The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: estrous cycle effects on behavior and protein expression in the nucleus accumbens

Abstract

Rationale Effective pharmacological treatments to prevent cocaine relapse remain elusive. In male rats, ceftriaxone attenuates the reinstatement of cocaine-seeking while increasing glutamate transporter-1 (GLT-1) and xCT expression in the nucleus accumbens core (NAc). Despite reported sex differences in cocaine relapse, these effects have not yet been confirmed in female rats. Objective We investigated the effects of ceftriaxone on cue-primed reinstatement and cocaine-induced alterations in glutamatergic proteins in the NAc of female rats. Potential interactions between estrous phase and treatment were also assessed. Method Male and female rats self-administered cocaine in the presence of discrete cues for 12 days, followed by 2–3 weeks of extinction. Ceftriaxone or vehicle was administered daily for a minimum of 6 days immediately preceding a cue-primed reinstatement test. Results Total cocaine intake was greater in females than in males, but reinstatement behavior was similar. Ceftriaxone attenuated reinstatement in both sexes and was accompanied by increased expression of GLT-1a and xCT in the NAc. However, ceftriaxone attenuated reinstatement only when females were tested during met-, di-, and proestrus phases and not during estrus. A significant increase in AMPA receptor subunit GluA1 surface expression was also observed during estrus, potentially influencing reinstatement. Conclusion These findings extend the beneficial effects of ceftriaxone on persistent cocaine-seeking from males to females, increasing its potential as a pharmacological treatment for preventing relapse. The effects of estrus on GluA1 expression and reinstatement observed here indicate that females may need additional interventions during some phases of the menstrual cycle.

Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cued cocaine relapse

“…The results of the Fos mapping studies are consistent with the hypothesis that ceftriaxone not only alters glutamate homeostasis within the NA core (Knackstedt et al 2010a;LaCrosse et al 2017;Bechard et al 2018), but also affects several regions that send glutamatergic projections to the NA core to reduce both relapse and the glutamate efflux that accompanies it.…”

“…Ceftriaxone ameliorates several cocaine-induced NA core adaptations and consistently attenuates cocaine relapse across different relapse primes (Knackstedt, Melendez & Kalivas 2010a;Fischer, Houston & Rebec 2013;Bechard et al 2018;Bechard & Knackstedt 2019).…”

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

“…In addition, we have previously shown the importance of the dorsal hippocampus (Fakira et al, 2016;Williams et al, 2019) and AMPAR signaling in the modulation of opioid-associated contextual memory (Morón et al, 2007;Billa et al, 2009;Billa et al, 2010;Xia et al, 2011). Sex differences in AMPAR activity have also been linked to cocaine-associated memory (Bechard et al, 2018;Ganguly et al, 2019). Therefore, the novel component of sex differences in spatial memory identified here suggest that CNIH3 could play a role in sex-dependent drug-associated memory.…”

“…Several studies have reported that differences between male and female rats in evoked AMPAR/NMDAR signaling in hippocampal synapses, along with differences in the magnitude of evoked LTP, may underlie sex differences in spatial memory (Monfort et al, 2015;Qi et al, 2016). Estrous has been shown to modulate diffusion of AMPARs to the surface in female mice (Palomero-Gallagher et al, 2003;Tada et al, 2015;Bechard et al, 2018), which may underlie part of the reported importance of estrogenic mechanisms for memory in females (Cordeira et al, 2018;Frick et al, 2018;Koss et al, 2018;Wang et al, 2018;Koebele et al, 2019). However, the sex-specific role of AMPARs in memory may also be specific to the type of memory task being tested, as a study by Dachtler et al concluded that the GluA1 subunit was necessary only for male, not female, mice in fear conditioning memory, but that hippocampal GluA1 was necessary for spatial learning in both sexes (Dachtler et al, 2011).…”

PKMζ in the nucleus accumbens acts to dampen cocaine seeking

“…Ceftriaxone, an antibiotic that normalizes basal extrasynaptic glutamate levels, attenuates reinstatement in males and non-estrus females. However, females in the estrus phase are unaffected by ceftriaxone, suggesting an interaction between the estrus cycle and glutamateric system following cocaine self-administration (Bechard et al, 2018). As the site-specific PKMζ knockdown was a chronic manipulation, we did not examine the role of the estrus cycle in the current study.…”