When presented with food or cocaine, dopamine (DA) in the nucleus accumbens (NAc) initially signals that the item is rewarding. When behaviors, such as drug taking, become compulsive we hypothesize that this reflects a shift in neural systems maintaining the behavior. There is enhanced DA release in the dorsolateral striatum (DLS) and attenuation of NAc DA release. Furthermore, within DLS, activity in the Direct Pathway from the striatum to the substantia nigra, that is important for initiation of appetitive behaviors is enhanced, while activity in the Indirect Pathway, from the striatum to the globus pallidus, that inhibits competing repetitive or stereotyped behaviors is attenuated. Females (women and laboratory rats) exhibit more rapid escalation of drug taking than do males and estradiol (E2) enhances acquisition of drug taking and motivation for drugs of abuse. Experiments from the Becker laboratory have demonstrated that E2 inhibits GABA release, down-regulates DA D2 receptors (D2DR), and enhances cocaine- or amphetamine-stimulated DA release in DLS but not NAc. The overarching hypotheses for this proposal are: 1) An attenuated cocaine-induced DA increase in NAc combined with an enhanced DA increase to cocaine in DLS is related to the propensity to develop a preference for cocaine over palatable food pellets in both males and females; 2) Estradiol's action in DLS of females enhances the cocaine-induced dopamine (DA) increase, inhibits GABA release, and inhibits D2 DA receptors. This combined effect enhances the rate of preference formation and motivation for cocaine over pellets in females; and 3) Decreased inhibition of the indirect pathway in DLS contributes to enhanced motivation for cocaine over pellets in both males and females. In females D2DRs are down-regulated in this pathway by E2, and this contributes to the more rapid preference formation in females and greater motivation for cocaine over pellets. Determining the mechanism(s) mediating formation of preference for cocaine over a highly palatable food reward, and how individual differences and sex differences contribute to this, are important for our understanding of and treatment of addiction in both men and women.
Cocaine abuse among women has increased in the last decade so that of the 2.4 million Americans who use cocaine, approximately 39.5% are now female. The proposed studies will investigate the neurochemical and neuroanatomical bases for enhanced vulnerability to drug abuse in both males and females.
| Yoest, Katie E; Quigley, Jacqueline A; Becker, Jill B (2018) Rapid effects of ovarian hormones in dorsal striatum and nucleus accumbens. Horm Behav : |
| Song, Zhimin; Kalyani, Manu; Becker, Jill B (2018) Sex differences in motivated behaviors in animal models. Curr Opin Behav Sci 23:98-102 |
| Westenbroek, Christel; Perry, Adam N; Jagannathan, Lakshmikripa et al. (2017) Effect of social housing and oxytocin on the motivation to self-administer methamphetamine in female rats. Physiol Behav : |
| Thomas, Mark B; Becker, Jill B (2017) Sex differences in prenatal stress effects on cocaine pursuit in rats. Physiol Behav : |
| Becker, Jill B; McClellan, Michele L; Reed, Beth Glover (2017) Sex differences, gender and addiction. J Neurosci Res 95:136-147 |
| Becker, Jill B; Prendergast, Brian J; Liang, Jing W (2016) Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol Sex Differ 7:34 |
| Sanchis-Segura, Carla; Becker, Jill B (2016) Why we should consider sex (and study sex differences) in addiction research. Addict Biol 21:995-1006 |
| Becker, Jill B (2016) Sex differences in addiction. Dialogues Clin Neurosci 18:395-402 |
| Becker, Jill B; McClellan, Michelle; Reed, Beth Glover (2016) Sociocultural context for sex differences in addiction. Addict Biol 21:1052-9 |
| Yoest, Katie E; Cummings, Jennifer A; Becker, Jill B (2014) Estradiol, dopamine and motivation. Cent Nerv Syst Agents Med Chem 14:83-9 |
