The neural substrates of enhanced salt appetite after repeated sodium depletions

Abstract

Sodium appetite is associated with a form of behavioral plasticity in which animals experimentally depleted of sodium progressively increase their intake of hypertonic NaCl over several successive (on 2 to 4 occasions) depletion. The present experiment explored the nature of this plasticity by quantifying Fos-immunoreactivity (Fos-ir) in structures implicated in the mediation of sodium appetite and in the signaling of reward. Rats were depleted of sodium with the diuretic furosemide three times (3F), one time (2V1F) or sham depleted (i.e., vehicle treated; 3V). Rats were given sodium appetite tests for the first two treatments. The sodium appetite test was omitted after the third depletion. Fos-ir activity was quantified in the paraventricular nucleus (PVN), subfornical organ (SFO), supraoptic nucleus (SON), nucleus accumbens (NAc) shell and core, basolateral (BLA) and central amygdala (CeA), and medial prefrontal cortex (mPFC). Animals receiving repeated sodium depletions increased sodium ingestion across initial depletions. Fos-ir activity was markedly enhanced in the SFO, BLA, and shell of the NAc of 3F rats relative to 2V1F and 3V animals. These results indicate that repeated experience with sodium depletion and ingestion affect both behavioral and neural responses to sodium. Experience with sodium depletion enhances its ingestion and may have a direct impact on central structures implicated in sodium appetite and reward signaling.

Salt craving: The psychobiology of pathogenic sodium intake

“…There appears to be a significant overlap in the neural substrates involved in drug addiction and sodium appetite sensitization, and cross-sensitization has been demonstrated between sodium depletion and psychostimulant treatment [26,196]. Rats depleted of sodium multiple times show a neurochemical profile similar to that seen following sensitization to drugs of abuse [17,26] and demonstrate a craving for sodium as exhibited by an increased breakpoint in a progressive fixed ratio operant task [14]. These findings suggest that changes in sodium status can alter the chemistry and anatomy of putative reward pathways in the brain, the same pathways impacted by drugs of abuse and potentially involved in maintaining addiction.…”

“…A recent experiment in our laboratory has elaborated on the potential neural mechanisms involved in facilitating sodium appetite sensitization [17]. We have found that experience with multiple sodium depletions differentially changes neural activity as a function of experiencing repeated deficits.…”

“…Particularly documented in certain strains of rats, so-called need-free ad libitum intakes are also increased in the days and weeks following a depletion [15 but also see 16]. Clinical and experimental observations in humans, along with recent animal studies suggest that a persistent and unresolved sodium appetite can induce behavioral characteristics that are qualitatively similar to psychological depression as well as induce plasticity in brain regions implicated in motivation, reward, and drug sensitization and withdrawal [17][18][19][20][21][22][23][24][25][26]. Such observations raise important questions about the psychobiological nature of sodium appetite.…”

“…This type of response modification reflects alterations in nervous system function. Repeated bouts of sodium deficit sensitize salt appetite such that an increase in sodium ingestion is seen over the course of the initial depletions [15,17,26,128,129] (Figure 4). An enhanced appetitive response for saline occurs over 2 to 4 sodium depletions at which point intakes plateau and remain stable over the course of additional instances of induced deficits [15,130].…”

“…Sodium depletion can be achieved through the administration of diuretic agents (e.g., furosemide), intraperitoneal dialysis, or injections of inert colloids (e.g., polyethylene glycol) into the peritoneal cavity or subcutaneously which provoke sodium appetite by directly depleting extracellular volume or functionally by sequestering extracellular fluid in localized edematous depots [17,59,60]. A disruption in body fluid homeostasis leads to activation of the renin-angiotensin-aldosterone system (RAAS) which is also important in cardiovascular regulation [61,62].…”