Although pathological gambling (PG) is relatively common and associated with significant distress and impairment (Argo & Black, 2004), little is known regarding effective pharmacotherapy for this disorder. The difficulty may stem from the inherent heterogeneity of PG (Blanco, Moreyra, Nunes, Saiz-Ruiz, & Ibanez, 2001) and the fact that several core psychopathologic domains could conceivably be targets for treatment: impulsivity (arousal), compulsivity (anxiety reduction), and addiction (symptoms of withdrawal) (Hollander, Kaplan,& Pallanti, 2004). In addition, neurobiological investigations of the etiology of PG have shown evidence of multiple system involvement (serotonergic, noradrenergic, and dopaminergic) (Shah, Potenza, & Eisen, 2004). High rates of psychiatric comorbidity with mood, anxiety, and substance use disorders (Bland, Newman, Orn, & Stebelsky, 1993; Ibanez et al., 2001; Linden, Pope, & Jonas, 1986) provide additional neuropsychopharmacological frameworks for treatment and add to the complexity of finding effective pharmacological interventions. In contrast to drug addictions in which illicit drugs are used to induce pleasure, gamblers engage in a behavior to bring about excitement (Holden, 2001). The neural substrates of drug addictions have been well studied and include the ventral tegmental area (VTA) to nucleus accumbens (NA) mesolimbic circuit (Di Chiara & North, 1992; Hyman, 1993; Koob, 1992; Koob & Bloom, 1988). Illicit drugs often stimulate VTA neurons to release dopamine in the NA or block reuptake of dopamine within the NA (Kalivas & Volkow, 2005; Phillips & LePiane, 1980; Stewart, 1984; van Wolfswinkel & van Ree, 1985). This neurotransmission and subsequent neurochemical cascades within the NA and downstream effects in connected brain regions are believed to underlie feelings of pleasure, serving to reinforce the addictive behaviors. Although gamblers do not uniformly use illicit drugs, gambling, anticipated reward, or uncertainty associated with reward probability activates dopamine neurons within VTA which in turn triggers increased release of dopamine in NA (Fiorillo, Tobler, & Schultz, 2005; Schultz, 2002). Thus, similar neural substrates and chemical mechanisms appear involved in both drug addictions and non-drug addictions such as PG. Consistent with the neurobiological findings described in the preceding text, pharmacological treatment strategies have targeted presumed region-specific dysfunctions. Low levels of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) and blunted serotonergic response within the ventromedial prefrontal cortex (vmPFC) have been associated with impulsive behaviors (Coccaro, 1996; Linnoila, Virkkunen, George, & Higley, 1993; Mehlman, Higley, & Faucher, 1995; Rogers et al., 1999; Virkkunen, Goldman, & Nielsen, 1995). Prefrontal glucose metabolism, especially within the orbitofrontal cortex (OFC), is inversely correlated with cerebrospinal fluid 5-HIAA levels. The processing of motivational drives and determination of object saliency involve the orbitofrontal and cingulate cortices (Bush et al., 2002; Jentsch & Taylor, 1999). The vmPFC includes the most ventral component of the anterior cingulate cortex and the medial portion of the OFC (Bechara, 2003). Disadvantageous decision-making as assessed by the Iowa Gambling Task has been observed both in individuals with stroke lesions in the vmPFC as well as in individualswith PG or substance use disorders (Bechara, 2003; Cavedini, Riboldi, Keller, D'Annucci, & Bellodi, 2002). As compared to control comparison subjects, individuals with PG demonstrate diminished activation of the vmPFC when viewing gambling-related videotapes or during prepotent response inhibition when performing the Stroop color-word interference task (Potenza et al., 2003a, 2003b). Individuals with PG also show relatively diminished activation of the vmPFC (and NA) during a simulated gambling task, and severity of gambling problem correlated inversely with signal intensity within these brain regions (Reuter et al., 2005). Together, the findings suggest that decreased serotonin function within vmPFC may engender disinhibition and contribute to PG. Thus, drugs targeting serotonin neurotransmission, such as serotonin reuptake inhibitors (SRIs), have been investigated in the treatment of PG. Many SRIs have been shown to be efficacious in targeting symptoms of depression, obsessive-compulsive disorder, and anxiety. By extension, SRIs may be hypothesized to reduce context-specific obsessions or ruminations, such as gambling-related thoughts or gambling urges. Given that the overlap between PG and major depression in men has been found to be largely genetic in nature (Potenza, Xian, Shah, Scherrer, & Eisen, 2005), similar genes, and by extension similar biological pathways, may underlie PG and major depression. As such, medications helpful for treating one disorder may have efficacy for the other. Another pharmacological treatment strategy has examined the opioid system that modulates dopamine function within the VTA-NA-OFC circuit. Mu-opioid receptor antagonists inhibit dopamine release in NA and ventral pallidum (VP) through the disinhibition of gamma-aminobutyric acid (GABA) input to the dopamine neurons in the VTA (Broekkamp & Phillips, 1979; Matthews & German, 1984; Phillips & LePiane, 1980; Stewart, 1984; van Wolfswinkel & van Ree, 1985). Thus, it was originally hypothesized that decreased dopamine in NA and motivation circuit would dampen excitement and cravings related to gambling behavior (Kim, 1998). Although modulation of drive and subsequent behavioral output by dopamine, endorphin, and GABA has been investigated, the specific mechanisms remain incompletely understood, particularly as related to PG (Kalivas & Barnes, 1993; Koob, 1992). Other hypotheses concerning the pathophysiology of PG have resulted in different classes of medication being studied for PG. Antiepileptic agents enhance GABA function within the central nervous system and reduce neuronal firing rates. Selected agents in this class may reduce craving symptoms significantly (Hollander et al., 2004). Although there are currently no existing medications approved by the Food and Drug Administration for the treatment of PG, multiple pharmacological interventions have been studied. This chapter reviews current pharmacological treatment strategies for PG, the neural substrates and transmitters that are proposed to underlie the symptoms of PG, and the rationales for applying various classes of psychotropic agents.