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

Abstract

There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be more sensitive than males to stress-induced drug seeking. The dorsal hippocampus (DH) is prominently involved in the stress response, as are the locus coeruleus norepinephrine (LC-NE) and dorsal raphe serotonin (DR 5-HT) systems. Moreover, DH receives strong inputs from LC-NE and DR 5-HT neurons. We hypothesized that the stress associated with non-reinforced drug seeking during early abstinence (on extinction day 1 (ED1)) may contribute to drug seeking via β-adrenergic and 5-HT neurotransmission in DH. We observed decreased drug-seeking behavior on ED1 following 10 mg/kg S-propranolol (β-adrenergic and 5-HT1A/1B receptor antagonist), R-propranolol (5-HT1A/1B receptor antagonist), or racemic propranolol in both male and female rats. ED1 increased Fos expression in DH, LC, and DR, and DH Fos was decreased by systemic S-propranolol. Based on these results, we investigated the effects of blocking 5-HT and β-adrenoceptor transmission in DH on drug seeking during ED1 by infusing a cocktail of WAY100635 plus GR127935 (5-HT1A/1B receptor antagonists), betaxolol plus ICI-118 551 (β1 and β2 antagonists), or S-propranolol alone. In males, WAY100635/ GR127935 was most effective in reducing drug-seeking on ED1, whereas betaxolol/ICI-118 551 was ineffective. In contrast, S-propranolol was most effective in females in reducing drug seeking on ED1, and WAY100635/GR127935 and betaxolol/ICI-118 551 were each partially effective. Our results indicate that drug seeking during initial abstinence involves 5-HT and β-adrenergic signaling in female DH, but only 5-HT signaling in male DH.

Striatal alcohol cue‐reactivity is stronger in male than female problem drinkers

“…Moreover, the current findings are also in line with several neural cue‐reactivity studies in nicotine dependence (Cosgrove et al., ; Dumais et al., ). Animal studies have also reported that acute and chronic alcohol exposure only alters striatal mRNA expression in male, but not in female rats (Baxter‐Potter et al., ) and that there is a differential involvement of serotonergic and noradrenergic signalling in cue‐induced reinstatement (Kohtz & Aston‐Jones, ). Altogether, the current study supports the hypothesis that different (neural) mechanisms may underlie the development and persistence of substance use disorders in males and females.…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…A candidate gene association study found an association with variants of HTR1A with suicide attempts in alcohol dependent patients (Wrzosek et al, 2011). A 5HT1A/B antagonist (WAY100635) reduces drug seeking during initial abstinence in rats (Kohtz and Aston-Jones, 2017). In addition, serotonin specific neuronal reduction in expression of Htr1A in mice contributes to cocaine seeking behavior and inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with prolonged extended access, but not 1 h access to the drug (You et al, 2016).…”

Impact of gender on corticotropin‐releasing factor and noradrenergic sensitivity in cocaine use disorder

“…For example, females show greater CRF receptor binding affinity; increased serotonin synthesis; and increased adrenergic, corticosterone, and GABA receptor expression compared with males (Turner, 1992;Madeira and Paula-Barbosa, 1993;Galea et al, 1997;Rhodes and Rubin, 1999;Shors et al, 2001). In addition, findings from a recent study by Kohtz and Aston-Jones (2016) demonstrate that selective inhibition of b-ARs with S-propranolol or with a cocktail of selective b-AR antagonists betaxolol 1 ICI-118,551 microinjected into the DH attenuates drug seeking during initial abstinence (ED1; F 1,40 5 5.083, P < 0.05). Post hoc analyses reveal that the betaxolol 1 ICI-118,551 cocktail was Fig.…”

“…It is unclear whether increased responding on ED1 in females is dependent on estrous cycle of the female rat (Feltenstein and See, 2007;Feltenstein et al, 2009). In a recent article, the authors hypothesized that the initiation of abstinence, ED1, is stressful because of the absence of drug, thereby engaging the CRF and NE systems to promote increased cocaine seeking (Cason et al, 2016;Kohtz and Aston-Jones, 2016). This hypothesis was tested by blocking CRF1 signaling using a selective CRF1 receptor antagonist, 526 (CP), and investigating the impact on drug seeking on ED1 measured by responding on an active lever previously associated with cocaine self-administration.…”