Serotonin transporter gene variation and sensitivity to conditioned cues: cause and cure in cocaine dependence

Until now, prevention and treatment of cocaine dependence have been only moderately successful, suggesting that the critical mechanisms underlying individual differences in vulnerability to cocaine dependence have not yet been identified. Behavior of cocaine addicts is strongly driven by cocaine-related conditioned stimuli (CSs). These CSs elicit positive and negative emotional states and craving in cocaine addicts, and are notoriously difficult to extinguish. This may be due to reduced prefrontal cortical (PFC) top-down control over the amygdala. Indeed, cocaine addicts have a smaller, and potentially hyperactive, amygdala. The basis of disruption of the PFC-amygdala circuit may lie in the low activity (short; s) allelic variant of the human serotonin transporter polymorphism (5-HTTLPR), which is associated with a smaller and tonically active amygdala and a loss of PFC top-down control over the amygdala. In addition, s-allele carriers show impaired extinction of conditioned fear responses. This is most likely due to the overwhelming effect of CSs on behavior. However, a direct link between 5-HTTLPR-mediated changes and vulnerability to cocaine dependence has not yet been demonstrated. Because serotonin transporter knockout rats, which model the 5-HTTLPR s-allele and have constitutively increased central serotonin levels, show amygdala hyperreactivity, impaired extinction of conditioned fear responses, and a high motivation to self-administer cocaine, it is our first hypothesis that inherited serotonin transporter down-regulation predisposes to cocaine dependence due to impaired prefrontal cortical top-down control over the amygdala and high CS sensitivity. To test this hypothesis, we propose a unique multidisciplinary and cross-species study in humans and rats. In the human experiments we will test 60 currently using cocaine addicts and 30 matched healthy subjects carrying the 5-HTTLPR s/s and l/l genotypes (controlled for genomic background). We will measure the interaction between addiction and fear extinction circuits using structural and functional magnetic resonance imaging (MRI) and spectroscopy under basal conditions and during PFC-amygdala dependent fear extinction. This will reveal whether s/s healthy subjects and cocaine addicts share phenotypes in the PFC-amygdala circuit. Furthermore, we will conduct complementary rat experiments to elucidate whether changes in the PFC-amygdala pathway and associated extinction failures in homozygous/heterozygous serotonin transporter knockout (SERT-/-; SERT+/-) rats are pre-existing (neurodevelopmental) traits or pave the path for cocaine-induced neuropathology. To this end, we will use longitudinal experimental (MRI) set-ups. While high CS sensitivity may predispose to cocaine dependence, it may also provide a foothold for therapy. That is, s-allele carriers, as well as SERT-/- rats, quickly acquire new conditioned responses at the expense of a previously acquired conditioned response when CS valence is changed. The currently applied behavioral-cognitive therapy in drug dependence is exposure therapy, which involves the extinction of a conditioned fear response, a process of new learning. S-allele carriers respond poorly to exposure therapy, but extinction learning can be facilitated by D-cycloserine (DCS), a partial NMDA receptor agonist that acts in the PFC and amygdala and stimulates new learning. Given that neurodevelopmental changes in SERT-/- rodents involve glutamatergic projections, and that DCS increases PFC synaptic plasticity and inhibits serotonergic functioning, DCS may strengthen extinction memory in s-allele carriers and SERT-/- rats at the expense of their fear/cocaine memory. Therefore, it is our second hypothesis that individuals characterized by inherited serotonin transporter down-regulation and high CS sensitivity benefit from DCS supplemented exposure therapy. Testing this hypothesis has a dual function: it provides further assessment of the theorized association between 5-HTTLPR-mediated changes in brain and behavior in cocaine addicts, and it reveals whether DCS supplemented exposure therapy can serve as individualized therapy in s/s cocaine addicts. Therefore, we will test whether a DCS challenge increases the recall of fear extinction memory and reduces cocaine craving, in both humans and rats. Taken together, we expect that our multidisciplinary cross-species studies will clarify whether high CS sensitivity associated with inherited serotonin transporter downregulation increases vulnerability to cocaine dependence on the one hand, and increases the responsivity to DCS supplemented exposure therapy on the other. Thereby, our project will lead to the identification of genetic, neural and behavioral biomarker(s) that predict both cause and cure in cocaine dependence. Furthermore, our experiments will shed new light on mechanisms underlying cocaine dependence, with focus on the PFC-amygdala circuit.