Differential effect of viral overexpression of nucleus accumbens shell 5-HT1B receptors on stress- and cocaine priming-induced reinstatement of cocaine seeking

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Highlights

  • NAccSh 5-HT1B overexpression attenuates cocaine priming-induced reinstatement

  • NAccSh 5-HT1B overexpression has no effect on footshock-induced reinstatement

  • This manipulation also has no effect social defeat-induced saccharin preference

Abstract

5-HT1B receptors are densely expressed on terminals of medium spiny neurons projecting from the nucleus accumbens shell (NAccSh) to the ventral tegmental area, where 5-HT1B receptors modulate GABA release directly, and firing of dopaminergic neurons indirectly. While interactions between NAccSh 5-HT1B receptors and stress have been reported in early stages of psychostimulant-induced neuroadaptations, specifically psychomotor sensitization, the effect of this interaction on later stages of drug seeking is currently unknown. Here, we examined the effect of herpes simplex virus (HSV)-mediated overexpression of NAccSh 5-HT1B receptors on reinstatement of cocaine seeking induced by exposure to stress or a cocaine prime. Rats were trained to self-administer cocaine (0.75 mg/kg/infusion) and the operant response was extinguished. Rats were then injected with viral vector expressing 5-HT1B and green fluorescent protein (GFP) or GFP alone into the NAccSh. The effect of 5-HT1B receptor overexpression was assessed on reinstatement induced by intermittent footshock (0.5 mA for 15 min) or a cocaine prime (10 mg/kg, ip). Results indicate that NAccSh 5-HT1B receptor overexpression had no effect on footshock reinstatement while significantly decreasing cocaine priming-induced reinstatement. We also found that NAccSh overexpression of 5-HT1B receptors had no effect on saccharin intake following social defeat stress. These results suggest that the efficacy of pharmacological agents targeting 5-HT1B receptors for the treatment of cocaine relapse will depend largely on the nature of the reinstating stimulus. Taken together with previous results, it appears that NAccSh 5-HT1B receptors influence stress responses in early, but not in the later stages of psychostimulant-induced neuroadaptations.

Introduction

Addiction to psychostimulant drugs such as cocaine has become a worldwide epidemic with major social and economic burdens on society. An important problem in the treatment of addiction to cocaine and other drugs of abuse is the vulnerability of individuals to relapse to drugs months or even years after cessation of drug use (Dackis and O'Brien, 2001, Gossop et al., 1989). Indeed, up to 90% of previously addicted individuals relapse to drug use within twelve months of abstinence (DeJong, 1994). Relapse in addicts can be induced by exposure to the drug itself, drug-associated cues or by exposure to stressful stimuli (Childress et al., 1988, Childress et al., 1993, Sinha et al., 2000, Sinha and Li, 2007).

The serotonergic neuronal system plays an important role in relapse to cocaine seeking (Filip et al., 2005, Filip et al., 2010). Interestingly, both enhancing (Burmeister et al., 2003) and decreasing (Tran-Nguyen et al., 2001) serotonin (5-HT) levels attenuate reinstatement of cocaine seeking induced by exposure to cues previously associated with cocaine self-administration, and have variable effects on priming-induced reinstatement of cocaine seeking. These inconsistencies in delineating the effects of serotonergic neuronal modulation on relapse to cocaine seeking are most likely due to the complexity of 5-HT receptor sub-types (Filip et al., 2010).

5-HT1B receptors are known to regulate the behavioral effects of cocaine (Miszkiel et al., 2011). These receptors are Gi/o-coupled receptors that negatively couple with adenylate cyclase, resulting in an inhibitory effect on neuronal activity (Morikawa et al., 2000). In situ hybridization histochemistry studies indicate that 5-HT1B receptors are expressed on medium spiny neurons throughout the striatum (Bruinvels et al., 1994); these GABAergic neurons project to several brain regions including the ventral tegmental area (VTA), ventral pallidum, and globus pallidus externa (Groenewegen et al., 1999). Physiological studies indicate that 5-HT1B receptors on these neurons are translocated to axon terminals where they negatively regulate GABA release (O'Dell and Parsons, 2004). The level of expression for these receptors is quite dynamic and is differentially regulated by stress, novelty, and both cocaine exposure and withdrawal (Furay et al., 2011, Hoplight et al., 2007, Neumaier et al., 2002a, Neumaier et al., 2009). Stimulation of VTA 5-HT1B receptors potentiates the effects of cocaine, likely via disinhibition of GABA release (O'Dell and Parsons, 2004, Yan et al., 2004). Previously we demonstrated in a conditioned place preference assay, that increased expression of 5-HT1B receptors in nucleus accumbens shell (NAccSh) neuronal terminals in the VTA shifts the cocaine dose–response curve to the left (Neumaier et al., 2002b). However, we later observed that these receptors can enhance or inhibit cocaine preference depending on whether the procedure was optimized to detect preference or aversion, respectively (Barot et al., 2007), suggesting a more complicated role of these receptors.

While many investigators have examined the effect of 5-HT1B receptor modulation on reinstatement of cocaine seeking induced by a cocaine prime or conditioned cues (Acosta et al., 2005, Pentkowski et al., 2009, Przegalinski et al., 2007, Przegalinski et al., 2008), the effect of 5-HT1B receptor modulation on stress-induced reinstatement is currently unknown. We have previously observed an interaction between coincident exposure to mild stress and increased 5-HT1B receptor expression in NAccSh projection neurons that facilitates the behavioral effects of exposure to drugs of abuse (Ferguson et al., 2009), suggesting an interplay between the stress response and 5-HT1B receptor overexpression. These interactions between 5-HT1B receptors and stress have been observed in the early stages of psychostimulant-related behavioral plasticity (Neumaier et al., 2002b, Neumaier et al., 2009, Ferguson et al., 2009, Hoplight et al., 2007, Furay et al., 2011) and we are now examining the effect of 5-HT1B receptors in stress-induced reinstatement of cocaine seeking.

In the present study, we examined the effect of transiently increasing 5-HT1B receptor expression in the NAccSh using herpes simplex virus-mediated gene transfer on footshock stress-induced cocaine reinstatement. The optimal way to ascertain the behavioral specificity of an experimental manipulation is to determine its effect on more than one reinstating stimulus (Nair et al., 2009). Hence, we also examined the effect of NAccSh 5-HT1B receptor expression on cocaine-priming induced reinstatement of cocaine seeking. To further study the role of NAccSh 5-HT1B receptors in stress responses, we examined the effect of 5-HT1B overexpression on saccharin preference following exposure of rats to social defeat stress.

Section snippets

Subjects

For cocaine reinstatement experiments, male Long-Evans rats (Charles River, Raleigh, NC), weighing 350–425 g were used. These rats were initially double-housed and allowed to acclimate for at least one week to the vivarium prior to the experiment. The temperature- and humidity-controlled vivarium was under a 12-h light–dark cycle (lights on at 6 a.m.). Following the acclimation period, rats were handled every other day for at least 6 days prior to surgery. After surgery, the rats were housed

Training and extinction

Fig. 2A depicts the mean ± SEM number of cocaine infusions and presses on the active and inactive levers for all rats that were subsequently tested in Exps. 1 & 2. The rats demonstrated reliable cocaine self-administration. Fig. 2B depicts the mean ± SEM number of lever presses on the previously active and inactive levers during the first 12 extinction sessions for these rats. As anticipated, during the extinction phase, response rates decreased over time.

Exp. 1

Exposure to footshock stress significantly

Discussion

In the present study, we examined the effect of herpes simplex virus-mediated overexpression of 5-HT1B receptors in the NAccSh on reinstatement of cocaine seeking in a rat operant reinstatement model. We found that NAccSh 5-HT1B receptor overexpression had no influence on reinstatement of cocaine seeking induced by exposure to intermittent footshock. 5-HT1B receptor overexpression also had no effect on saccharin preference following social defeat stress. In contrast, enhanced expression of 5-HT

Acknowledgments

This work was supported by the National Institutes of Health DA106432 grant to J.F. N. The authors thank Dr. Yavin Shaham for advice on cocaine reinstatement procedures and Dr. Scott Ng-Evans for invaluable technical assistance. The authors also thank Denis Smirnov for proof-reading the manuscript.

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