Abstract
Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.
Highlights
Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity.[1]
Hypothesis that individual differences in cocaine cue reactivity as measured as appetitive approach behavior [lever presses reinforced by the discrete cue complex]6 would associate with reduced 5-HT2C receptor (5-HT2CR) protein expression and sensitivity to a selective 5-HT2CR agonist
The present study demonstrated that cocaine-dependent subjects who carry the less-common Ser[23] variant of the HTR2C exhibit significantly higher cocaine cue reactivity than did those who carry the Cys[23] variant, adding the HTR2C to handful of genes potentially identified as candidates involved in cocaine cue reactivity.[53,54]
Summary
Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity.[1]. With a history of cocaine use, environmental contexts and stimuli (for example, paraphernalia) become reliably associated with its use leading to durable conditioned responses (‘cue reactivity’) that can predict relapse as well as treatment success.[2,3,4,5] Drug cue reactivity is the attentional orientation toward such drug-associated cues that are measurable as conditioned physiological effects (for example, heart rate), subjective properties (for example, craving), appetitive approach behaviors (for example, drug-seeking) and activation of specific corticostriatal subcircuits.[1,5,6] Individual variation in the magnitude and influence of cue reactivity over behavior in humans[7,8] and animals[9,10] suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse.[8,11,12] A greater understanding of the neural underpinnings of cocaine cue reactivity promises to shed light on therapeutic approaches to effectively intervene in cocaine dependence and improve recovery outcomes.
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