Tamoxifen or Estradiol Limited to the Induction Phase of Nicotine Sensitization Enhances the Expression of Locomotor Sensitization in Ovariectomized and in Intact Female Rats

In both humans and rodents, females are more vulnerable to addiction than males, which has been linked to higher concentrations of the hormone estradiol in females. In rats, nicotine injections produce greater sensitization (neurological changes responsible for drug cravings) in females than in males, which could contribute to sex differences in susceptibility to addiction. The purpose of these experiments was to investigate the effects of estradiol during three nicotine injections (two consecutive days and a third injection nine days later). Results from these experiments indicate that depletion of estradiol via ovariectomy attenuates nicotine sensitization in females, which can be rescued by estradiol injection limited to the induction phase of sensitization. Administration of tamoxifen (antagonist at nuclear estradiol receptors, agonist of the membrane-bound estradiol receptor GPER1) did not alter sensitization in gonadally intact rats, and was sufficient to restore expression of sensitization in ovariectomized females (similar to estradiol). Findings from these experiments indicate that the enhancing effects of estradiol on nicotine sensitization occur during the induction phase, and may be mediated by membrane bound estrogen receptors (e.g., GPER1)

Influence of Inflammatory Pain and Dopamine on Synaptic Transmission in the Mouse ACC

Dopamine (DA) inhibits excitatory synaptic transmission in the anterior cingulate cortex (ACC), a brain region involved in the sensory and affective processing of pain. However, the DA modulation of inhibitory synaptic transmission in the ACC and its alteration of the excitatory/inhibitory (E/I) balance remains relatively understudied. Using patch-clamp recordings, we demonstrate that neither DA applied directly to the tissue slice nor complete Freund’s adjuvant (CFA) injected into the hind paw significantly impacted excitatory currents (eEPSCs) in the ACC, when recorded without pharmacological isolation. However, individual neurons exhibited varied responses to DA, with some showing inhibition, potentiation, or no response. The degree of eEPSC inhibition by DA was higher in naïve slices compared to that in the CFA condition. The baseline inhibitory currents (eIPSCs) were greater in the CFA-treated slices, and DA specifically inhibited eIPSCs in the CFA-treated, but not naïve group. DA and CFA treatment did not alter the balance between excitatory and inhibitory currents. Spontaneous synaptic activity revealed that DA reduced the frequency of the excitatory currents in CFA-treated mice and decreased the amplitude of the inhibitory currents, specifically in CFA-treated mice. However, the overall synaptic drive remained similar between the naïve and CFA-treated mice. Additionally, GABAergic currents were pharmacologically isolated and found to be robustly inhibited by DA through postsynaptic D2 receptors and G-protein activity. Overall, the study suggests that CFA-induced inflammation and DA do not significantly affect the balance between excitatory and inhibitory currents in ACC neurons, but activity-dependent changes may be observed in the DA modulation of presynaptic glutamate release in the presence of inflammation