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An example of a cost-utility approach is the use of quality-adjusted life years (QALYs) (38 generic bupron sr 150 mg amex,39) generic 150mg bupron sr overnight delivery. As noted above, different stakeholder groups value different outcomes differ- COST-EFFECTIVENESS ently; hence, approaches such as QALYs create an effective- ness metric representative of at best only one stakeholder The success of interventions in schizophrenia, whether med- group, and at worst the resulting metric is representative of ications or psychosocial rehabilitation programs, is reflected no one. Although elegant in presentation, as with sausages, in multiple domains. An antipsychotic may have an impact observing their creation can reduce enthusiasm for their use. These scheme—deciding, for example, what weight gain is the are all measures of the effectiveness of the agent, some posi- equivalent of what change in extrapyramidal side effects tive and some negative. Some, such as hallucinations and (EPSs) and what change in psychotic symptoms. Typically, delusions, may be influenced much more directly by the one does this either by interviewing individuals representa- medication than more distal outcomes such as housing or tive of the population under study (e. Sim- with schizophrenia used weights derived as part of a doctoral ilarly, some people are very troubled by changes in weight dissertation by Kleinman (Johns Hopkins University, 1995) or sexual functioning, whereas such changes mean little to of mainly African-American women, only about half of others. Hence, much as we would like a composite measure whom (55%) were diagnosed with schizophrenia (the rest across all effectiveness domains, this reductionistic approach were diagnosed with major depression, bipolar, and other is fraught with untenable compromises. We were unwilling to take the leap of tion among different patients and different providers, pa- faith needed to generalize from groups this disparate when tients and payers ascribe different values to the same out- presenting cost-effectiveness results from our own work come (e. Nevertheless, Rosenheck and colleagues are to be com- public mental health systems may be more concerned about mended for providing the information necessary to follow decreases in violence and patients may be more concerned back their methods to see what was used. This is not always with increases in quality of life). Another type of utility analysis is the measure of symp- Cost-effectiveness analyses have evolved to deal with the tom-free days (42). Under such analyses, interventions are multiple domains touched by a single treatment. Such anal- compared with respect to the number of symptom-free days yses report the change in a given effectiveness measure asso- they produce. Following the methodology of Lave and col- ciated with a particular cost investment in treatment. A leagues (43), Simon and colleagues (42) credited a study medication may be cost-effective with respect to certain out- participant with having one depression-free day if the study comes, cost-neutral for others, and costly for yet others. Many Lehman (37) reminds us that the current explosion of new people with depression, as well as many researchers, would knowledge about effective treatments and the advent of evi- take issue with saying that someone was symptom free for dence-based quality standards for treating schizophrenia half a year if they reported having 50% of full symptoms come at a time when cost containment is paramount in the for each day of that year. Symptom-free days may be a poor health policy agenda. Policy makers need to know the im- measure within schizophrenia studies simply because, unlike pact of dollars invested in treatment—but not just in a with depression, symptoms and functioning are poorly cor- 812 Neuropsychopharmacology: The Fifth Generation of Progress related, and the likelihood of having a completely symptom- lion in the pharmacy budget for medication X, what can I free day is rather small. What will it equals one lost year of healthy life, can also be used to buy me in terms of reductions in hospital use, improvements express years lost, both to premature death and to disabilities in vocational functioning, reductions in violent episodes, associated with living with schizophrenia (44). In a population my sexual functioning, and in my body movements? DALYs are calculated by adding together the than to others. An analogy is a proposal for a city park number of years between mortality and life expectancy to be funded from multiple sources. Calculating YLDs requires making as- park would impact the value of your property, your safety, sumptions about the relative impact of illness onset, dura- your recreational options, what you are called on to invest), tion, and severity on healthy living (for example, making the park may or may not be a good idea. And, depending an assumption that a first psychotic episode at age 15 is on who is paying for what, and which outcome domains worse than a first episode at age 25). As with QALYs, these are most important to you, you may stand to get a lot or metrics can be derived by surveying individuals with schizo- a little out of the dollars going into the park. The challenge phrenia or their proxies, with the accompanying assump- is to present the data on costs and effects in such a way that tions that how one weights hypothetical events is the same the various payers (the city, private foundations, neighbor- as the trade-offs one would make if one could trade fewer hood organizations, individual contributors) can each look days of healthy life for more days of life with particular from their own perspective, see what the expected gains and disabilities. Because such ratings are inherently untestable losses are in the outcome domains they care about most by rigorous methods, whether reliable or not, their validity (less street noise, more open space, more dogs, more people remains suspect. Further, the calculation of DALYs 'pre- drawn to the neighborhood), perform their own idiosyn- supposes that life years of disabled people are worth less cratic weighting of these factors, and decide if they are in than life years of people without disabilities' (46), and may favor of the park or not. In contrast to cost-utility analysis, cost-effectiveness anal- Schizophrenia brings with it an increased risk of suicide ysis does not reduce the impact of an intervention into one (48), which is consistent with DALYs ranking some lives measure. Some outcomes may be clearly preferential or as worse than death. However, assuming that person A and 'dominant choices' (e. Other outcomes are not as clearly dominant, and in fates are worse than death presumes an ecologic validity to these cases it may be useful to show the likely range of DALY ratings that may be unwarranted. One Cost-utility measures such as QALYs, DALYs, and mea- method of examining these ranges is to create sampling dis- sures like symptom-free days, have enormous appeal because tributions for costs and effectiveness measures to show the of their ability to reduce multiple effectiveness domains to precision of estimates as well as their mean. Where the measure is reduced to dollars (as in and plot these estimates as a cost-effectiveness plane. Boot- QALYs), one may even compare the values of interventions strapping techniques offer one means of describing confi- between different conditions (38), for example, if dollars dence intervals for incremental cost-effectiveness ratios expended on diabetes reap more benefits than dollars spent (ICERs) (49,50).

This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed generic 150 mg bupron sr with visa, the full report) may be included in professional journals 85 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising cheap 150 mg bupron sr with mastercard. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Female LEC, school 1 I found it quite easy because my mum was really supportive. And because we especially did it over the weekend and the holidays, I found that extremely hard because in the holidays and that, I kind of let myself go and like, have a lot of chocolate, that sort of thing. So if we had done it during the week I think I would have found it a lot easier, so maybe next time. P, school 9 Yeah so she really owned her goals as well. She was very responsible about it which was good because it gave her something to be responsible for and it was only kind of small changes so um. Male LEC, school 7 Sometimes I found it hard, but sometimes it was quite easy because when I got more in to the programme I found it easier because I started doing it more, in the beginning I found it really hard to make any changes. Specific to the goal-setting phase, it was hoped that the children would use a number of strategies they had learnt during phase 2 to help them achieve their goals (e. It was also hoped that parents would support them by increasing access to and availability of healthy snacks and physical activity, and enforcing rules about screen time. When the children discussed their experiences of making changes in the focus groups, some commented that their parents had supported them in this way: My parents helped a lot with my goals because my mum made a rota which is so I only get an hour or half an hour on screen time every day. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 87 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Female EC, school 12 We know that changes at a family level can have a positive impact on children making changes to their eating and activity behaviours,128 and there was strong evidence for this from parents and children alike. The results of the parent questionnaire indicated that 74% of families had made changes (see Appendix 17), with 78% of parents providing further details. P, school 13 Yeah definitely yeah because like you know if she would get a snack and she has a carrot, and then thinks oh yeah you will all have carrots, so in that respect you know she has pulled the whole family to a healthier snack rather than just herself. P, school 7 Yes we definitely decreased the fruit juice that we have. Male LEC, school 9 Um yeah, we started doing more as a whole family together and going out more, like going on family walks on the weekend, instead of just having one person go out by themselves, and literally just going out all together. The focus group and interviews suggested that children had made changes to their diet and/or activity/ sedentary behaviours: The one area that I did really notice that he picked up on is looking at ingredients of food. P, school 4 Teachers also reported being aware of changes the children had made: It was perfect timing, to have that farm trip after the 80 : 20 programme to see if they had adjusted their lunchboxes to be a little bit more, there was more water and less fizzy drinks, less sweets, more fruit. Because I went around looking at the packed lunches as we were sitting on these bales of hay, and it was a kind of relaxed fashion, and the children were just openly talking about it straight away. T, school 13 The evidence from the focus groups and interviews of reported changes was supported by data from the parent questionnaire. Fifty-five per cent of parents noticed changes to screen time, with 67% reporting changes to physical activity. In response to the question asking whether or not any observed changes had been maintained, 78% reported that they had (see Appendix 17). When given the opportunity to provide details of these changes, 89% of parents responded and provided a brief description of the change they had observed in their child. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 89 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Adverse events There was one adverse event reported during the 5-year trial. The trial manager spoke to the mother and followed up with an e-mail detailing the actions taken as a result of her concerns. The mother was happy for her child to continue with the programme, and the HeLP co-ordinator subsequently set goals with the child that did not focus on changing physical activity or dietary behaviours (which were already meeting the 80 : 20 balance). The HeLP co-ordinator informed both the school head teacher and the class teacher of this event and all were very supportive of the programme and the way the messages were delivered. Overall I think the message that they were left with was pretty good. Prespecified assessment criteria of engagement and interview and focus group data from teachers, parents and children showed that HeLP appeared to engage schools, children and their families across the socioeconomic spectrum.

Synaptic transmission can either be enhanced or de- Paired-Pulse Facilitation and Depression pressed by activity discount 150mg bupron sr mastercard, and these alterations span temporal do- mains ranging from milliseconds to enduring modifications When two presynaptic stimuli are delivered within a short that may persist for days or weeks and perhaps even longer generic bupron sr 150 mg without a prescription. More lasting changes are thought to play impor- vals. Given these diverse functions, it is not sur- presynaptic plasma membrane, waiting to be released. Many prising that many forms and mechanisms of synaptic plastic- synapses at longer interstimulus intervals (20to 500milli- seconds) exhibit paired-pulse facilitation that is thought to ity have been described. In this chapter, I provide a brief result from the influx of calcium that occurs in response to overview of some of the forms of synaptic plasticity found the first action potential. Malenka: Department of Psychiatry and Behavioral Sciences, tial facilitation. However, with a single action potential, the Stanford University School of Medicine, Palo Alto, California. Furthermore, given that presynaptic pro- there is much interest in the possibility that transient modu- teins that may be involved in short-term plasticity may be lation, by activation of protein kinases, of some of the pre- abnormal in neuropsychiatric disorders (11), it is not unrea- synaptic phosphoproteins that are known to be involved in sonable to speculate that abnormal short-term synaptic dy- the control of transmitter release may play an important namics in specific neural circuits may contribute to the path- role in very short-term synaptic plasticity. For example, ophysiology of any number of mental illnesses. Whether a specific synapse displays paired-pulse facilita- During the last decade, there was enormous interest in eluci- tion or depression depends on the initial state of the synapse dating the mechanisms responsible for activity-dependent and its recent history of activation. Because these forms of long-lasting modifications in synaptic strength. The great plasticity largely result from changes in the probability of interest in this topic is largely based on the simple idea that transmitter release, synapses that begin with a very high external and internal events are represented in the brain as probability of release tend to show depression, whereas those complex spatiotemporal patterns of neuronal activity, the with a low probability of release exhibit facilitation. Consis- properties of which result from the pattern of synaptic tent with this idea, activation of presynaptic receptors that weights at the connections made between the neurons that cause a decrease in transmitter release almost always causes are contributing to this activity. The corollary to this hy- an increase in the magnitude of paired-pulse facilitation (or pothesis is that new information is stored (i. This simple idea was put forth by Ramon y Cajal almost 100 years ago, but experimental support for such a process was lacking until Facilitation and Depression Following the early 1970s, when it was demonstrated that repetitive Trains of Stimuli activation of excitatory synapses in the hippocampus caused Longer-lasting forms of plasticity are observed following re- an increase in synaptic strength that could last for hours or petitive or tetanic stimulation of synapses with prolonged even days (12,13). This long-lasting synaptic enhancement, (approximately 200-millisecond to 5-second) trains of stim- LTP, has been the object of intense investigation because uli applied at high frequencies (10to 200Hz). Augmentation it is widely believed that LTP provides an important key and posttetanic potentiation refer to enhancements of trans- to understanding the molecular mechanisms by which mitter release that can last anywhere from seconds (augmen- memories are formed (14,15) and, more generally, by which tation) to several minutes (posttetanic potentiation). Furthermore, the activity- are thought to result in large part to the buildup of calcium and experience-dependent refinement of neural circuitry concentration in the presynaptic terminal during the trains that occurs during development shares features with learn- of stimuli. This residual calcium may both combine with ing, and thus a role for LTP in this process has been pro- the calcium influx elicited by subsequent single action po- posed (16–18). At some synapses, repetitive Long-Term Potentiation activation leads to depression that can last for several sec- onds or even minutes. As in paired-pulse depression, this No form of synaptic plasticity has generated more interest generally occurs at synapses that exhibit a high probability and has been more extensively studied than LTP in the CA1 of release and is thought to result, at least in part, from a region of the hippocampus. The excitement surrounding transient depletion of the synaptic vesicles that are poised this phenomenon derives mainly from four sources. The functional relevance of such short-term mation storage (20,21). Like memories, LTP can be gener- synaptic dynamics has received much less attention than ated rapidly and is prolonged and strengthened with repeti- long-lasting forms of synaptic plasticity and is just begin- tion. It is also input specific in that it is elicited at the ning to be explored (8). One potential role of these short- synapses activated by afferent activity and not at adjacent term forms of synaptic plasticity is to transform incoming synapses on the same postsynaptic cell. This feature dramati- information in the temporal domain into a spatially distrib- cally increases the storage capacity of individual neurons Chapter 11: Synaptic Plasticity 149 TABLE 11. AREAS OF BRAIN IN WHICH LTP HAS BEEN DEMONSTRATED Hippocampus Amygdala Dentate gyrus Cerebellum CA1 Thalamus CA3 Striatum Cerebral cortex Nucleus acumbens Visual Ventral tegmental area Somatosensory Motor Prefrontal FIGURE 11. Model for the induction of long-term potentiation (LTP). During normal synaptic transmission (left), synaptically re- that, because synapses can be modified independently, can leased glutamate acts on both NMDA and AMPA receptors. Na participate in the encoding of many different bits of infor- flows through the AMPA receptor channel but not through the NMDA receptor channel because of the Mg2 block of this chan- mation. Third, LTP is readily generated in in vitro prepara- nel. Depolarization of the postsynaptic cell (right) relieves the tions of the hippocampus, thus making it accessible to rigor- Mg2 block of the NMDA receptor channel and allows Na and Ca2 to flow into the cell. The resultant rise in Ca2 in the den- ous experimental analysis. Indeed, much of what we know dritic spine is a necessary trigger for the subsequent events lead- about the detailed mechanisms of LTP derives from studies ing to LTP.

Local Anesthetics bupron sr 150 mg line, Pharmacokinetics and Adjuvants Amedeo Costantini The action of local anesthetics is elicited through a specific block of the sodium channels in the peripheral and central nervous system generic 150 mg bupron sr with amex. They block both nerve impulse generation and propagation. Local anesthetics have a particularly high level of activity in the central nervous system and the cardiovascular system. When using local anesthetics for regional anesthesia blocks, patient safety procedures such as a safe vein access, oxygen availability, intensive care equipment, adequate monitoring, immediate availability of general anesthesia, and a sterile procedure should be assured according to national and international guidelines (Bertini 2006). Guidelines for an adequate postoperative pain treatment strategy and management of local anesthetic systemic toxicity must be also taken into account (Savoia 2010, Neal 2010). Dose, Concentration and Volume Correlations The concentration is defined as the mass of a constituent (the local anesthetic) divided by the volume of the mixture (volume of solution) (Table 12. Local Anesthetics, Pharmacokinetics and Adjuvants | 85 Table 12. C = Concentration (mg/ml) C = M / V M = Mass (mg) M = C x V V = Volume (ml) V = M / C The right approach to a local anesthetic dosing is to calculate the dose per kg of weight and to dilute it in order to obtain the desired volume or concentration. The total dose (the product of volume x concentration) should be tailored to the minimum mass of local anesthetic necessary to achieve the desired clinical effect (Table 12. Recommended doses Ropivacaine Levobupivacaine Bupivacaine Adults 2-3. Local anesthetic Infiltration anesthesia (doses with epinephrin are in brackets) Ropivacaine 200-225 mg Levobupivacaine 150 mg Bupivacaine 150-175 (225) mg Table 12. Recommended concentrations Ropivacaine Levobupivacaine Bupivacaine Adults 2-7. Special attention should be posed to obese patients in which a dosing on a milligram of local anesthetic-per-kilogram of weight basis would be dangerous. In these patients, a dosing based on the ideal weight may be more correct. Maximum recommended doses are valid in relation to normal conditions (70 kg healthy persons) and do not constitute a maximum (Rosenberg 2004). They must be varied individually depending on the type and site of block, the weight and the clinical condition of the patient. Monitoring according to the technique of administration and to the expected plasma concentration is highly advised (Rosenberg 2004). Long-lasting local anesthetics The long lasting amide anesthetics, bupivacaine, levobupivacaine and ropivacaine, are highly lipophilic molecules of similar properties and efficacy. The efficacy and block duration is dose dependent (Mulroy 1999). As reflected by clinical studies, the duration of analgesia after IFB/LIA, IIB and TAPB after a single injection of long lasting local anesthetics typically lasts less than 12 h. However, the benefits on the subjective pain levels at rest and under stress, on the postoperative amount of analgesics and on postoperative mobilization may last for 24 hours to 10 days (Pettersson 1998, Ding 1995, Harrison 1994). Among the long-lasting local anesthetics, ropivacaine is preferred for abdominal blocks because it is less cardiotoxic than bupivacaine (Knudsen 1997). Local Anesthetics, Pharmacokinetics and Adjuvants | 87 the levoenantiomer of bupivacaine) causes cardiovascular and CNS toxicity at higher doses than bupivacaine (Bardsley 1998). Absorption Pharmacokinetic parameters (for example plasma concentrations of local anesthetics) vary widely between individuals. The pharmacokinetic variables depend on the absorption from the site of injection, the distribution in the tissues and body fluids according to lipid solubility and protein binding, and the metabolism and clearance of the drug. The passage of the local anesthetic into the blood will depend on the total dose, the capillarity of the site of injection and on the ratio between the volume of the drug and the surface in contact with it. A smaller absorption surface may counterbalance a high drug concentration whereas the unpredictable spread of a large volume of local anesthetic may become a reason for side effects (Rosenberg 2004). The pattern of the absorption rate for different blocks is generally intercostal > epidural /caudal > brachial plexus > sciatic block > subcutaneous. The absorption after an IIB or a TAPB may be faster than a caudal block (Ala-Kokko 2000, Ala-Kokko 2002, Stow 1988). Moreover, absorption may be influenced by local or systemic inflammation (Rosenberg 2004). The emergence from anesthesia may be also associated with increased absorption and a second plasma peak (Smith 1996). Absorption from the abdominal wall The pharmacokinetics of local anesthetics in the TAM plane is an area of current investigation. The common landmarks are close to important vessels that run through the fascias. The TAM plane has a big surface that requires high volumes of diluted solutions in order to achieve an extended block. Even at a dilute concentration, large volumes of local anesthetics may cause 88 | Ultrasound Blocks for the Anterior Abdominal Wall serious consequences after an intravascular injection or if there is rapid uptake from the tissues. Moreover, it is to be considered that an IFB/LIA involves soft tissue infiltration.

The positron emitters used for which can be done using imaging modalities that measure imaging have shorter half-lives than the single photon emit- electrical activity cheap bupron sr 150mg with mastercard, CBF effective bupron sr 150mg, or brain metabolism. Of the modali- ties used for functional imaging, fMRI has the highest spa- tial resolution. Conversely, MEG and EEG are the imaging technologies with the highest temporal resolution, which Nora D. Volkow: Medical Department, Brookhaven National Labora- enables the examiner to assess the temporal displacement tory, Upton, New York. Fowler: Chemistry Department, Brookhaven National Labora- of activation signals as they propagate in brain on the order tory, Upton, New York. IMAGING MODALITIES USED TO INVESTIGATE THE LIVING HUMAN BRAINa Parameter Temporal Spatial Measured Resolution Resolution Sensitivity MEG Function 1 ms 5 mm EEG 1 ms 10–15 mm CT Structure ms MRI Structure ms 1. Research instruments have been developed that have better performance. CT, computed axial tomography; EEG, electoencephalography; MEG, magnetoencephalography; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computed tomography. The effect of drugs of abuse on neurotransmission has thus can provide information on potential organ toxicity. PET and SPECT have the highest sensi- has been evaluated with PET. Co- PHARMACOLOGIC PROPERTIES OF DRUGS caine and MP were found to have a large brain uptake (7% OF ABUSE IN THE HUMAN BRAIN to 10% injected dose) and to have an almost identical pat- tern of distribution in the human brain, where they bound The investigation of the pharmacologic properties of drugs entails studies of their pharmacokinetics (primarily using PET and the [11C]-labeled drug) as well as their pharmaco- TABLE 103. DRUGS WITH ABUSE LIABILITY THAT dynamics (using PET or SPECT and a radiotracer with HAVE BEEN LABELED WITH A POSITRON EMITTER specificity for a particular molecular or biochemical target (CARBON-11) or using PET, SPECT, and fMRI to assess brain function). Drug Class Specific Drug Reference or Review Because these studies are done in awake human subjects, one can investigate the relationship between the behavioral Psychostimulants Cocaine 5,6 effects of drugs and their effects on brain function and neu- Methylphenidate 113 Metamphetamine 114 rochemistry. Opiates Morphine 115 Heroin 115 Codeine 115 Pharmacokinetics Buprenorphine 116 Methadone 117 PET can be used to measure the absolute uptake, their re- Cannabinoids THC 118 11 Nicotine Nicotine 119–120 gional distribution, and the kinetics of [ C]-labeled drugs Caffeine Caffeine 112 in the human brain. Moreover, the labeled drug can also LSD LSD 121 be used to determine the target organs for the drug and Chapter 103: Application of Imaging Technologies in Drug Addiction 1477 rate of drug clearance is relevant in their reinforcing effects. In the case of cocaine, the fast rate of clearance enables repeated, frequent administration that is characteristic of cocaine bingeing (cocaine is taken every 15 to 30 minutes), whereas for MP, its relatively slow clearance from brain is likely to produce accumulation and toxicity that thus pre- vents frequent repeated administration. Pharmacodynamics Multiple parameters pertaining to the mechanisms of action of the drug of abuse can be investigated with imaging. These include measurement of the efficacy of the drug of abuse at the molecular target that is associated with the reinforcing effects of the drug of abuse (i. These parameters can be assessed both in nonaddicted control subjects and in ad- FIGURE 103. Left: Images at the level of the striatum obtained dicted patients to determine whether there are differences with [11C]cocaine and with [11C]methylphenidate at different in the responses between them. Right: Time activity curves for radiotracer concentration in striatum and temporal course for the 'high' expressed as a percentage from peak after pharmacologic doses of intravenous cocaine (upper panel) and of intravenous methylphenidate (lower panel). Studies on theirpharmacokinetics anddistribution inhuman brain. Arch Gen The efficacy of the drug of abuse at the molecular target is Psychiatry 1995;52:456–463, with permission. With PET and appropriate radiotracers, it is possible to measure the levels of DAT occupancy achieved by drugs that block predominantly to the striatum and where the specific bind- DAT in human subjects reproducibly (8). Both drugs had a very DAT occupancy by different doses of intravenous cocaine were assessed with PET and [11C]cocaine in active cocaine fast rate of uptake, with peak concentrations in striatum achieved for cocaine between 4 and 6 minutes and for MP abusers (9). This study showed that cocaine is very effective between 6 and 10 minutes after injection (6). For both drugs, 'high,' and that for cocaine to induce a 'high' it had to their fast uptake in striatum paralleled the temporal course block more than 60% of DAT function. A similar study for the experience of 'high' reported by subjects given phar- done with intravenous MP showed that the ED50 (the dose macologic doses of intravenous cocaine or of MP. However, required to block 50% of the DAT) was half that of cocaine whereas for cocaine the rate of clearance paralleled the de- (MP, 0. As for co- cline in the 'high,' for MP the 'high' declined while there caine, the magnitude of the DAT occupancy was signifi- was still significant binding of the drug in brain (Fig. Although the sponds to 640 and 390 nM, respectively) (11). In analyzing rate at which psychostimulants enter the brain had been the implications of the similar in vivo efficacy for DAT recognized as an important variable in their reinforcing ef- blockade by cocaine and MP, regarding the low abuse po- fects (7), the relevance of their rate of clearance had not. Because the rapid- is relevant for understanding their toxicity as it relates to ity of drug effects is an important variable in the reinforcing cerebrovascular disease. The discrepancy could also reflect effects of drugs of abuse (12) and routes of administration the finding that changes in metabolism reflect an average affect drug pharmacokinetics, the results with intravenous of the changes that occur over the uptake period of FDG MP cannot be extrapolated to oral MP. SPECT studies measuring the levels of receptor occupancy by the benzodiazepine drug lorazepam showed that only a few receptors are occupied at pharmacologic doses (13), findings that support the no- CHRONIC EFFECTS OF DRUGS OF ABUSE IN tion that in humans there is a 'reserve' of benzodiazepine THE HUMAN BRAIN receptors. Imaging studies have been done to assess neurochemical Effects on Dopamine Concentration and functional changes in the brain of addicted subjects that are associated with the process of addiction as well as Because the ability of drugs of abuse to increase extracellular changes associated with drug toxicity. Functional imaging DA concentration is considered crucial for their reinforcing strategies have also been used to assess the brain region in- effects, the estimation of DA changes becomes particularly volved in drug-related states such as drug craving.