Neurotransmitter Imaging of the Dopamine System

The classical psychiatric disorder primarily affecting the dopaminergic system is schizophrenia. Beyond that, dopamine is also thought to play a mayor role in substance abuse and the neurobiology of addiction, as well as in Tourette syndrome. A comprehensive review summarizing the state of knowledge on the involvement of dopamine in psychiatric and neurologic disorders was recently published (Verhoeff, 1999) and, although missing the more recently acquired knowledge, it is recommended to readers with special interest in the subject.

Dopamine and Schizophrenia. The dopamine hypothesis of schizophrenia (also see Chapter 9) was first formulated by Carlsson and Lindquist (1963). The central role for dopaminergic transmission in the pathogenetic model of schizophrenia has since been substantiated and developed by numerous later investigations, many of which were made possible by the new methodological possibilities afforded by the introduction of SPECT and PET into clinical research. Carlsson and Lindquist speculated that schizophrenia would be characterized by a hyperactivity of dopaminergic transmission. The correctness of this central idea has by now been well demonstrated in a number of PET investigations showing an increase in the level of both tonic and phasic subcortical dopaminergic transmission in schizophrenic patients (Abi-Dargham et al., 2000; Gjedde and Wong, 2001; Laruelle et al., 1996).

After more than 25 years of discussion about possible alterations of striatal D2 receptors in schizophrenia, which were studied both postmortem and in vivo, there is now a consensus that specific alterations of the dopaminergic neurotransmission exist in schizophrenia. On the one hand, schizophrenic patients showed an increase in [18F]fluorodopa binding with increased dopadecarboxylase activity (Reith et al., 1994), and on the other hand, schizophrenia was associated with an increased release of intrasynaptic dopamine after amphetamine challenge (Breier et al., 1997; Laruelle et al., 1996). It is still unclear whether the number of striatal D2 receptors is altered in schizophrenia. The number of striatal D2 receptors was not altered in antipsy-chotic naive patients examined with [123I]iodobenzamide (IBZM) or [11C]raclopride (Farde et al., 1990). In contrast to studies with these benzamides, a PET study using [11C]N-methylspiperone found an elevated number of D2 receptors in schizophrenia (Wong et al., 1986). The discrepancy can be explained by the benzamides' sensitivity for intrasynaptic dopamine changes, whereas butyrophenones such as spiperone can undergo an agonist-mediated D2 internalization. That schizophrenia indeed may be associated with an elevation of striatal D2 receptors has recently been confirmed in another IBZM SPECT study after application of a-methylparatyrosine (AMPT). This led to an acute dopamine depletion in the synaptic cleft, which confirmed an elevated number of striatal D2 receptors in schizophrenia (Abi-Dargham et al., 2000). Interestingly, in a similar study investigating the effect on both D1 and D2 receptors, AMPT-induced dopamine depletion uncovered D2 receptors, but it did not do so for D1 receptors (Verhoeff et al., 2002). It has been speculated that the relative up-regulation of D2 receptors in schizophrenia may reflect constantly increased, basal dopamine levels (Gjedde and Wong, 2001). Besides a putative role for striatal D2 receptors in the pathology of schizophrenia, there are reports of reduced Dx receptor density in the prefrontal cortex, which were positively correlated with the severity of schizophrenic negative symptoms (Okubo et al., 1997), and of reduced extrastriatal D2 receptors in the anterior cingulate cortex, which were inversely correlated with the severity of positive symptoms (Suhara et al., 2002). Recent studies point toward prefrontal Dx receptor pathology being associated with negative symptoms (Okubo et al., 1997), and relatively reduced D2 receptor number in the anterior cingulate cortex as one possible contributing factor in schizophrenic positive symptoms (Suhara et al., 2002). In summary, modern neuroimaging procedures provide strong evidence of a subcortical "hyperdopaminergic" system in the pathology of schizophrenia.

Dopamine and Antipsychotics. Even more important than their role in elucidating the primary pathology of schizophrenia, studies using SPECT and PET significantly advanced our knowledge of basic mechanisms of actions of antipsychotic drugs. The D2 receptor is thought to be key for both the clinically desired "antipsychotic" effects and unwanted motor side effects. Using PET or SPECT to investigate the relative proportion of receptors occupied by a drug versus the available (i.e., drug-free) receptors, which is termed receptor occupancy of a given drug, it has been possible to establish a minimal threshold necessary for clinical antipsychotic effects with typical neuroleptics. Also established are upper thresholds with high risks for drug-induced extrapyramidal motor side effects (EPS) such as dystonic reactions, drug-induced parkinsonism, akathisia, tardive dyskinesia, or the consequences of increased prolactin secretion such as galactorrhea, amenorrhea, and impaired libido. Although these thresholds represent averages across a population and significant interindividual variations are possible, these findings represent a major advance in antipsychotic pharmacotherapy. From these studies, a minimal occupancy of approximately 65 percent D2 receptors appears to be necessary for achieving antipsychotic effects clinically, while dopamine-dependent motor side effects begin to appear at occupancy levels from 78 to 80 percent upward (Farde et al., 1988; Kapur et al., 2000; Tauscher et al., 2002c). The importance of these findings can be underscored by the fact that one of the most frequently used classical neuroleptics, haloperidol, is commonly used in doses ranging from 10 to 20 mg/d, and more. This stands in stark contrast to results from PET and SPECT studies suggesting that the optimal dose of haloperidol lies between 2.5 and 5 mg/d, with complete saturation of D2 receptors reached at around 7 mg in most patients (Kapur et al., 2000; Tauscher and Kapur, 2001). Findings from SPECT and PET as well as from clinical studies do not point to an advantage of the higher doses commonly used in clinical practice; rather such dosage may lead to a higher incidence of side effects. Most novel antipsychotics have been examined with either PET or SPECT to obtain dose/occupancy relationships. Results from these studies point to an optimal dose range of risperidone from 2 to 4 mg (Kapur et al., 1995) and of olanzapine from 10 to 20 mg (Kapur et al., 1998; Tauscher et al., 1999).

The use of neuroimaging techniques has also improved our understanding of the pharmacokinetics of antipsychotic drugs. The dosing of psychotropic drugs relies on their plasma kinetics (also see Appendix A). Consequently, drugs with shorter plasma elimination half-lives are dosed more frequently than longer-lasting drugs. However, it has recently been demonstrated that the kinetics in the brain differ substantially from the kinetics in plasma, with plasma half-lives for the atypical antipsychotic drugs risperidone and olanzapine being significantly shorter than the half-lives of these drugs in the brain (Tauscher et al., 2002a). The results of this study imply that for some antipsychotics dosing intervals of longer than once daily might be sufficient, whereas the current practice of dosing according to plasma kinetics may in fact lead to drug accumulation in the brain (Fig. 6.2). Furthermore, it may not even be necessary for

Figure 6.2. Significant dissociation of brain and plasma kinetics after a single dose of a novel antipsychotic questioning the current reliance on plasma elimination half-lives as a rational for developing dosing schedules with psychotropic medications. (With permission from Nature Publishing Group, this figure was first published on the cover of Molecular Psychiatry, vol. 7, no. 3, 2002.) See ftp site for color image.

Figure 6.2. Significant dissociation of brain and plasma kinetics after a single dose of a novel antipsychotic questioning the current reliance on plasma elimination half-lives as a rational for developing dosing schedules with psychotropic medications. (With permission from Nature Publishing Group, this figure was first published on the cover of Molecular Psychiatry, vol. 7, no. 3, 2002.) See ftp site for color image.

antipsychotics to exert constant high D2 blockade to achieve antipsychotic response. In a recent PET study with quetiapine, antipsychotic efficacy was demonstrated despite only transiently high D2 receptor blockade with quetiapine administered once daily (Tauscher-Wisniewski et al., 2002).

Dopamine Neuroreceptor Imaging in Substance Abuse. Apart from schizophrenia and receptor-occupancy-imaging studies with antipsychotic drugs, SPECT and PET have also provided valuable information in other psychiatric illnesses thought to reflect abnormalities in dopaminergic function. The dopaminergic system in the nucleus accumbens (ventral striatum) is thought to be centrally involved in the regulation of the endogenous reward system. Some of the behaviorally most reinforcing psychoac-tive drugs, such as cocaine and methamphetamine, cause an increase in dopaminergic transmission by blocking the dopamine transporters (DAT) necessary for reuptake of dopamine. A number of PET studies investigating the pharmacological properties of these drugs, and the relationships of these to the symptoms of drug abuse and dependence have been performed. Much of this research has been performed on cocaine as this substance blocks DAT, an effect that is responsible for both the elicitation of euphoria and for the reinforcing effects of the drug. An interesting approach has been to correlate the subjective effects of cocaine with the extent of DAT blockade effected by the drug (Volkow et al., 1997). In this study, the minimal dose of cocaine able to elicit reinforcement was found to lie at less than 0.1 mg/kg, while the minimal dose needed to elicit euphoria was found to lie between 0.3 and 0.6 mg/kg. Correspondingly, the same study found that DAT occupancy rates from 47 percent upward were already sufficient to elicit reinforcement, while the doses commonly used by intravenous cocaine abusers, around 25 to 50 mg/kg, cause DAT occupancy rates between 65 and 80 percent. As evidenced by these findings, significantly lower doses than those needed to cause the euphoric effect sought by the abuser already appear to be sufficient for unleashing the reinforcing effects of the drug. Therefore, contrary to previous hypotheses, it appears possible that the neurobiologic basis of psychological drug addiction is not completely identical with that causing the subjective feeling of a "high." Another interesting finding from this line of research has been that a low density of central D2 receptors may represent a susceptibility factor for some substance use disorders (Volkow et al., 1999). It has been found that a low density of central D2 receptors correlates with a positive subjective experience with methylphenidate (a compound with similar phar-macologic actions to cocaine) use, while subjects with a high density of D2 receptors have subjectively negative experiences with the same drug.

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