By D. Lukjan. Bluefield College.
Thus purchase 500 mg antabuse otc, the chapter does not at- and with it purchase antabuse 250 mg with visa, the initiation of molecular mechanisms that tempt to produce an exhaustive list of the known molecular may produce tolerance discount antabuse 250mg with visa, dependence buy antabuse 250 mg without prescription, sensitization, and com- effects of addictive drugs, but focuses on a subset of those pulsive use. Although the mesocorticolimbic dopamine sys- that illustrate important principles and that can be related tem is a site of convergence for the rewarding effects of to the long-term effects of addictive drugs in humans. The integration of such information about drug action in the brain with information about human risk fac- The best-characterized and most widely abused psychostim- tors is in its early stages and will benefit enormously from ulants are cocaine and the amphetamines. The details of the eventual discovery of risk-producing alleles from human their mechanisms of actions differ, but both result in in- genetic studies. The discovery of alleles that confer vulnera- creases of extracellular dopamine and other monoamines bility to drug use or addiction will help focus molecular and produce similar effects on behavior. In humans, psycho- and cellular studies of pathophysiology, as well as suggest stimulants increase alertness and produce a sense of well biochemical pathways that can be exploited for treatment. In animal studies, psychostimulants produce a dose- dependent increase in locomotor activity at low doses and stereotypies at high doses. If cocaine or amphetamine is MOLECULAR TARGETS OF ADDICTIVE used repeatedly, some acute drug effects may diminish (tol- DRUGS erance), whereas others are enhanced (sensitization). Cocaine and amphetamines produce their effects by po- The overall effect of each of the addictive drugs depends tentiating monoaminergic transmission through actions on on the particular neurons and circuits that express their dopamine, serotonin, and norepinephrine reuptake trans- molecular targets, and the nature of those targets. These proteins normally transport previously example, morphine-like opiates are analgesic and sedating, released neurotransmitter back into the presynaptic nerve whereas cocaine is a psychomotor stimulant; these different terminal, and thereby terminate transmitter action. Cocaine properties are based on differences in localization and func- binds to these transporters and competitively inhibits their tional properties of the proteins with which they interact, functioning, thereby increasing the duration of action of the -opioid receptor for morphine and the dopamine reup- neurotransmitter released into the synaptic cleft. However, as described mines and related drugs increase dopamine, serotonin, and in other chapters in this section, addictive drugs share the norepinephrine neurotransmission by acting as a substrate ability to activate mesocorticolimbic dopamine projections for their transporters. Amphetamines are transported into Chapter 96: Molecular and Cellular Biology of Addiction 1369 the presynaptic terminal where they cause neurotransmitter a descending pathway extending from the periaqueductal release by reversing the usual direction of transport (i. These same Whereas psychostimulants affect all three transporters, drugs appear to produce both reward and reinforcement by it is their actions at the DAT that are most directly related means of at least two mechanisms: (a)activation of the to the reinforcing effects of psychostimulant drugs. Lesions VTA, which results in dopamine release in the NAc; and of the dopamine system or administration of dopamine re- (b)direct binding to opiate receptors in the NAc, an action ceptor antagonists, but not similar manipulations of seroto- that is independent of dopamine. Activation of VTA dopa- nin or noradrenergic systems, markedly attenuate cocaine mine neurons by opiates results from disinhibition: mor- self-administration. The central role of the DAT in psycho- phine-like opiates inhibit GABAergic interneurons in the stimulant action is highlighted in studies using mice in VTA that tonically inhibit the dopamine projection neurons which the DAT has been genetically inactivated. Increased activity of these dopamine neurons produces absence of the DAT, animals are insensitive to the locomo- increases in extracellular dopamine levels in the NAc. Con- tor stimulatory effects of cocaine and amphetamine (5). By sistent with this arrangement, the reinforcing effects of in- contrast, animals lacking serotonin (5-HTT / )or norepi- travenous heroin can be partly attenuated by administration nephrine (NET / )transporters exhibit normal locomotor of an opioid receptor antagonist directly into the VTA or responses to psychostimulants (6,7). Interestingly DAT / lesioning the dopaminergic neurons of the VTA. Opiates animals still self-administer cocaine and amphetamine to also produce reinforcement through direct dopamine-inde- some degree (8), but the interpretation of this result is com- pendent action on , and perhaps , receptors expressed by plex because DAT / animals have very high levels of ex- NAc neurons. Consistent with this mechanism, morphine is tracellular dopamine at baseline (lacking a DAT to remove self-administered even in the presence of dopamine receptor synaptic dopamine), which might magnify a psychostimu- blockade or following a 6-hydroxydopamine lesion that de- lant-mediated effect on norepinephrine or serotonin. Moreover, lesions of the evidence demonstrates that the dopamine system is obliga- NAc or pharmacologic -receptor antagonists applied to tory for psychostimulant-induced reinforcement, but the the NAc dose dependently reduce the reinforcing effects of serotonin and noradrenergic systems, whose transporters are heroin and morphine (12,13). Thus, opiates and dopamine also inhibited by psychostimulants, may play a role as well. In contrast, -opioid receptor activation is tive analgesic agents known, and at the same time can pro- not reinforcing. Activation of receptors can decrease dopa- duce tolerance, dependence (including somatic depen- mine release in the NAc by both presynaptic mechanisms- dence), and addiction. Physical dependence on opiates can there are receptors on a subset of dopamine terminals. As contribute to addiction, but can also occur independently a result stimulation of opiate receptors may produce aver- of it. For example, patients with cancer pain may become sive responses in both animals and humans. As will be de- physically dependent on these drugs but do not compul- scribed in the following, opiate receptors may play a role sively abuse them. The three subtypes, denoted , , and , are members of Ethanol the G protein-coupled receptor family, and all interact with G proteins of the G /Gi o types. This coupling results in inhi- Ethanol is a central nervous system depressant that produces bition of adenylyl cyclase, activation of inwardly rectifying behavioral disinhibition, euphoria, reduced anxiety, de- K channels, and inhibition of voltage-gated Ca2 chan- creased motor coordination, and sedation. Opiate receptors thus typically mediate inhibitory re- anisms underlying behavioral effects, including reinforce- sponses that reduce membrane excitability and reduce likeli- ment, are thought to be facilitation of GABAA receptors hood of cell firing and neurotransmitter release; however, and inhibition of NMDA glutamate receptors (14). At the different opiate receptor subtypes are expressed on dif- higher doses, ethanol also inhibits the functioning of most ferent cells, resulting in different biological effects when voltage-gated ion channels. Morphine-like opiates, including heroin, are which ethanol affects these receptors and channels are not both analgesic and addictive, and interact with highest affin- yet certain; two types of mechanisms have been hypothe- ity with the -receptor. One possible mechanism attributes the effects of Morphine-like opiates suppress afferent nociceptive in- ethanol on receptors and channels to its generalized effects formation by acting on opiate receptors contained within on cell membranes, in which it is highly soluble. Certain 1370 Neuropsychopharmacology: The Fifth Generation of Progress ligand-gated and voltage-gated channels may be preferen- Serotonin also appears to be involved in ethanol con- tially affected by ethanol because, as complex multimeric sumption and reinforcement; ethanol consumption is gen- proteins, they may be particularly vulnerable to ethanol- erally curbed by experimental manipulations that increase mediated changes in their lipid environment. The alterna- serotonergic function, and experiments with rats selectively tive hypothesis is that ethanol interacts with specific hydro- bred for ethanol preference suggest that strong ethanol pref- phobic regions of these proteins to produce allosteric erence is associated with reduced serotonergic function. Mice lacking 5-HT1B serotonin recep- more specifically, in interaction with particular regions of tors consume higher levels of ethanol yet demonstrate less proteins, ethanol has been shown to allosterically regulate ataxia (21). A The anxiolytic and sedative effects of ethanol, like those of Nicotine barbiturates and benzodiazepines, are believed to result from Nicotine is the main psychoactive ingredient of tobacco and facilitation of the GABAA receptor, although the precise is responsible for the stimulant effects, reinforcement, and mechanism differs for each drug. For example, 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).
For voxel cluster extent) trusted antabuse 500mg, there was significance bilaterally in the example discount antabuse 500 mg without a prescription, the DTI-measured diffusion coefficients are larger anterior cingulate gyri and insula (regions not examined when measured along (parallel to) white matter fibers (in 3 2 with ROI) buy 500 mg antabuse free shipping, but not in medial temporal lobe where ROI the range of 1 buy 250mg antabuse overnight delivery. Taken together, these data suggest the following meth- nature of the measured diffusion tensor within a voxel is odologic conclusions: thus a meaningful measure of fiber tract organization. The degree of anisotropy in schizophrenia has been in- 1. Each VBM study should be compared with manual ROI vestigated in two recent studies. Using DTI, Buchsbaum definitions until validity is established. VBM may be useful for generating hypotheses to be isotropy in some inferior portions of prefrontal white matter validated with traditional ROI analyses. Much work remains to be done in comparing the validity co-workers (32) found that abnormally low white matter of VBM and ROI analysis, and formulating reasons for anisotropy in patients with schizophrenia was present in any differences. For group statistics, Lim and co-workers used the median value of voxel anisotropy (mea- Shape Analysis sured as fractional anisotropy; 1 is maximal and 0 minimal) in each slice within the white matter regions of interest in It is readily apparent that ROI shape as well as volume may the control and schizophrenia groups. These studies raised carry information about pathology. Casanova and col- the important question of whether white matter connectiv- leagues (29) used 3D Fourier techniques to characterize ity is disturbed in schizophrenia, although Lim and col- shape of temporal lobe regions, finding schizophrenics and leagues caution that the proper statistical measures for DTI controls differed. However, Fourier techniques cannot pin- are still being worked out. LSDI also has higher resolu- schizophrenia subjects were localized to the lateral aspect of tion, exhibits minimal image distortion, and does not re- the head of the hippocampus and medial aspect of the body, quire cardiac gating, head restraints, or post-processing where the subiculum is found. It also can be implemented without spe- number of different algorithms is a current area of very cialized hardware on all standard MRI scanners. Although the individual axons and the tensor field and then deriving a scalar measure from the surrounding myelin sheaths cannot be revealed with the averaged field is not the same as averaging a scalar field limited spatial resolution of in vivo imaging, distinct bands derived from the original field. By using geometrically de- of white matter fibers with parallel orientation may be dis- fined diffusion measures on locally averaged tensors local tinguished from others running in different directions if directionality consistency can be determined (e. This averaging approach can be used preferred direction of diffusion is determined. For example, a measure quantified and displayed using color-coding. An important of linearity derived from the averaged tensor field can be point for summarizing data made by Westin and associates used for quantitative evaluation of fiber tract organization. The operation begins with a seed point vectors to produce summary statistics. In processing DTI in a voxel element and then generates a tracking sequence A C FIGURE 55. The ver- tical line shows the approximate plane of the coronal diffusion tensor image to the right. Note the cor- pus callosum (top blue arrow) and anterior commissure (bottom blue arrow). White matter tracts perpendicular to the plane are coded red-orange. Note the cingulum bundle (top arrows), the white matter tract within the cingulate gyrus, and the uncinate fasiculus (bottom arrows), the tract connecting anterior temporal lobe with inferior frontal lobe. Uncinate fasciculus in schizophrenia: a diffusion tensor study. American Psychiatric Association New Research Abstracts, 2000. Chapter 55: Structural MRI Studies in Schizophrenia 769 if the adjacent elements have similar linear orientation. This 90 degrees from the steady-state field orientation), followed similarity is at the voxel level, and does not, of course, permit by one or more refocusing pulses, and directed 180 degrees tracking of individual fibers; rather, it tracks groups of fi- from the orientation of the steady-state field. The reformation of phase co- CONCLUSION herence induces another signal known as a 'spin echo,' which does not have the potential confounds of magnet and A clear current and positive trend is to use as much automa- tissue inhomogeneity (they remain constant over pulses), tion as possible in structural MRI analysis because of the and thus this signal provides a better measure of T2. Currently, how- spin echo pulse sequences the repetition time (TR) is the ever, the field is still in a state of flux with respect to the time between excitation pulses, whereas the echo time (TE) validity of the new techniques, such as VBM and brain is the time from the excitation pulse to the echo maximum. Validity evaluation for new technologies is thus a produce proton density weighted images at short TE (less high priority item. Fast spin echo sequences are a variant of multiecho Similarly, as discussed in another chapter in this volume by sequences that maximize efficiency of data collection and Dr. Berman, 'functional' imaging is becoming increasingly shorten acquisition time. They are commonly used to pro- multimodal and a desideratum is the combination of struc- duce T2-weighted images. Inversion recovery pulse se- tural and functional approaches, just as anatomy and physi- quences are still another variation of the spin echo sequence, ology are inextricably linked in basic neuroscience studies. It is clear that functional studies have defined more prominent abnormalities in frontal lobe than in tem- poral lobe, whereas structural studies have tended to show Gradient Echo Pulse Sequences a greater degree of abnormality in temporal lobe. The mis- These sequences do not use 180-degree refocusing pulses. Functional neuroimaging 'ac- GRASS (SPGR) in GE imagers and FLASH in Siemens tivation' in a region primarily represents postsynaptic po- imagers. This pulse sequence uses a 'spoiling scheme' to tentials; these and not action potentials constitute the major dephase the transverse (x-y plane) magnetization following metabolic and energetic load and hence the main signals signal detection, commonly using 'spoiler' (also called used in functional analysis. It is consequently often very 'crusher') gradient pulses that have the same duration and difficult to disambiguate abnormalities in input to frontal magnitude as the first excitation pulse, but the opposite lobe from intrinsic abnormalities. This has as a consequence that, at the time of poral lobe gray matter volume changes appear quantitatively the next excitation, only the longitudinal direction (vertical larger than those in frontal cortex, no brain region acts on direction in our analogy) has any remaining coherence. If its own and interconnections and abnormalities of intercon- the first pulse has a low excitation angle (small 'tilt' of the nections, as well as intrinsic volume changes must be consid- tops in our analogy) this allows shorter repetition times to ered in the explanation of the features of schizophrenia. Signal Intensity of Tissue Elements and T1 and T2 Weighting APPENDIX A: STRUCTURAL MRI PULSE SPGR pulses lead to proton density-weighted images, be- SEQUENCES cause the small 'tilt' and short TR diminishes any T1 or T2 effects. In a proton density image produced by the SPGR Spin echo pulse sequences use at least two pulses. The first is sequence most commonly used in schizophrenia research, an initial excitation pulse (tilting the magnetization vector CSF appears dark, gray matter is gray, and white matter 770 Neuropsychopharmacology: The Fifth Generation of Progress has the most signal (is brightest). Metaanalysis, decision analysis, and cost-effectiveness produce proton density, T2- or T1-weighted images. Hippocampal vol- longer T1 relaxation time than white matter and thus shows ume reduction in schizophrenia as assessed by magnetic resonance a brighter signal with sequences allowing longer T1 relaxa- imaging: a meta-analytic study. Because the ability to capture relatively complete 433–440. MRI anatomy of T1 relaxation depends on longer TRs, longer TRs thus give schizophrenia. The neuropathology of schizophrenic diseases: histori- The tissue intensity in T2-weighted images depends on the cal aspects and present knowledge. Eur Arch Psychiatry Clin Neu- TE in spin echo sequences. CSF has longer T2 values than rosci 1999;249(Suppl 4):2–13. A critical review of the data and their interpretation. Brain 1999;122: weighted acquisitions with the long TE values commonly 593–624. Cell biology of the hippocampal formation in TR allows more time for T1 relaxation and produces more schizophrenia. Elevated neu- allows more time for T2 relaxation and produces more sig- ronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional stereologic counting nal from tissues with long T2 values. Temporal lobe sulco- gyral pattern anomalies in schizophrenia: an in vivo MR three- ACKNOWLEDGMENTS dimensional surface rendering study. An automated Supported in part by VA Medical Research Service, Depart- registration algorithm for measuring MRI subcortical brain struc- ment of Veterans Affairs Center for Clinical and Basic Neu- tures. Adapting multi-grid methods to the class 52807 (RWM). Parts of the introduction are adapted from of elliptic partial differential equation appearing in the estimation of displacement vector fields. In: Cantoni V, Creutzburg R, Levi- a previous review: McCarley RW, Wible C, Frumin M, et aldi S, et al, eds.
It should be noted cheap antabuse 250mg mastercard, however safe 500 mg antabuse, that free patients with schizophrenia reported normal cortical 5-HT2A receptor binding (98–100) order antabuse 250mg online, whereas one study re- these very high affinity ligands do not allow accurate deter- ported a significant decrease in PFC 5-HT2A binding in a mination of D2 receptor availability in the striatum order 250 mg antabuse overnight delivery. In con- trast, [18F]fallypride enables accurate determination of D2 small group (n 6) of drug-naive schizophrenic patients (101). The most consistent abnormality of 5-HT param- receptor availability in both striatal and extrastriatal areas eters reported in postmortem studies in schizophrenia is an (119), and preliminary PET experiments in primates with increase in the density of 5-HT receptors in the PFC, [18F]fallypride indicate that clozapine and risperidone 1A reported in seven out of eight studies (97). Several groups achieve similar D2 receptor occupancy in striatal and extra- are currently evaluating the binding of this receptor in vivo striatal regions (120). Finally, it is important to point out with PET and [11C]WAY100907. Improved resolution of PET cameras cur- Maybe the most widespread use of neuroreceptor imaging rently allows dissociating signals from ventral and dorsal in schizophrenia over the last decade has been the assessment striatum (123,124), and it is now feasible to specifically of neuroreceptor occupancy achieved by typical and atypical study the clinical correlates of D2 receptor occupancy in antipsychotic drugs, a topic that has been the subject of ventral striatum in humans. Neuroreceptor studied included Another unresolved question is the discrepant values of essentially D2 receptors, but also 5-HT2A and D1 receptors. The haloperidol plasma concentration as- sociated with 50% inhibition of [11C]NMSPbinding (3 to threshold of occupancy of striatal D2 receptors (about 80%) above which extrapyramidal side effects are likely to occur 5 mg/mL) (125) is ten times higher than that associated with 50% inhibition of [11C]raclopride binding (0. Quetiapine, at a dose of 750 mg, decreased [11C]raclopride-specific binding by 51%, but failed to affect sponse (105,106). Yet, most studies were performed at doses [11C]NMSP-specific binding (127). These observations achieving more than 50% occupancy, and the minimal level of occupancy required for therapeutic response remains un- contribute to the debate regarding differences between ben- defined. Two studies performed with low doses of relatively zamides and butyrophenones binding to D2 receptors. For example, despite major research ef- of the nucleus. An MRS experiment involves four steps, forts, direct measurement of parameters of glutamate trans- analogous to an MRI procedure. First, specific nuclei are mission are still not available. Radiotracers enabling evalua- excited with a brief 'pulse' of a radiofrequency (RF) mag- tion of second messengers and intracellular pathways are netic field supplied by an RF transmitter coil. A growing collaboration tion causes magnetized spins to transiently assume a higher between academic centers and industry currently holds the energy state, from which they 'relax' to a lower energy state promise of increasing access to molecules for evaluation as of equilibrium magnetization. Because the energy states are candidate radiotracers. These resonant frequencies are more informative than simple measurement of receptor den- unique for each atom, and vary in proportion to the strength sity. With the exception of the cholinergic system (129, 11 of the external field. The motion of spins in the process of 130), the paradigm used with [ C]raclopride and 123 returning to equilibrium ('relaxation') induces a current [ I]IBZM has been difficult to extend to other neurore- in a receiver coil, which represents the MR signal. Additional research is warranted to better characterize linear magnetic gradients that add localizing characteristics the factors that confer vulnerability of radiotracers in vivo to the signal. The third step involves translating the signal binding to functional status of neurotransmission. The fourth step involves the mathematical and sta- the high cost of these investigations. This growing availability should be associated with but most abundantly in water and lipids. Although the sig- a vigorous research effort toward the development of more nal from hydrogen contains frequencies corresponding to F-18 based probes, since the relatively longer half-life of F- many different molecules, the water and lipids signals domi- 18 compared to C-11 does not require that these ligands nate and the signals from hydrogen in other molecules are be radiolabeled locally. MRS, however, is based on resolving these other technetium-based neuroreceptor ligands (131) will further molecular signals. These molecules are identifiable because enhance the availability of these techniques to the nuclear of the phenomenon called 'chemical shift. This shielding effect will cause the nucleus to experience a slightly different MAGNETIC RESONANCE SPECTROSCOPY external field, and thus to resonate at a slightly shifted fre- quency. Because the degree of shielding varies from one Magnetic resonance spectroscopy (MRS) is a chemical assay molecule to another, depending on the electron sharing of technique. It is the only clinically available method for the the chemical bonds in the molecule, the exact shift in the direct measurement of chemical moieties in the living brain. In addition to electron resonance imaging (MRI), which involves characterizing shielding, complex interactions between neighboring spins atoms and molecules based on how they interact with a ('j-coupling') also may affect the resonant frequency of a magnetic field. This interaction occurs because the nuclei nucleus in certain molecules. A Fourier transformation of of atoms with an odd number of nucleons (i. The spin properties of spe- chemical environment of the target nucleus. The area under cific atoms and of the specific molecules that they compose the peak is directly proportional to the concentration of are unique and are exploited in an MRS experiment. It is customary to label peaks in the spectrum the advantage of being more anatomically precise. This based on their relative displacement ('chemical shift') in means that regions based on known anatomy, rather than parts per million from a standard peak (e. There also are spectra, water is assigned a value of 4. However, because of the smaller quencies to the left. The use of relative shift units allows voxels, imaging studies have reduced SNR and require for peaks to be identified regardless of the strength of the longer scanner times (20 to 60 minutes for a multislice magnet. This also makes it possible to compare in vivo and study). Because the amplitudes and frequencies of peaks in a In schizophrenia research, MRS has been used to ap- spectrum are critically dependent on the magnetic field sur- proach four general topics: (a) assays of brain chemicals, rounding a target nucleus, magnetic field uniformity within (b) evidence of tissue pathology, (c) functional analysis of a voxel and between voxels is essential. Field homogeneity specific neuronal populations, and (d) drug effects. Before is routinely honed with 'shimming' procedures. It is also considering the results of these efforts, it is important to possible to make additional corrections based on field map- consider some general methodologic issues that are germane ping, which corrects for frequency shifts between voxels. Most studies in the literature have used shim procedures supplied by the manufacturer of the scanner, and it is doubt- ful that these procedures have been optimal and comparable MRS Methodology across studies (133). Coil design is another important pa- MRS is a methodologically complex technique that requires rameter in data acquisition and STN. Small surface coils many quality control steps, both at the front end in data have been used in many of the phosphorus spectroscopy collection and at the back end in data analysis. However, surface coils introduce potential variance in studies that compare signals turnkey technique, and careful scrutiny of the raw data is from specific locales across individuals. There are no absolute stan- transmitters, surface coils excite spins with a gradient of dards for the quality of spectral data, e. Neverthe- 1 19 tivity drops off across the volume of activated tissue. Clearly, less, spectra derived from a particular atom (e. Because the goal about absolute quantification of chemical concentrations. References in the in the range of three to five orders of magnitude less abun- schizophrenia MRS literature to studies that have employed dant than water, it is necessary to make compromises to absolute quantification are inaccurate, as all studies have maximize the signal-to-noise ratio (SNR) in the data. One employed some normalization procedure, often based on of the first decisions to be made in an MRS experiment is measures acquired in normal subjects. Most MRS studies in the sure absolute concentration of a chemical peak, it is neces- schizophrenia literature have sampled from relatively large sary to control for all the variables that will affect the ampli- (5 to 80 mL) single volume elements ('voxels'), though tude of the peak from a given voxel. These include factors so-called MRS imaging (MRSI) approaches have also been that affect field homogeneity, relaxation times of the mole- utilized. The single-voxel approach benefits from enhanced cule(s) responsible for the peak, transmission efficiency and signal-to-noise (STN) and reduced scanner time (5 to 20 reception sensitivity of the RF coil ('coil loading'), and minutes per voxel), but it suffers from imprecise and limited partial volume effects.
The transporter has also been the subject of examination in postmortem brain tissue cheap 250 mg antabuse with amex. Early studies in this area pointed to decreased binding in suicide brains (48); however cheap antabuse 250mg mastercard, more SEROTONIN recent studies have failed to confirm these findings (49) buy 500 mg antabuse with mastercard. These data raise questions regarding the significance of ab- Serotonin (5-HT) is a monoamine neurotransmitter in- normalities in the activity SERT in the pathophysiology of volved in mood and appetite regulation generic 250mg antabuse otc. In brain, it is syn- depression and the relationship of peripheral and central thesized within the raphe from l-tryptophan. There are a number of methodo- self does not cross the blood–brain barrier. Synthesis logic problems inherent in postmortem tissue that may ac- includes an initial conversion to 5-hydroxytryptophan (5 count for differences among studies, including accuracy of HTP) via the enzyme, tryptophan hydroxylase. This system has been 123I- -CIT), that bind selectively to the transporter has al- studied in the brains of suicide victims. In one study, a significant ates reported [3H] phorbol dibutyrate binding to protein difference in binding using SPECT was observed between kinase C in prefrontal cortex was lower in teenage suicide depressed patients and controls (50). More recently they observed that both phos- cant differences were not observed in platelet binding to pholipase C activity and the 1 isozyme protein level were 3H-paroxetine, raising questions regarding whether the decreased of teenage suicide victims (63). Depression per transporter is regulated differently in the two tissues. In contrast Hrdina and associates (64) reported unaltered protein kinase C activity in antidepres- Receptors sant free depressives who suicided, and Coull and colleagues Presynaptic and postsynaptic 5HT receptors have also been (65) reported that phorbol dibutyrate binding sites were studied in depressed patients. Over a dozen serotonin recep- increased in the prefrontal cortex of adults with similar his- tors have been identified, although the possible roles for tories. Age, diagnosis of depression, antidepressant use, and many have not. Two that have attracted most study for the time to collection of brain may play a role in these disparate longest periods are the 5HT1A and 5HT2a types. As with the transporter, multiple studies have ple groups have explored the potential use of pindolol, a investigated 5HT2a binding sites in the platelets of depressed 5HT1a antagonist, to hasten response to antidepressants or patients. An increase in binding sites (B-max) has been re- bring out responses in refractory patients. These studies ported in depressed and suicidal patients with some sugges- have yielded mixed results suggesting that pindolol may tion that increased binding in suicidal patients may be inde- hasten response to antidepressants in milder or first-episode pendent of a diagnosis of major depression (51–53). As with the serotonin transporter, results here activity in suicide victims (66–68). GeneticStudies 5HT2a receptors are found in frontal cortex suggesting a A number of studies have explored the possible role of ge- role in the cognitive aspects of depression. PET ligands have been developed to study 5HT2a activity 18 Long and short forms of the transporter gene appear to be in brain. One study employed [ F]- altanserin and reported relatively common in the general population. An early study a reduction in activity in right posterolateral frontal, orbito- indicated a relationship of the short form with an increased frontal, and anterior cingulate regions in depressives (58). In another study, no differences were found between nonsu- 18 Allelic variation has also been applied to predicting drug icidal depressives and controls using [ F-] setoperone (59). In three studies in Europe and the United States, The exclusion of patients with recent suicidal ideation may homozygotes or heterozygotes for the S-form were reported have played a role in not finding differences between pa- to show sluggish responses to SSRIs (70–72). Studies on effects of antidepressants on was found in a Korean study (73). Clearly, further work is 5HT2a binding using PET have also yielded mix results. More recently, Mann perone binding (60), whereas another recently reported that and colleagues (69) reported that the short form genotype 3 to 4 weeks of desipramine treatment resulted in a signifi- was associated with a diagnosis of major depression but not cant decrease in 5HT2 activity in multiple areas, particularly with suicide or 5HT-transporter binding in postmortem in frontal cortex (61). Depletion Studies 5HT2A receptors are coupled to the phosphoinositide second messenger system. When 5HT2a receptors are acti- Brain concentrations of serotonin are highly dependent on vated by agonists, phosphatidyl inositol 4,5 bisphosphate is circulating levels of tryptophan, which competes with other Chapter 72: Molecular and Cellular Mechanisms in Depression 1043 amino acids for transport into the brain. Charney and Del- theories of depression, DA has been emphasized far less in gado have pioneered in the use of an amino acid cocktail depression in spite of its being widely distributed in brain. In these lite, are decreased in depressives (2,85,86), although some studies, the drink was first administered to subjects who had studies have reported elevated CSF DA, but not HVA levels responded to various antidepressants and who were being (87). Urinary DOPAC levels are decreased in depressives maintained on medication. Diphenhydramine has been compared with controls (88); in one study, DOPAC levels commonly used as the comparison cocktail. Euthymic pa- appeared associated with suicidal behavior (85). Dopami- tients on SSRIs but not TCAs rapidly experienced depres- nergic agents such as psychostimulants, nomifensine, and sive symptoms when depleted of L-tryptophan, suggesting the dopamine agonist pramipexole all have antidepressant the need for maintaining adequate serotonin levels to ensure effects in nondelusional patients. Parallel decreases in glu- In contrast, elevated mesolimbic DA activity has been cose utilization in frontal and thalamic regions using PET hypothesized to play a role in delusional depression (89). In contrast, there are multiple chotic symptoms and agitation in major depression (89), reports of depletion not causing a clear recurrence of symp- and increased plasma DA and HVA levels have also been toms in patients treated with bupropion or electroconvul- reported in delusional depression (90,91). Studies have used a variety of dif- limbic DA activity has been postulated to occur secondary ferent methods (e. Recent studies in rats, nonhuman primates, and differences may account for the discrepant findings. The psychotic depressives suggest elevated glucocorticoid activ- degree and duration of response observed before the deple- ity could also result in altered or decreased prefrontal corti- tion challenge is administered may be of particular impor- cal dopamine metabolism and to alterations in attention tance (79). Patients who are in remission or have shown a and response inhibition (92,93). These data suggest in- prolonged response are unlikely to demonstrate significant creased HPA axis activity could affect DA turnover differ- worsening of moods (79). These data suggest recent re- ently in specific brain regions—alterations that have been sponders are those who are susceptible to experiencing re- suggested in schizophrenia. Antipsychotic drugs appear to lapse with depletion strategies. Depletion of unmedicated play a key role in treatment of delusional depression and euthymic depressives does not appear to induce recurrence, glucocorticoid receptor antagonists are being actively stud- indicating maintaining serotonin tone is important primar- ied in the disorder. Of interest is a recent report that women controls show GABA much lower rates of 5HT synthesis and a greater decrease in response to depletion than men do (80). This gender- GABA has become a focus of greater study over the past based difference is consistent with a recent observation that several years with the increasing use of anticonvulsants in chronically depressed women are more responsive to an mood disorders. GABA is a major inhibitory neurotransmit- SSRIthan men are (81). There are two types of Fenfluramine Challenge GABA receptors. GABAA receptors have been studied in anxiolysis because of their location within a benzodiaze- Fenfluramine, previously marketed as an appetite suppres- pine–GABA receptor complex that is coupled to chloride sant, causes a release of serotonin from presynaptic neurons 2 channels. Prolactin responses In rats, antidepressants and mood stabilizers appear to up- to fenfluramine challenge are blunted in depressed patients regulate frontal-cortical GABAB, but not GABAA, receptors (82,83) and there are some data to suggest this may be a (94,95). GABAB agonists may enhance cAMP responses to trait marker (84). However, bipolar manic and axis II pa- norepinephrine and -adrenergic down-regulation in re- tients may also demonstrate blunted prolactin responses, sponse to tricyclic antidepressants, suggesting a facilitative raising questions regarding the specificity of the test. GABA levels have DOPAMINE been reported to be decreased in the CSF of depressed pa- tients in some but not all studies (96,97). Plasma GABA As indicated, dopamine (DA) is a precursor for norepineph- levels have also been reported to be lower in unipolar depres- rine. Although NE has played a central role in etiologic sives (98,99), and this may not normalize with treatment 1044 Neuropsychopharmacology: The Fifth Generation of Progress (100). Alcoholism can also be associated with low plasma drome contributor to DEX nonsuppression, greater than GABA levels (101). In refractory depressed patients the effect of severity or melancholia (107). Outpatients with undergoing cingulotomy, GABA levels are inversely related milder and nonpsychotic disorders show much lower rates to degree of depression (102). This difference in types of patients stud- tively exploring using fMRIto image GABA in the brains ied may help explain the variability in DEX nonsuppression of patients with mood disorders, both before and after treat- rates across studies. NEUROENDOCRINE SYSTEMS Glucocorticoid overactivity has been hypothesized to play a direct role in the development of cognitive impair- Neuroendocrine systems were originally studied as gateways ment and delusions in patients with psychotic major depres- to the exploration of neurotransmitter activity, such as nor- sion (89).