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The estrus phase of the rat/mouse cycle occurs on the day following the E2 and progesterone surges; this is when the female rodent ovulates and is sexually behaviorally receptive (Becker et al., 2005). The striatum of male rats contains about 10% more D1 DA receptors than that of intact female or OVX rats. Generally speaking, there are no sex differences in the number or binding characteristics of striatal D2 DA receptors (Hruska and Silbergeld, 1980; Levesque and Di Paolo, 1988), however, one experiment reported female rats had fewer D2 receptors than males . Interestingly, E2 rapidly downregulates D2 DA receptor binding in the striatum of females . Taken together, HC-intake seems to chronically alter HPA axis regulation, mirrored by blunted cortisol responses after acute psychosocial and physical stressors and elevated baseline cortisol levels [41, 42••] .
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Although specific neurobiological mechanisms remain to be fully elucidated, there is much evidence implicating the combined effect of cocaine and E2 on VTA DAergic neurotransmission and on striatal GABAergic, DAergic, and glutamatergic neurotransmission. Additionally, it has been demonstrated that drug use, whether it be cocaine or opiates, produces persistent enhanced activation of the mesolimbic reward circuit resulting in long-term structural and functional changes. These neuroadaptive changes include enhancement in neurotransmitter release, increased synaptic plasticity and dendritic arborization within areas of the mesolimbic reward pathway. The increased neurotransmission activates downstream molecular mechanisms within these areas.
Collectively, these data indicate that women may be more severely affected by cocaine use than men. Negativity biases in key facets of emotion processing such as emotion recognition and emotional reactivity are thought to substantially contribute to the development and maintenance of depressed mood . Mitigating negativity biases in emotion recognition and reducing emotional reactivity to negative stimuli can be effective strategies to improve mood . With currently more than 100 million users worldwide , hormonal contraceptives represent one of the most influential discoveries of the twentieth century . HCs provide an effective option for contraception and safe family planning as well as for managing cycle-related physiological symptoms (e.g., ovulation pain, acne, hirsutism).
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The increases in cAMP in response to D1 receptor stimulation initiate activation of downstream protein kinases, including protein kinase A and extracellular signal-regulated kinase . These kinases, along with many other downstream effects, can phosphorylate the transcription factor CREB (Kano et al., 1995). CREB activation in the NAc is essential as a regulator of cocaine reward and for cocaine-dependent alterations in gene expression (McClung and Nestler, 2003; Lemberger et al., 2008; Renthal et al., 2009). Post synaptic D2 receptors either inhibit or have no effect on adenylyl cyclase activity; presynaptic D2 receptors function as auto-receptors (Clark and White, 1987; Meador-Woodruff et al., 1991; Surmeier et al., 2007).
In addition, we demonstrated a correlation between activation of CREB in the tVTA and severity of morphine withdrawal symptoms in females (Bobzean et al., 2019). Overall, these findings indicate that ovarian hormone status may influence the severity and/or persistence of symptoms and CREB expression. Sex-based differences in the cellular and neurobiological mechanisms underlying sex differences in the rewarding properties of opioids are poorly understood (Dahan et al., 2008; Lee and Ho, 2013; Huhn et al., 2018).
Inhibition of protein phosphorylation by opioid-inhibited adenylyl cyclase in rat brain membranes. The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice. PPARgamma activation attenuates opioid consumption and modulates mesolimbic dopamine transmission. Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro. The effect of housing and gender on morphine self-administration in rats. The hippocampus has been implicated in the formation of drug-context memories, drug-cue associations, and reconsolidation of drug memories.