Inactivation of the dorsal raphé nucleus reduces the anxiogenic response of rats running an alley for intravenous cocaine

Abstract

Rats traversing a straight alley once a day for delivery of a single i.v. injection of cocaine develop over trials an ambivalence about entering the goal box. This ambivalence is characterized by the increasing occurrence of "retreat behaviors" where animals leave the start box and run quickly to the goal box, but then stop at the entry point and "retreat" back toward the start box. This unique pattern of retreat behavior has been shown to reflect a form of "approach-avoidance conflict" that stems from the animals' concurrent positive (cocaine reward) and negative (cocaine-induced anxiety) associations with the goal box. Cocaine blocks reuptake of the serotonergic (5-HT) transporter and serotonin has been implicated in the modulation of anxiety. It was therefore of interest to determine whether inactivation of the serotonergic cell bodies residing in the dorsal raphé nucleus (DRN) and projecting to brain areas critical for the modulation of anxiety, would alter the anxiogenic state exhibited by rats running an alley for single daily i.v. injections of 1.0 mg/kg cocaine. Reversible inactivation of the DRN was accomplished by intracranial application of a mixed solution of the GABA agonists baclofen and muscimol. While DRN inactivation had no impact on the subjects' motivation to initiate responding (i.e., latencies to leave the start box were unaffected) it reliably reduced the frequency of approach-avoidance retreat behaviors (conflict behavior). These data suggest that inactivation of the dorsal raphé reduces the conflict/ anxiety otherwise present in experienced cocaine-seeking animals.

Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner

“…of rats during cocaine self-administration, but did not alter motivation for cocaine (Ettenberg et al, 2011). Our studies indicate that DRN is activated on ED1 in both male and female rats, whereas MRN is only activated in males, and VLPAG is primarily activated in females.…”

On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats

“…Thus, the more negative the drug experience is for subjects (as measured by CPA magnitude) the longer those same subjects subsequently took to leave the start box (r s =0.62), the more retreats they made in the runway (r s =0.62), and the longer they took to finally enter the goal box (r s =0.65). Finally we note that although animals were all tested first in the place condition test and then in the runway, there was no evidence to show that the modest prior drug exposure from the CPP/CPA tests had in any way altered subsequent runway behavior – i.e., the runway test produced response patterns and magnitudes that were highly comparable to those that we had previously reported in animals that did not have any prior cocaine exposure (e.g., see recent studies by Ettenberg et al 2011; Su et al 2012; Wenzel et al 2014). …”

Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction

“…Given the role of 5-HT to control responsiveness to multiple types of external and internal stimuli (Izquierdo, et al, 2012; Lucki, 1998; Soubrié, 1986), future efforts will be need to deconstruct its involvement in key aspects of impulsivity, cocaine reward and cue reactivity. One aspect that warrants attention is the extent to which 5-HT-mediated reductions in the reinforcing effects of cocaine could be due to the alleviation of simultaneously-experienced aversive effects (Ettenberg, et al, 2011; Riley, 2011). The distinction between these aspects of how 5-HT influences reward versus aversion may be important when considering recent findings that SSRIs limit the neural activation observed upon presentation of either rewarding or aversive stimuli (Kranz, et al, 2010; McCabe, et al, 2011).…”