Genetics, behavior, and brain dopamine systems

Even for the reader unfamiliar with the topic of this chapter but familiar with dopamine and behavior, it is obvious that the topic of genes, behavior and brain dopamine systems cannot be covered in detail. Rather, the goal of the chapter is to provide the reader with an introduction and some examples, largely extracted from work in the authors’ laboratories. Previous reviews (Hitzemann et al., 1995; Hitzemann, 1998) can be referenced for important background material. The focus of this chapter will be largely on D2 dopamine receptors. The reasons for this emphasis include the longstanding emphasis on D2 receptors in the etiology and/or expression of a variety of behaviors including schizophrenia, substance abuse and alcoholism (Hitzemann, 1998). The other reason for this emphasis is the amazing variability among individuals in D2 receptor density and in the response to drugs which either stimulate or block these receptors. The reasons for this variability remain unclear, but there is ample evidence to suggest that genetic factors have an important role. Here we provide a clinical example to illustrate the variation in receptor density and drug response. Twenty-three normal controls were administered 0.5 mg/kg of methylphenidate iv. after being told they would receive either placebo or methylphenidate; behavioral effects were measured before and after the injection and included self-ratings of pleasant and unpleasant drug effects. On another day, the subjects were scanned for D2/D3 receptor density using positron emission tomography (PET) and 11C-raclopride as the ligand. Twelve of the 23 subjects (52%) reported the drug effects as very pleasant, 9 subjects (39%) reported the drug effects as unpleasant and 2 subjects (9%) reported no marked behavioral effects (Volkow et al., 1999). Importantly, the individuals who reported the drug effects as pleasant had lower levels of D2 receptor availability when compared with the “unpleasant” group (Figure 25.1). Although the average difference was small (20%), it was similar to the persistent differences reported between normal controls and withdrawn chronic alcoholics, cocaine, methamphetamine and heroin addicts (see, e.g., Volkow et al. 1993). These differences were nominally thought to be associated with receptor down-regulation as a result of drug-induced dopamine release. However, the data described in Figure 25.1 suggest that low D2 receptor availability could be a risk factor for drug abuse since presumably, the “pleasant” group would be more likely to try the drug again. The data in Figure 25.1 also illustrate that in this sample the range of D2 receptor availability was more than 100%. For other clinical samples, including postmortem samples, the range of D2 receptor availability has been similar and in some cases even greater (Hitzemann et al., 1998).