By F. Snorre. The Ohio State University.

Initial studies into the chemical authors reported that after a winning streak described as a composition of CSF from men with PG found no signifi- 'fever order carbidopa 300mg online,' six men who were regular Pachinko players were cant differences in levels of 5-HT or its metabolite 5-hy- found to have elevated levels of DA carbidopa 125 mg online. The authors suggested droxyindolacetic acid (5-HIAA) as compared to levels in the DA changes may be related to the motivational processes healthy men (57–59). Given that multiple factors can com- underlying repeated Pachinko playing. Alterations in mea- plicate evaluation of CSF data (56,60,61) and the finding sures of arousal, NE, endogenous opiates, and immune sys- that men with PG have significantly longer CSF tapping tem function were also described. Although the results of times than healthy male controls (62), the authors calculated the foregoing studies and additional evidence from neu- the concentrations of monoamine metabolites per minute roimaging and molecular genetic studies suggest DA dys- of tapping to obtain an estimate of mass flow through the function in PG (see later), more studies are needed to clarify lumbar puncture needle. When taking tapping time into the involvement of DA pathology in PG. These findings, particularly in light of reports of low CSF levels of 5-HIAA in individuals with impulsive charac- NE has been hypothesized as mediating aspects of arousal, teristics, such as those attempting suicide (39–41), lend attention, and sensation seeking in individuals with PG (38, further support to a central role for 5-HT in the underlying 57,58,68). Additional data emerging from pharmaco- ripheral, and central levels of NE or the NE metabolites therapy trials, neuroimaging studies, and investigations into MHPG and vanillylmandelic acid (VMA) and found the monoamine oxidase (MAO) function (see later) are also PG subjects to have higher CSF levels of MHPG and higher consistent with 5-HT dysfunction in PG. In a subsequent report, the are needed to define the nature and extent of 5-HT pertur- investigators found in the same group of 17 men with PG bations in PG more precisely, particularly as they relate to originally studied, scores of extraversion on the Eysenck specific aspects of PG (e. More recently, increased CSF 1728 Neuropsychopharmacology: The Fifth Generation of Progress levels of NE and MHPG were found in a second group of bling-concentrated days, differences in blood pressure mea- men with PG (59), although a subsequent report from the surements did not reach statistical significance. A separate same research team reported findings of decreased MHPG study found no evidence of abnormal cortisol responsivity in men with PG when correcting for CSF flow. Independently, CSF levels of corticotropin-releasing Pachinko players found NE system changes under gaming hormone and corticotropin were found not to be signifi- conditions (67). Specifically, blood levels of NE were found cantly different between healthy and PG-affected men (57). Peripheral MAO tion of -aminobutyric acid (GABA) input to DA neurons derived from platelets is of the MAO B subtype and has in the ventral tegmental area (83,84), studies exploring - been suggested to be an indicator of 5-HT function (70, endorphin function in gaming behaviors has been explored. Decreased platelet MAO activity has of -endorphins were found to be elevated during Pachinko been reported in association with impulsive behaviors (72, play, peaking during the start of "fever. Individuals with PG have mOR antagonist naltrexone in the treatment of PG (see also been reported to exhibit decreased platelet MAO activi- later), suggest further investigation into opioid function in ties (78,79). In one study, 15 men with PG were found to PG are warranted. A separate study involving 27 men Other Neurotransmitter Systems with PG found MAO activity levels 41% lower than in Studies of the possible dysregulation of other neurotrans- matched male controls (79). Each group investigated per- mitter systems as related to PG have been undertaken. One several measures of sensation-seeking in the other (78). Immune system and cortisol changes have been related to Neuroimaging Studies gaming behaviors. The foregoing study involving Pachinko players (67) found alterations in T cells (decreased number Few neuroimaging studies directly investigating PG have of T cells and decreased CD3-56 activity) and natural killer been performed to date. One study investigated the poten- cells (increased number of natural killer cells without change tial role of the MCL DA system in a study in which partici- in activity). A separate study of male and female Kimberley pants were paid increasing amounts of money depending aborigines found significantly higher cortisol levels on days on the skill level reached while playing a video game (90, in which gambling behavior was concentrated (Thursdays 98). Positron emission tomography (PET) studies using 11 and Fridays) as compared with temporally distinct days C-labeled raclopride, a ligand with high affinity for D2- (Mondays and Tuesdays) (80). Significantly higher epi- like DA receptors (D2Rs), found decreased levels of striatal nephrine levels were also found on the gambling-con- binding in eight male study subjects playing a tank video centrated days, a finding further implicating adrenergic game as compared with when they viewed a gray screen function in gambling behaviors. The authors concluded that the observed 13% Chapter 120: Pathologic Gambling and Impulse Control Disorders 1729 reduction in [su>11C]raclopride signal during the gaming cision-making processes (102). Individuals with substance condition is consistent with at least a twofold increase in use disorders also have demonstrated impaired performance levels of extracellular DA. Because the game involved in- on the Iowa Gambling Task (103–105), and poor perfor- creasing monetary reward associated with each skill level mance has been shown to correlate with decreased blood reached during the video game, the paradigm is similar but flow measurements to the VM in cocaine-dependent sub- not identical to actual gambling. The extent to which dysfunction of the An independent study investigated for specific DA and VM, amygdala, or other brain regions involved in regulation 5-HT abnormalities in individuals with PG (91). Using of emotion and decision making may be involved in the PET, the researchers found decreased striatal binding in pathophysiology of PG remains to be explored more com- PG subjects of [11C]N-methylspiperone, a ligand with high pletely. The striatal signal, corresponding to D2R-receptor occu- Genetics pancy, could be explained by multiple, non–mutually ex- clusive possibilities including decreased numbers of avail- Twin studies investigating disordered gambling behaviors able D2Rs, decreased affinity of D2Rs for the tracer, or have been published (107,108). One study observed signifi- increased synaptic concentrations of DA. PG subjects were cantly greater rates of similarities in male monozygotic as also found to have impaired performance on multiple neu- compared with male dizygotic twins with regard to partici- rocognitive tests, including the Halstead-Reitan, Wisconsin pation in past-year high-action forms of gambling (e. No differ- gional cerebral blood flow to the frontal cortex and anterior ences were observed in the two groups of males with regard cingulate was found to be significantly lower in PG as com- to measures of low action forms of gambling or in female pared with healthy subjects during performance of an audi- monozygotic versus dizygotic groups with regard to past- tory continuous performance attention task. These findings year participation in either high- or low-action forms gam- are consistent with prior studies implicating involvement of bling. A larger study used the monozygotic (n 1,869 the frontal cortex and anterior cingulate in attention (93), pairs) and dizygotic (n 1490 pairs) twins who served in among other processes, and suggest a role for these brain the military in the Vietnam War era on whom questions regions in mediating attentional deficits in individuals with pertaining to PG from the Diagnostic Interview Schedule PG (35). The authors found in- Multiple neuroimaging studies into the neural bases of herited factors to contribute between 35% and 54% of the drug use disorders have been performed. Studies of drug liability for each of the five individual PG-related factors. The results are comparable ies investigating whether similar brain regions may be in- to findings derived from the same sample for the heritability volved in PG are under way, with preliminary data suggest- of drug use disorders, with 34% and 28% of the variance ing the involvement of parallel neural activities (96,97). The findings are consistent with the notion that developed and used in investigations into decision making genetic influence significantly affects the risk of developing (98–101). The tool involves four piles of cards, each associ- PG. Selection from two of the piles, each associated with have been performed (110–115). Investigations described lower rewards and lower punishments, will ultimately result to date have been association studies exploring the involve- in long-term gains, and selection from the other two piles ment of genes related to NE, 5-HT, and DA systems. Without prior instruction first of these studies investigated a role for the D2A1 allele of into the reward and punishment profile of each pile, individ- the D2R, an allele previously reported by the same research uals are instructed to select from the piles and to maximize group to be implicated in such compulsive-addictive behav- gains. Interestingly, individuals with stroke lesions in either iors as drug abuse, cocaine abuse, and compulsive eating the ventromedial prefrontal cortex (VM) or amygdala per- and smoking (116,117).

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From a practical perspective purchase carbidopa 300 mg online, the total and free drug in plasma will subsequently be stable purchase 125mg carbidopa overnight delivery. In an analogy to in vitro receptor binding studies, this stable condition is a state of equilibrium receptor In summary, three basic methods can be used to estimate binding. The concentration of receptor- the target parameter is typically Bmax/Kd, which equals the bound tracer (B) can be estimated as target minus back- equilibrium value of B/F under tracer occupancy conditions ground. The level of free tracer in plasma (F) can be mea- (i. From a practical concentration of tracer in plasma is measured with the as- Chapter 31: In Vivo Molecular Imaging 417 sumption that free concentration in plasma equals that in surements of both the tracer and the competing displacer brain. An alternate out- in conjunction with D2-receptor imaging and a stimulant come measure for each of these three methods uses the non- challenge (25,26). Although D2-ligand displacement corre- displaceable activity in a background region of brain as a lated with the increase in extracellular dopamine measured value proportional to free tracer concentration. The reasons that the changes in binding are ESTIMATION OF ENDOGENOUS so much lower (although still, it is hoped, linear) relative NEUROTRANSMITTER LEVELS to the increase in extracellular dopamine are unclear. For exam- brain region occurs over a much slower time course than ple, a D2-receptor probe can be used not only to measure the relatively rapid changes in extracellular dopamine. Nevertheless, these stimulant-induced displacement studies D2 receptors but also the extent of competition of this bind- appear to provide some reflection of changes in synaptic ing caused by endogenous dopamine. In fact, the most ex- dopamine levels because they are relatively well correlated tensively studied indirect measurements have been the inter- and because depletion of tissues levels of dopamine can action of dopamine with D2-receptor ligands. These studies block the effects of amphetamine (27). The percentage of unmasking reflects the Dopamine transmission in striatum is thought to occur in percentage of D2 receptors occupied by dopamine under two different modes, tonic and phasic (22,23). Dopamine depletion has been mine release represents the steady-state level of dopamine induced in both animals and humans, with a resulting in- in the extracellular space, which is estimated to be in the crease in D2 radiotracer binding (28,29). On the other hand, in phasic release, high of these studies, especially in humans, is the difficulty of extracellular concentrations of dopamine (millimolar range) knowing whether depletion is essentially complete, so that are released within or near a synapse during an action poten- the full extent of dopamine occupancy of the receptor has tial. Close relationships have been proposed between abnor- been measured. For example, if differences in unmasking malities in phasic and tonic dopamine release and the symp- are found in two subjects, does that reflect different levels toms of schizophrenia. Namely, excessive phasic release of endogenous dopamine—or just different levels of dopa- causes psychosis, and decreased tonic release causes cogni- mine depletion? A second limitation of this depletion para- tive deficits and negative symptoms (24). These agents elevate synaptic dopamine One mechanism to minimize this potential confound is to concentrations either by releasing dopamine in a reverse perform the measurements as soon after dopamine deple- manner via a dopamine transporter (amphetamine) or by tion as possible. However, one clear advantage of the deple- blocking dopamine transporter-mediated reuptake of dopa- tion paradigm in comparison with the stimulant-induced mine (methylphenidate). In an imaging study, the elevation increase is that the depleted levels can typically be stably of synaptic dopamine levels is estimated by the decrease in maintained during the scan. Thus, the relative slowness of D2 radiotracer binding following stimulant administration the imaging measurements does not present a pharmacoki- in comparison with control conditions. Just as careful quan- netic confound, as it does in studies with stimulant-induced tification is required for direct radiotracer binding to a mo- release of dopamine. In addition, stimulant depletion studies have tors (39,40). Thus, the endogenous agonist dopamine pre- found greater unmasking of striatal D2 receptors in patients sumably facilitates the intracellular trafficking of D2 recep- with schizophrenia, which suggests that basal/tonic synaptic tors (41), and radiotracers may differ in their affinity for dopamine levels are higher in this disorder (33). Thus, neurotransmitters may occupy The relationship between affinity of the radiotracer and the a smaller percentage of extrasynaptic receptors than of re- sensitivity of its binding to endogenous dopamine is a source ceptors within the synapse, and the in vivo measurement of confusion. Under in vitroequilibrium conditions and at may not truly reflect synaptic neurotransmitter levels. Abnormalities in psychiatric disorders likely represent the However, such equilibrium binding conditions are achieved complex interaction of several neurotransmitter systems in for neither the tracer nor the displacer if each is injected the brain. PET imaging has recently been used to examine as a bolus. Even under these conditions, the sensitivity of aspects of neurotransmitter interactions. For example, Dewy radioligand binding to endogenous dopamine levels is theo- and colleagues (44–46) have pioneered studies on interac- retically (at least based on the in vitro theories) independent tions among dopamine, GABA, and acetylcholine (ACh) of the affinity of the radioactively labeled ligand when both systems in striatum. GABA neurons in the striatum have the tracer and the displacer have achieved equilibrium bind- inhibitory effects on nigral dopamine neurons, nigral dopa- ing conditions. However, if either the radiotracer (as in the mine neurons have inhibitory effects on striatal ACh neu- bolus injection paradigm) or endogenous dopamine (as in rons, and striatal ACh neurons have facilitating effects on stimulant-induced release) changes dynamically over time, striatal GABA neurons. By estimating dopamine levels in the equilibrium condition is not achieved, and the apparent striatum as described above, Dewey and collaborators sensitivity of the radioligand to endogenous dopamine levels showed in human or anesthetized nonhuman primates that is determined by the kinetic properties of the radioligand the blockade of cholinergic transmission by benztropine 11 (34,35). Equilibrium conditions can be achieved for both (44) or scopolamine (45) decreased [ C]raclopride binding tracer and displacer in the dopamine depletion paradigm. The high-af- pine agonist) increased [ C]raclopride binding (decrease 123 finity D2 radioligand [ I]epidepride provides an instruc- in dopamine levels) (46). In addition, they showed that tive example of the differences seen in kinetic and equilib- a dopamine antagonist, N-methylspiroperidol, induced a rium studies. The kinetics of its uptake in brain are slow decrease in [N-11C-methyl]benztropine binding, indicating and do not show displacement by transiently increased do- an increase in ACh levels (44). However, Other interactions have also been studied with PET. In stable low levels of dopamine induced with AMPT show two human studies, an N-methyl-D-aspartate (NMDA) an- unmasking of D2 receptors (37). In two human studies with similar tech- niques, the binding of [11C]raclopride was decreased by In Vivo Confounding Factors stimulation of 5-hydroxytryptamine (5-HT) transmission Although the displacement of radioligand binding by neu- with fenfluramine (a 5-HT releaser) (49) or psilocybin (a rotransmitter can be simply described with in vitro tissue mixed 5-HT2A and 5-HT1A agonist) (50). However, these homogenates, several factors complicate the interpretation results are discordant with those of previous studies in ba- of in vivo experimental results. Key aspects of the by the receptor to guanyl nucleotide-binding proteins (38).

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Psychosis NOS is a residual diagnostic category not show rates of schizophrenia above those predicted for for patients with psychotic symptoms who do not fit into the general population carbidopa 300 mg low cost. In many cases purchase carbidopa 110 mg visa, the NOS Limitations of adoption studies include the possibility designation serves as a temporary diagnosis for patients with of transmission by the mother during pregnancy or delivery new onset of disease until the course of their symptoms of a liability for schizophrenia via nongenetic biological, or reveals their true diagnosis. For phrenic adoptees had schizophrenia, in comparison with example, in a survey of family history and family, twin and only 2% of paternal half-siblings of nonschizophrenic adoption studies, Prescott and Gottesman (33) found that adoptees. Because paternal half-siblings have different 13 of 15 studies demonstrated evidence of a familial/genetic mothers, these results cannot be attributed to in utero (envi- component for schizoaffective disorder. Data from the Finnish adoption studies (47,48) provide Nonpsychotic Spectrum Disorders additional support for both genetic and environmental in- Personality Disorders fluence in the transmission of schizophrenia. Together, fam- ily, twin, and adoption studies show consistently that the Milder forms of schizophrenic illness are characterized by biological relatives of people with schizophrenia themselves nonpsychotic symptoms, such as poor social relationships, show higher rates of schizophrenia and related disorders anxiety in social situations, and limited emotional responses. These symptoms are observed most fre- quently in three personality disorders, including schi- EPIDEMIOLOGY OF SPECTRUM DISORDERS zotypal, schizoid, and paranoid personality disorders. Sev- eral studies found that (DSM) cluster A personality disorder The term related disorders is used to describe schizophrenic traits often precede the onset of psychosis in subjects in illness of (generally) lesser severity. In fact, genetic studies whom schizophrenia subsequently develops (51,52). More- provide evidence for a spectrum of disorders that are similar over, in the New York high-risk project (53), offspring of to schizophrenia and caused by the same genes. A disorder schizophrenic mothers demonstrated elevated rates of these is considered to be in the schizophrenia spectrum if it occurs personality disorders when they were considered together, more frequently among the biological relatives of schizo- although not separately. Many of the behavioral tives of schizophrenic patients have related schizotypal per- genetic methodologies used to delineate genetic and envi- sonality disorder to the schizophrenia spectrum more ronmental factors in the etiology of schizophrenia (e. Evidence in favor of including schi- of a genetic etiology in schizophrenia spectrum conditions. Although sidered next for several candidate disorders. The the criteria for either schizophrenia or a mood disorder (18, incidence of the disorder in schizophrenic families has been 49). Two prominent examples are schizoaffective disorder estimated at between 4. As the name contrast, results for schizoid and paranoid personality dis- suggests, the term schizoaffective disorder describes patients orders have been somewhat more controversial and contra- with features of both schizophrenia and affective disorders dictory, with positive findings sometimes occurring in (also known as mood disorders), although subgroups may combined paranoid–schizotypal or schizoid–schizotypal Chapter 49: Molecular and Population Genetics of Schizophrenia 675 samples (55). Thus, although some symptoms may overlap or schizotypal personality disorder. These criteria underlie a conception of schizotaxia as gested that a subtle but widespread neurointegrative defect a neurodevelopmental condition resulting from genetic and results from this vulnerability that predisposes individuals adverse environmental (e. Current criteria in adult, nonpsychotic, depending on the protection or liability afforded by envi- first-degree relatives of schizophrenic patients include mod- ronmental circumstances. Later, Meehl reformulated the erate or greater levels of negative symptoms and neuro- concept to allow for the possibility that some people with psychological deficits (as described above). The concept of schizotaxia would not progress to either schizophrenia or schizotaxia demonstrates considerable utility because it ac- schizotypal personality disorder, although most would (65). Moreover, because schizotaxia may be con- Schizotaxia did not, although the term was used in a general sidered as a risk factor for schizophrenia, as well as a clini- sense by researchers to describe the liability for schizophre- cally meaningful syndrome in its own right, its recognition nia. Now, almost 40 years after the concept was introduced, may eventually facilitate the development of early interven- a broad literature shows that the liability for schizophrenia tion and prevention strategies. Psychiatric features in such relatives frequently include Given the evidence outlined above for a substantial genetic negative symptoms (e. Positive symptoms, how- the most likely mode of inheritance. Commonly, a mixed ever, are usually less evident in these relatives than they are model (75) comprising both major gene and polygenic ef- in schizophrenia or schizotypal personality disorder. Neuro- fects is compared with the submodels of a single major locus psychological impairments in biological relatives of people and polygenic inheritance. However, large sample sizes are with schizophrenia are also similar to those in patients with required to distinguish between models, especially the poly- schizophrenia, but are generally of lesser severity (67–71). In addition However, it has not been possible to distinguish between a to specifying the clinical consequences of schizotaxia more polygenic and a mixed model (77). Among these is whether schizotaxia degree of genetic relatedness decreases, is also compatible always or even usually progresses to schizotypal personality with a model of multiple loci with epistasis (interaction disorder or schizophrenia. Our empiric analyses suggest that between genes) (79). However, the number of susceptibility the basic symptoms of schizotaxia occur in 20% to 50% of loci, the disease risk conferred by each locus, and the degree adult relatives of patients with schizophrenia (68,69). This of interaction between loci all remain unknown. The contri- rate is considerably higher than the rates of schizophrenia bution of individual genes to the familiality of a disorder or schizotypal personality disorder likely to develop in first- can be expressed in terms of (s (i. The false-positives were largely the patible with the existence of a single locus having a value consequence of a combination of multiple testing and the of (s greater than 3. Unless extreme epistasis (interaction use of statistical methodology and significance levels derived between loci) exists, models with two or three loci having from work on single-gene disorders. It should be Despite the failure to identify regions of unambiguous emphasized that these calculations are based on the assump- linkage in multiply affected families, modest evidence for tion that the effects of genes are distributed equally across several regions has been reported in more than one data set. It is quite possible that genes of larger Areas implicated for which supportive data have also been effect are operating in a subset of patients—for example, obtained from international collaborative studies include those from families with a high density of illness. A number of other promising evidence that genetic factors increase the risk for schizophre- areas of putative linkage are also currently under investiga- nia. However, although it is possible to state that, as a group, tion by international consortia. However, in each general population, it is not currently possible to translate case, both negative and positive findings have been ob- this figure to the level of risk for a particular sibling in a tained, and in only two cases, those of chromosomes particular family. Another These positive findings contrast with those from a large important point is that risk to related individuals does not systematic search for linkage in which a sample of 196 af- directly equate with genetic risk because some relatives carry fected sibling pairs, drawn typically from small nuclear fami- one or more susceptibility alleles for schizophrenia but re- lies rather than extended pedigrees, was used (101). In other words, the results of simulation studies suggest that the power of this accumulation of susceptibility alleles, environmental risk study is greater than 0. This study yielded evidence at the level of the definition of Lander and Kruglyak (102) of 'suggestive' linkage to chromosomes 4p, 18p, and Xcen. However, none MOLECULAR GENETICS: LINKAGE STUDIES of the findings approached a genome-wide significance of 0. This was done in the hope that such families, in the search for genes for complex traits (103–106).