Neurobiological Changes Mediating the Effects of Chronic Fluoxetine on Cocaine Use

Abstract

Acute SSRI (selective serotonin reuptake inhibitor) treatment has been shown to attenuate the abuse-related effects of cocaine; however, SSRIs have had limited success in clinical trials for cocaine abuse, possibly due to neurobiological changes that occur during chronic administration. In order to better understand the role of serotonin (5HT) in cocaine abuse and treatment, we examined the effects of chronic treatment with the SSRI fluoxetine at clinically relevant serum concentrations on cocaine-related neurobiology and behavior. Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans. Self-administration and reinstatement were monitored throughout the treatment and washout period. In vivo microdiaylsis was used to assess changes in dopaminergic and serotonergic neurochemistry. Positron emission tomography was used to assess changes in the 5HT transporter and 2A receptor binding potential (BP). Functional output of the 5HT system was assessed using prolactin levels. Cocaine-primed reinstatement and cocaine-elicited dopamine overflow were significantly suppressed following chronic fluoxetine treatment. 5HT2A receptor BP was increased in the frontal cortex following treatment while prolactin release was blunted, suggesting desensitization of the 5HT2A receptor. These effects persisted after a 6-week washout period. Measures of pre-synaptic serotonergic function and cocaine self-administration were unaffected. These data demonstrate that acute and chronic fluoxetine treatments exert different effects on cocaine-related behavior. Furthermore, chronic fluoxetine treatment causes alterations in 5HT2A receptors in the frontal cortex that may selectively disrupt cocaine-primed reinstatement. Fluoxetine may not be useful for treatment of ongoing cocaine abuse but may be useful in relapse prevention.

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

“…Consistent with their in vitro DAT versus SERT selectivity profiles (Rothman et al, 2001), S(1)-amphetamine produced a selective increase in NAc DA versus 5-HT levels, whereas fenfluramine produced a selective increase in NAc 5-HT versus DA levels. These results are consistent with previous microdialysis studies in both rats (Baumann et al, 2000;Kehr et al, 2011) and nonhuman primates (Laruelle et al, 1997;Murnane et al, 2010;Sawyer et al, 2012), and confirm the sensitivity of this microdialysis procedure to changes in NAc DA and 5-HT levels produced by agents that have been extensively evaluated. Also consistent with a previous MCAT microdialysis study (Cozzi et al, 2013), MCAT displayed a greater potency to increase NAc DA versus 5-HT levels.…”

Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Increases in the SERT after chronic cocaine have been reported in cells (Kittler et al, 2010), rodents (Cunningham et al, 1992), nonhuman primates (Banks et al, 2008;Gould et al, 2011), and humans (Jacobsen et al, 2000;Mash et al, 2000). Chronic self-administration of cocaine in rhesus monkeys also resulted in an upregulation of 5-HT 2A R in the frontal cortex (Sawyer et al, 2012) as determined in vivo with PET imaging and the selective 5-HT 2A R ligand [ 11 C]M100907 (Fig. 2).…”

“…The images shown were obtained in a control subject. Note that chronic self-administration of cocaine in a group of four male rhesus monkeys over a 3.5-month period significantly increased 5-HT 2A R availability in the frontal cortex (Sawyer et al, 2012). sertraline delayed relapse in recently abstinent cocainedependent patients (Oliveto et al, 2012). Although the reasons for the general lack of efficacy with SERT inhibitors in clinical studies remain speculative, one possible explanation is that the indirect activation of all 5-HT receptor subtypes is not an ideal pharmacotherapeutic strategy, and thus, studies have begun to explore the therapeutic potential of more specific protein targets within the 5-HT system.…”

Chronic Interferon-α Decreases Dopamine 2 Receptor Binding and Striatal Dopamine Release in Association with Anhedonia-Like Behavior in Nonhuman Primates

“…Subjects were surgically prepared with guide cannulae implanted bilaterally above the caudate nucleus as described previously (Sawyer et al, 2012). Cannula placement was verified for each animal by MRI.…”