Browsing by Subject "Cocaine"

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A role for the medial preoptic area in neuroendocrine modulation of sex differences in reward
(2022-08-12) Martz, Julia R.; Dominguez, Juan M.; Gore, Andrea C; Delville, Yvon; Serafine, Katherine M
The medial preoptic area (mPOA), located in the rostral hypothalamus, is an important regulator of motivated behaviors in rats. While its role in naturally rewarding behaviors, such as maternal care and sexual behavior, is well established, its role in drug response is just beginning to be explored. As a major site of neuroendocrine integration with direct connections to the mesolimbic dopamine system, it is not surprising that the mPOA is implicated in the modulation of sex differences in reward responses. Prior work has demonstrated that activation of the mPOA in response to sexual and parental reward differs between males and females, but whether sex differences are present in medial preoptic responses to drugs of abuse is unknown. Here, a role for the mPOA in the regulation of neuroendocrine-induced sex differences in neural and behavioral responses to cocaine is uncovered. Furthermore, while it is known that the mPOA influences the mesolimbic dopamine system through efferent connections with the ventral tegmental area (VTA), whether there are sex differences in the extent and profile of these projections remains unclear. The use of an iontophoretically injected tract-tracer, in conjunction with immunohistochemical techniques, revealed sex differences in mPOA efferents to the VTA. Specifically, projections from the central mPOA to the VTA contain more estrogen receptors and fewer androgen receptors in females, compared to males. Taken together, this work identifies the mPOA as a modulator of neuroendocrine-induced sex differences in downstream reward processing.
Affective responses in cocaine-experienced rats reveal cue-induced drug craving and cocaine reward magnitude
(2011-08) Maier, Esther Yvonne; Duvauchelle, Christine L.; Schallert, Timothy; Gonzales, Rueben A.; Gore, Andrea C.; Monfils, Marie H.
The development and persistence of cocaine dependence are greatly influenced by emotional affect and cocaine associative learning. Cocaine is known to enhance nucleus accumbens (NAcc) dopamine, serve as a positive reinforcer and produce negative effects, such as anxiety that may influence cocaine intake behavior. In the first study, I investigated the effects of the anxiolytic, diazepam on NAcc dopamine levels and cocaine self-administration behavior. These are two factors associated with cocaine rewarding effects. Diazepam has no effect on NAcc dopamine, but affects cocaine self-administration. This supports the notion that decreasing the anxiogenic effects of cocaine increases the rewarding value in a dopamine independent manner. Therefore, increasing the aversive effects of cocaine might be a novel approach to fight cocaine dependence. In the second study, I studied cocaine-induced associative learning and changes in affect during cocaine conditioning and extinction. 50-kHz ultrasonic vocalizations (USVs) in rats are thought to reflect positive affect and occur upon appetitive stimuli and with cocaine delivery. First, I explored whether USVs might be elicited in anticipation of impending drug delivery. Shortly into conditioning, rats elicited USVs when placed in the cocaine-associated environment. USVs progressively increased, indicating a growing learned association between cocaine intake and cocaine-associated cues. This suggests that USVs may be a useful model for investigating cocaine craving and serve as a pharmacological target for interventions aimed to reduce cocaine craving and relapse. I then examined the effects of short-term deprivation of cocaine and cocaine cues on cocaine-conditioned USVs, which were both exaggerated after abstinence. The results may have clinical implications, in that intermittently avoiding cues or context may enhance drug cue salience and increase the probability of relapse. Motivational aspects of cocaine were assessed comparing commonly measured lever response rate and locomotion with cocaine-induced USVs during cocaine administration and extinction. In agreement with prevailing findings, lever responding for cocaine and cocaine-induced locomotor activity increased across conditioning sessions. However, the number of USVs evoked in response to cocaine infusion decreased with cocaine experience. These findings suggest growing tolerance to the rewarding properties of cocaine. These studies underscore the value of USV assessment during drug dependence studies.
A role for the medial preoptic area in mediating a response to cocaine
(2014-12) Tobiansky, Daniel Jonathan; Dominguez, Juan M.
The salience of natural or drug-associated reward is mediated by phasic dopamine (DA) release in the nucleus accumbens (NAc) arising from DAergic cells in the ventral tegmental area (VTA). Circulating sex steroid hormones can modulate reward associated with drugs of abuse; yet, it still remains unclear which brain regions are responsible for this modulation. The medial preoptic area (mPOA) is a hypothalamic brain area involved in the expression of naturally rewarding behaviors as well as the regulation and reception of circulating sex steroid hormones in female rats. Considering its role in regulating naturally rewarding behaviors, its well-established anatomical connectivity with the VTA, and its responsiveness to circulating sex steroid hormones, the mPOA is an ideal neural node through which hormones could modulate the rewarding facets of drugs of abuse. Here I show that preoptotegmental efferents to the VTA are primarily GABAergic, that they appose putative DAergic cell bodies in the VTA that project to the NAc, and that they are capable of responding to sex steroid hormones and changes in DA release. Furthermore, cocaine influences neural activity in mPOA efferents that project to the VTA. Removal of the mPOA also enhanced cocaine-induced locomotion, Fos-immunoreactivity in the mesolimbic reward system, DA release in the NAc, and augmented conditioned place preference. Together these findings suggest that the mPOA modulates the release of DA in the mesolimbic reward circuitry via inhibitory connections with DA neurons residing in the VTA, and sex steroid hormones, in turn, may act in the mPOA to modulate response to cocaine.
The role of the preoptic area in response to cocaine
(2016-05) Will, Ryan Gregory; Dominguez, Juan M.; Marinelli, Michela; Duvauchelle, Christine L; Gore, Andrea C; Jones, Theresa A; Monfils, Marie H
The preoptic area of the hypothalamus is ideally suited to modulate the behavioral and neural response to drugs of abuse such as cocaine. The preoptic area is broken up into two major subregions the medial preoptic area (mPOA) and the lateral preoptic area (LPO), both of which send dense projections to mesolimbic dopamine system. Specifically, both project to the ventral tegmental area (VTA), a brain region implicated in drug-associated reward. Previous work has demonstrated the mPOA is involved in the behavioral and neural response to cocaine in female rats, however the mechanism through which the mPOA modulates response to cocaine is unclear. Whether or not the mPOA also plays a role in response to cocaine in male rats is still not clear. Furthermore the role of the adjacent LPO in response to cocaine is unexplored, despite its anatomical relationship to the VTA and involvement in intracranial self-stimulation. Here I demonstrate that estradiol acts in the mPOA of female rats to modulate response to cocaine. Specifically, microinjections of estradiol directly into the mPOA one day prior to cocaine administration increase cocaine-induced dopamine levels in the nucleus accumbens. The mPOA is also involved in the behavioral regulation of response to cocaine in male rats, as mPOA lesions enhanced cocaine-induced locomotion and reward. Finally, activation of the LPO, with pharmacology or chemogenetics, potentiates reinstatement of cocaine seeking, an animal model of drug relapse. Together these results demonstrate that the preoptic area as a whole is involved in the regulation of the neural and behavioral response to cocaine and shed light on underlying regulatory mechanisms.