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

Psychopharmacology (Berl). 2018 Mar;235(3):837-848. doi: 10.1007/s00213-017-4802-7. Epub 2017 Dec 2.


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.

Keywords: GLT-1; GluA1; GluA2; mGlu5; xCT.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Ceftriaxone / pharmacology*
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / metabolism
  • Cues
  • Drug-Seeking Behavior / drug effects*
  • Estrous Cycle / physiology*
  • Female
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Sex Characteristics


  • Anti-Bacterial Agents
  • Receptors, AMPA
  • Ceftriaxone
  • Cocaine
  • glutamate receptor ionotropic, AMPA 1