about 12 dis- collaterals, which travel either horizontally or vertically tinct subtypes (56,57). Although the differences among sub- within the gray matter, and a principal axonal projection, types can be described on the basis of the morphologic fea- which enters the white matter and travels to another brain tures of the cell body and proximal dendrites (e. These axons utilize excitatory amino acids, such as multipolar, bitufted), the most discriminating and function- glutamate, as a neurotransmitter and form synapses that ally meaningful classification system is based on the organi- have the characteristic morphology associated with excita- zation of the axonal arbor and synaptic targets of the axon tory neurotransmission. In addition, GABA neurons are chemically het- apses are characterized by the presence of small round vesi- erogeneous, and separate subpopulations can be identified cles in the axon terminal, and a postsynaptic density that by the presence of specific neuropeptides or calcium-bind- is thick and asymmetric in appearance (54). Together, these morphologic and chemical features de- fine subpopulations of GABA neurons that appear to have Nonpyramidal Neurons different biophysical properties and different roles in dPFC Of the other major type of cortical neurons, nonpyramidal circuitry (Fig. For example, GABA neurons of the cells, about 90% utilize the inhibitory neurotransmitter - chandelier class, which may also express either the neuro- aminobutyric acid (GABA). The axon characterized by pleomorphic vesicles in the axon terminal terminals of these neurons, which are arrayed as distinct and symmetric pre- and postsynaptic densities. Layer 1, which is located just below the pial surface, contains relatively few neurons, but approximately 90% of these neurons utilize GABA. Layers 2 and 4 are thin and densely packed with small 'granular' cells. The majority of these neurons are small pyramidal cells, and GABA neurons constitute approximately 30% and 15% of all neurons in layers 2 and 4, respectively (55). Layers 3 and 5, the thickest cortical layers, contain prominent pyramidal neurons with a classic morphology. In both of these layers, the size and packing density of the pyramidal neurons is greater near their borders with layer 4. These patterns make it possible to subdivide layers 3 and 5 into superficial (to- ward the pial surface) and deep zones. Pyramidal cells in layer 6 have a modified or atypical appearance. In general, GABA cells constitute 20% to 30% of the neurons in layer 3, and about 15% of the neurons in layers 5 and 6 (55). Different types of axonal projections to the dPFC termi- nate in certain cortical layers, and projections from the dPFC to other brain regions generally originate from pyra- FIGURE 53. Schematic drawing of the synaptic interactions be- midal neurons in specific lamina. Thus, the laminar specific- tween different classes of local circuit neurons and a layer 3 pyra- ity of abnormalities in the dPFC in schizophrenia may reveal midal neuron (P) in monkey prefrontal cortex. C, parvalbumin information about the types of connections that are affected.