Alcohol-seeking behavior: the roles of the hypothalamic-pituitary-adrenal axis and the endogenous opioid system

Abstract

Both the hormones of the hypothalamic-pituitary-adrenal (HPA) axis and the endogenous opioid system are activated in response to stress as well as after alcohol consumption, supporting the hypothesis that stress can influence both alcohol consumption and craving for alcohoL Activation of the HPA axis by stress or alcohol results in the production of glucocorticoid hormones, such as cortisol. Those hormones, in turn, are important for the release of the brain chemical dopamine in certain brain areas that are associated with the rewarding and reinforcing effects of alcohol and other drugs. Alcohol-induced release of certain endogenous opioids similarly results in dopamine release in those brain regions. Through this mechanism, both the HPA axis and the endogenous opioid system may influence alcohol consumption. Consequently, genetically determined differences in the activities of the HPA axis and endogenous opioid system may help determine a person's alcohol consumption level and vulnerability to alcoholism.

Figure 1

The major components of the stress response. Both alcohol and stress can induce nerve cells in one brain region (i.e., the hypothalamus) to produce and release corticotropin-releasing hormone (CRH). Within the hypothalamus, CRH stimulates the release of a hormone that produces morphinelike effects (i.e., β-endorphin). CRH also is transported to a key endocrine gland, the anterior pituitary gland. There, CRH stimulates production of a protein called proopiomelanocortin (POMC). POMC serves as the basis for a number of stress-related hormones, including adrenocorticotropic hormone (ACTH), β-lipotropin (β-LPH), and β-endorphin. ACTH stimulates cells of the adrenal glands to produce and release the stress hormone cortisol. When cortisol levels reach a certain level, CRH and ACTH release diminishes. Other neurons releasing serotonin (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA), or endogenous opioids also regulate CRH release. NOTE: ⊕ excites; ⊝ inhibits.

Figure 2

Lengthwise view of the rat brain showing the brain regions in which certain stress hormones (i.e., endogenous opioids) are released. Those hormones—endorphins (light purple), enkephalins (purple), and dynorphins (black)—and the brain chemical (i.e., neurotransmitter) dopamine are involved in the processes of reward and reinforcement. Endorphin-producing nerve cells are located primarily in the arcuate nucleus (ArcN); they extend to and release endorphin in various brain areas (purple). Nerve cells in several regions produce enkephalins and dynorphins, which may be released either in the same region or in distant regions through networks of nerve cells (not shown). A nerve-cell network called the mesolimbic dopaminergic system (gold line) carries dopamine from the ventral tegmental area (VTA) to various parts of the brain. NOTE: Amyg = amygdala; CPu = caudate putamen; FC = frontal cortex; Hpc = hippocampus; NAc = nucleus accumbens; PaG = periaqueductal grey area; Sept = septum.

Figure 3

Schematic representation of hormones derived from proopiomelanocortin (POMC) in the hypothalamus and anterior pituitary gland, brain areas fundamental to hormone production and regulation. POMC, which itself is inactive, is cut into smaller, active hormones in a process called posttranslational processing. The products of this process differ in the hypothalamus and pituitary gland. The major products in the hypothalamus are β-endorphin, α-melanocyte–stimulating hormone (α-MSH), and small amounts of adrenocorticotropic hormone (ACTH). The major products in the anterior pituitary are ACTH, β-lipotropin, and β-endorphin.

Figure 4

Schematic representation of the possible influence of β-endorphin (β-EP) on dopamine release in the nucleus accumbens (NAc). Dopamine is a brain chemical (i.e., neurotransmitter) involved in reward and reinforcement processes, and the NAc is a brain region involved in mediating alcohol’s positive reinforcing effects. β-EP is produced in the arcuate nucleus of the hypothalamus (ArcN) by nerve cells (i.e., neurons) that extend to other brain regions, including the ventral tegmental area (VTA) and the NAc. β-EP can stimulate dopamine release in the NAc through two mechanisms. First, it can interfere with (i.e., inhibit) neurons in the VTA that produce gamma-aminobutyric acid (GABA), a neurotransmitter that normally inhibits the dopamine-producing neurons in the VTA. Inhibition of GABA production leads to increased dopamine production and release in the NAc. Second, β-EP can directly stimulate (i.e., excite) dopamine-producing neurons in the NAc. Alcohol stimulates β-EP release in both the VTA and NAc. Purple structures indicate excitatory mechanisms, and gold structures indicate inhibitory mechanisms.