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This may in turn induce a negative feedback loop that blunts rewarding effects of cocaine and eventually drives escalation (Dong et al., 2006). Phosphorylation of CREB also drives formation of new dendritic spines by increasing the expression of NMDARs but not AMPARs leading to the formation of “silent synapses” (Murphy and Segal, 1997; Segal and Murphy, 1998). Studies have indicated formation of “silent synapses” to be critical to the enhancement of cocaine seeking (Huang et al., 2015). NF-κB is upregulated in NAc post chronic cocaine administration (Ang et al., 2001).

This input is believed to modulate the activity of VTA-DA neurons (Koo et al., 2012; Tan et al., 2012; van Zessen et al., 2012; Taylor et al., 2016). Studies using male rodents show that opioid drugs induce rewarding effects through inhibition of GABAergic interneurons, leading to excitation of VTA-DA neurons (Gysling and Wang, 1983; Johnson and North, 1992b). This VTA-DA excitation is mediated via GABAergic projections from the tVTA/RMTg. The tVTA/RMTg, caudal to the VTA, is a GABAergic area innervating VTA-DA cells (Bourdy et al., 2014). MORs are densely packed on these tVTA-GABAergic neurons (Jhou et al., 2009b, 2012; Jalabert et al., 2011; Kaufling and Aston-Jones, 2015), and MOR binding decreases their firing rate (Jalabert et al., 2011; Kaufling and Aston-Jones, 2015). Consequently, DA neurons in VTA are disinhibited and freely transmit DA to projection sites in the NAc and other limbic regions which leads to overstimulation of the circuitry mediating addiction-related behaviors.

Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse. Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats. The human menstrual cycle occurs over 28 days and is comprised of fluctuating levels of E2 ; and progesterone (P4; bottom). E2 levels then drop, rise, and plateau between during the mid-luteal phase (approximately Days 14–28). Progesterone levels begin to at the end of the ovulation (Days 0–14) and reach their peak during the mid-luteal phase of the cycle .

It is involved in expression of cocaine reward and the induction of dendritic spines in the MSNs of NAc (Russo et al., 2009). Genes transcribed by NF-κB are essentially required in the regulation of synaptic plasticity of neurons within the mesolimbic reward regions . ΔFosB is induced in the D1-type MSNs by chronic exposure to cocaine and has been proposed to be the molecular switch for addiction (Nestler, 2008; Perrotti et al., 2008). Its expression is regulated by cocaine and CREB within NAc MSNs and increases cocaine reward and self-administration (Nye et al., 1995; Vialou et al., 2012; Robison et al., 2013). It is also necessary and sufficient for cocaine-induced dendritic spine formation through increase in the expression of “silent synapses” in the D1-type MSNs of NAc.

Hence, normal rewarding stimuli become less rewarding and full activation of the reward pathway requires drug consumption. The mesolimbic reward system is necessary for organisms to engage in reinforcing behaviors and to motivate actions that produce rewarding feelings of pleasure . Midbrain dopamine neurons that arise in the ventral tegmental area and substantia nigra project to forebrain regions that regulate the storj price prediction 2030 motivational and cognitive processes necessary for organisms to engage in behaviors that produce rewarding feelings of pleasure . Chronic drug use produces a persistent enhanced activation of these systems which results in long-term structural and functional changes . Moreover, female rats acquire cocaine self-administration more quickly and at lower doses than males (Lynch and Carroll, 1999; Davis et al., 2008).

Females also demonstrate increased responsivity toward drug taking under stress than males indicating a higher intensity of negative physical and psychological withdrawal symptoms and therefore, higher relapse probability . Lastly, female rodents more readily reinstate drug use after a period of abstinence in the absence of any reinforcing cues when compared to males (Anker and Carroll, 2010; Buffalari et al., 2012). Taken all together, these data demonstrate sex differences in preclinical rodent models of drug administration/reward and recapitulate and extend findings from the clinical literature. Specifically, female rodents are decisively more vulnerable to developing addiction-like behaviors after exposure to drugs of abuse than males.

IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Comparing levels of cocaine cue reactivity in male and female outpatients. Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal dopamine release. Pharmacological studies of the regulation of chronic FOS-related antigen induction by cocaine in the striatum and nucleus accumbens. Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens. Modulation of the binding characteristics of hypothalamic mu opioid receptors in rats by gonadal steroids.

Converging evidence from the reproductive and pain literatures suggests interactions among opioids, gonadal hormones, opioid receptors, and estrogen receptors may underlie sex differences in addictive responsiveness to opioid drugs . Adverse effects of hormonal contraceptives on mood seem most consistent in women with a history of depressive symptoms and/or previous negative experience with HC-intake. Current evidence supports a negativity bias in emotion recognition and reactivity in HC-users, although inconsistent to some extent. Some data, however, do indicate a trend towards a blunted reward response and a potential dysregulation of the stress response in some HC-users. The MOR is a conventional G-protein coupled receptor in that it is a cell surface protein with seven transmembrane domains consisting of α, β, and γ subunits, and an effector protein. Upon activation by an agonist, the Gα and Gβγ subunits dissociate from one another and subsequently regulate a variety of intracellular effector pathways.

E2 administration to OVX animals restores acquisition of cocaine self-administration to levels comparable with those of intact female rodents (Lynch et al., 2001; Hu et al., 2004; Larson et al., 2005; Frye, 2007). Furthermore, this effect was specific for female rodents since there was no effect of E2 replacement on cocaine self-administration behaviors of male rodents (Jackson et al., 2006). Estradiol and DA systems interact to modulate striatal function and resultant behavior (Di Paolo et al., 1985; Becker and Beer, 1986; Becker, 1990; Bitar et al., 1991).

The rat estrous cycle is similar to the human menstrual cycle but occurs over a 4/5-day period. Four phases; metestrus, diestrus, proestrus, and estrus comprise the rat estrous cycle. Estrogen levels peak toward the end of diestrus and beginning of proestrus. Enjoy Rewards also offers registration rewards such as a one-time 10-cents-a-gallon discount and five free fountain drinks or coffees. Customers may pick up a card at any Enmarket location and can register the card online or on the Enmarket Enjoy Rewards mobile app to start redeeming their fuel discounts. From there, Enmarket customers have the option to either use the physical card or enter their phone number at checkout to access their accounts and rewards.

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