Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats

Abstract

Rationale Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the Bed Nucleus of the Stria Terminalis (BNST) which have been implicated in the production of anxiogenic states. Objectives The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration. Methods Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0μg/side) were administered to inhibit local 5-HT release via activation of 5-HT1B autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT1B antagonist NAS-181. Results Intra-BNST infusions of the 5-HT1B autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT1B antagonist. Neither start latencies (a measure of the subject’s motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment. Conclusions Inhibition of 5-HT1B signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug.

Exercise Modifies the Brain Metabolic Response to Chronic Cocaine Exposure Inhibiting the Stria Terminalis

“…A subregion of the st is the stpm, which is known to be involved in stress-triggered drug relapse [95]. Inhibition of the bed nucleus of the stria terminalis via serotonin signaling was found to decrease the anxiogenic effects of cocaine [96]. A pathway between the amygdala and the st containing corticotropin-releasing factor was also found to play a mediating role in stress-induced cocaine-seeking behavior [97].…”

Activation of 5-HT1B receptors in the Lateral Habenula attenuates the anxiogenic effects of cocaine

“…The drug NAS-181 was selected due to its high affinity for the 5-HT 1B receptor and ability to block agonist binding (Stenfors et al 2000;De Groote et al 2002;De Groote et al 2003). Previous work from our laboratory has shown that 0.1μg of NAS-181 is sufficient to reverse the behavioral effects of an even higher dose of CP 94,253 than was used in the present study (Klein et al 2017).…”

“…As previously described (Klein et al, 2017), each subject was deeply anesthetized with an intramuscular injection of ketamine and xylazine (56.25 and 7.5 mg/kg, respectively; Abbott Laboratories) and fitted with an indwelling intravenous (i.v.) catheter (13 mm of microrenathane tubing, 0.014 mm inner diameter, 0.33 mm outer diameter; Braintree Scientific) inserted into the right jugular vein, secured in place by silk sutures, and subcutaneously (s.c.) passed to a threaded guide cannula (catalog #313G; Plastics One) that exited though a 2 mm hole on the animal's back.…”

Latest updates on the serotonergic system in depression and anxiety

“…Activation of 5-HT1B heteroreceptors can lead to antidepressant-like effects. The reduced expression of 5-HT1B heteroreceptors in the ventral striatum is associated with human depression and is believed to interact with p11 (a 5-HT1BR binding protein) to affect depressive behavior (Klein et al, 2017 ). The combination of 5-HT1B receptor antagonist GR-127935 or SB-216641 with imipramine, desmethylimipramine, or cobinamide had a significant anti-static effect on rats in a forced swimming test by disinhibiting 5-HT release by blocking presynaptic 5-HT1B autoreceptors (Carr and Lucki, 2011 ).…”