Inactivation of the dorsal raphé nucleus reduces the anxiogenic response of rats running an alley for intravenous cocaine
Research Highlights
► Cocaine has both positive (rewarding) and negative (anxiogenic) properties. ► Brain serotonergic (5-HT) systems have been implicated in the modulation of anxiety. ► Inactivation of the dorsal raphé nucleus reduced the anxiogenic response to cocaine. ► 5-HT is involved in the anxiogenic state produced by cocaine.
Introduction
In addition to cocaine's well-known positive/rewarding properties, the drug produces a host of negative and/or aversive effects. So while cocaine is readily self-administered by both humans and animals (e.g., Comer et al., 2008, Fischman and Schuster, 1982, Haney, 2009, Porrino et al., 2004, Wolverton, 1992), produces preferences for places associated with its administration in animals (Aguilar et al., 2009, Bardo et al., 1995, Carr et al., 1989) and is described as having rewarding or euphoric properties by human users (Lynch et al., 2006, Rotheram-Fuller et al., 2007, Singha et al., 1999), the “crash” that follows its administration in human cocaine users is characterized by feelings of anxiety, agitation and craving for more drug (Gawin, 1991, Gawin and Kleber, 1986, Resnick and Resnick, 1984, Rohsenow et al., 2007, Williamson et al., 1997). Similarly, while animals develop preferences for places associated with the immediate positive effects of cocaine, they exhibit place aversions for locations paired with the effects present 15 min after an i.v. injection (Ettenberg and Bernardi, 2007, Ettenberg et al., 1999, Knackstedt et al., 2002). Cocaine has also been reported to enhance the anxiogenic response of animals to the presentation of a variety of learned and unlearned aversive stimuli (e.g., Costall et al., 1989, Dworkin et al., 1989, Hayase et al., 2005, Paine et al., 2002, Simon et al., 1994).
The mixed positive and negative properties of cocaine can be assessed concurrently in the same animal during the same trial. In our laboratory, rats trained to run a straight alley once each day for an i.v. injection of cocaine develop over trials a unique “retreat behavior” in which the subjects rapidly approach the goal, but then stop at the goal-box threshold, and turn and retreat back toward the start box (Ettenberg and Geist, 1991). This unique pattern of runway behavior closely resembles that of animals approaching a goal box with known positive and negative associations (e.g., food + foot-shock; Cohen et al., 2009, Geist and Ettenberg, 1997, Miller, 1944). Retreats are therefore thought to reflect a form of “approach–avoidance conflict” that stem from cocaine's immediate positive (cocaine reward) and delayed negative (cocaine-induced anxiety) properties (Ettenberg, 2004, Ettenberg, 2009). Indeed, like other forms of conflict behavior, retreat frequency is dose-dependently attenuated by pretreatment with anxiolytic drugs (Ettenberg and Geist, 1991, Guzman and Ettenberg, 2004, Knackstedt and Ettenberg, 2005).
Given the growing literature implicating 5-HT circuitry in the modulation of anxiety-related states (e.g., Abrams et al., 2004, Begg et al., 2005, Chaouloff, 2000, Hammack et al., 2009, Sena et al., 2003), it was of interest to investigate the role of 5-HT function in the anxiogenic response to self-administered cocaine. Toward that end, we have shown that the 5-HT1A partial agonist buspirone (Eison and Temple, 1986, Jahanshahi et al., 2010) can reduce the approach–avoidance conflict of rats running an alley for i.v. cocaine (Ettenberg and Bernardi, 2006) and block the delayed aversive effects of cocaine as measured in a conditioned place preference test (Ettenberg and Bernardi, 2007). 5-HT1A receptors are typically coupled to inhibitory G-proteins whose activation produces a hyperpolarization of cell membranes that results in an inhibition of neuronal activity (Aghajanian, 1995, Albert et al., 1997), thus the effects of buspirone could be accounted for by an inhibition of 5-HT neurotransmission. However, since buspirone has been shown to exert effects on multiple neurotransmitter systems (e.g., Eison and Temple, 1986, Jahanshahi et al., 2010), the current study adopted a more direct approach by examining the impact on cocaine-induced approach–avoidance conflict behavior of inactivating the dorsal raphé nucleus — the primary source of 5-HT in the rat forebrain (Azmitia and Segal, 1978, Vertes, 1991).
Section snippets
Subjects
The subjects were 16 male Sprague Dawley rats obtained from Charles River Laboratories (Wilmington, MA, USA). The animals were housed individually in plastic cages located within a secure and temperature-controlled vivarium (23 °C). Subjects were gentled each day during the week prior to surgery and provided ad libitum access to food and water throughout the study. All aspects of the experimental protocol were reviewed and approved by the University of California at Santa Barbara's Institutional
Results
Histological analyses confirmed the location of the cannulae in the dorsal raphé nucleus in eight of the ten subjects (see Fig. 1). A problem with the freezer component of our cryostat rendered two of the samples unreadable and no confirmation of cannula location could be determined for these animals. The data from these two subjects were nevertheless included in the data analyses since their behavioral responses during both the vehicle and baclofen/muscimol trials were comparable to those of
Discussion
The present results build upon and extend our prior work with the 5-HT1A partial agonist, buspirone, and lend further support to the growing consensus that 5-HT cells emanating from the dorsal raphé nucleus (DRN) play an important role in the modulation of anxiety-related states (e.g., Abrams et al., 2004, Begg et al., 2005, Chaouloff, 2000, Eison and Eison, 1994, Graeff, 2002, Hammack et al., 2009, Sena et al., 2003). In previous work we reported that buspirone dose-dependently reduced the
Acknowledgements
This work was supported by a grant from the National Institute of Drug Abuse (DA05041) awarded to AE and a UCSB Undergraduate Research and Creative Activities Grant awarded to OAO.
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2019, Behavioural Brain ResearchCitation Excerpt :Given that 5-HT has been strongly linked to the development and expression of anxiety-like behavior [28–30], coupled with the fact that cocaine is known to elevate synaptic 5-HT through inhibition of the serotonin transporter (SERT) [31–34] suggests a putative role for 5-HT in the aversive behavioral response to cocaine. Consistent with this hypothesis are prior studies from our own laboratory demonstrating that inactivation of 5-HT cell bodies in the DRN [35] and systemic treatment with the 5-HT1A partial agonist, buspirone [36], reduced the development of approach/avoidance “retreat” behavior in a runway model of drug self-administration. Buspirone was also effective at selectively diminishing the delayed aversive effects of the drug, while leaving the initial positive effects intact as measured in tests of place conditioning [37].
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