β‐Endorphin Neuronal Transplantation Into the Hypothalamus Alters Anxiety‐Like Behaviors in Prenatal Alcohol‐Exposed Rats and Alcohol‐Non‐Preferring and Alcohol‐Preferring Rats

Abstract

Background Alcohol exposure has adverse effects on stress physiology and behavioral reactivity. This is suggested to be due, in part, to the effect of alcohol on β-endorphin (β-EP) producing neurons in the hypothalamus. In response to stress, β-EP normally provides negative feedback to the HPA axis and interacts with other neurotransmitter systems in the amygdala to regulate behavior. We examined whether β-EP neuronal function in the hypothalamus reduces the corticosterone response to acute stress, attenuates anxiety-like behaviors, and modulates alcohol drinking in rats. Methods To determine if β-EP neuronal transplants modulate the stress response, anxiety behavior and alcohol drinking, we implanted differentiated β-EP neurons into the paraventricular nucleus of the hypothalamus (PVN) of normal, prenatal alcohol exposed, and alcohol-preferring (P) and non-preferring (NP) rats. We then assessed corticosterone levels in response to acute restraint stress and other markers of stress response in the brain, and anxiety-like behaviors in the elevated plus maze and open-field assays. Results We showed that β-EP neuronal transplants into the PVN reduced the peripheral corticosterone response to acute stress and attenuated anxiety-like behaviors. Similar transplants completely reduced the hyper-corticosterone response and elevated anxiety behaviors in prenatal alcohol exposed adult rats. Moreover, we showed that β-EP reduced anxiety behavior in P rats with minimal effects on alcohol drinking during and following restraint stress. Conclusions These data further establish a role of β-EP neurons in the hypothalamus for regulating physiological stress response and anxiety behavior, and resembles a potential novel therapy for treating stress-related psychiatric disorders in prenatal alcohol exposed children and those genetically predisposed to increased alcohol consumption.

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

“…Fetal alcohol exposure increases POMC neuronal death in the hypothalamus [ 10 ] and results in abnormality in the feedback regulation of stress axis function during a stress challenge [ 14 , 15 , 27 , 28 ], but the mechanism by which POMC neuronal death occurs is not completely understood. In this study, using a rat animal model, we demonstrated that ethanol exposures during the neonatal period, a period equivalent to third trimester of human pregnancy, increase the levels of proinflammatory signaling molecules within the hypothalamus, an area where many POMC neurons are distributed.…”

Persistent Changes in Stress‐Regulatory Genes in Pregnant Women or Children Exposed Prenatally to Alcohol

“…These data are consistent with the data in rodent in which PAE increased Pomc gene methylation in the hypothalamus and elevated ACTH and cortisol levels in plasma (Govorko et al., ). Animal studies have connected the stress axis functional abnormalities in PAE with alcohol‐induced epigenetic modification of PER2 and POMC genes (Boyadjieva et al., ; Gangisetty et al., ; Logan et al., ).…”

“…It has been shown that the expression levels of Pomc and Per2 genes are reduced and the corticosterone response to a stress challenge is increased in both alcohol‐dependent animals and in PAE animals (Agapito et al., ; Chen et al., ). Also shown is that the hyperstress response of PAE animals is reduced following implantation of proopiomelanocortin (POMC) neurons in the hypothalamus (Logan et al., ; Sarkar et al., ). Additionally, Per2 genes deletion has been shown to prevent PAE effects on Pomc expression and alter the rhythmic changes in corticosterone levels in the blood (Agapito et al., , ).…”

Acupuncture on the Stress-Related Drug Relapse to Seeking

“…These effects have been confirmed in a variety of experimental studies showing that acupuncture suppressed CRF neuronal activity in the various regions of brain including the amygdala [ 90 , 91 ]. Interestingly, β -endorphin is important in reducing response of the hypothalamic CRF neuron to stress and attenuating anxiety-like behavior [ 92 , 93 ]. Thus, acupuncture inhibition of drug-seeking behavior might result from modulation of stress response system in the amygdala through activation of β -endorphinergic neurons in the arcuate nucleus of the hypothalamus.…”