Please note, this is recovered content from the former website of the New York Obesity Research Center website.


Understanding Background of Natural and Artificial Stimuli On Brain Activity and Eating Behaviour

Date: April 10th, 2003
Title: “Interaction between Natural Motivational Systems and those which Respond to Drugs of Abuse”
Speaker: Ilene L. Bernstein, University of Washington, Seattle, WA

Levi Levi
This describes an experiment with rats.

Betty Betty
They deprived rats of salt.

David David
And studied their brains under the microscope.

Billy Billy
I’m going to skip reading this one.


Salt deprived, craving salt, looks similar to drug addiction changes in the brain.

Artificial StimuliThe interface between neural systems which respond to natural motivational stimuli and artificial stimuli, such as drugs of abuse, remains to be understood. Activation of natural motivational systems, through strong homeostatic challenges, may affect responses to subsequent challenges. Furthermore, recent findings indicate that such treatments can have effects on the brain and behavior of animals, effects which are strikingly similar to those which occur following drug sensitization.

Sensitization is a well-documented effect of repeated exposure to drugs such as amphetamine and cocaine (Pierce and Kalivas, 1997). Sensitization represents a form of long-term plasticity, which, in important respects, differs from associative learning but may share some common mechanisms. In the laboratory, sensitization is displayed by increases in the psychostimulant effects of the drugs following multiple prior exposures. Unlike transient drug effects, such as tolerance and withdrawal, sensitization can last as long as a year after the last drug administration in rats. The persistence of these effects implicates mechanisms distinct from those responsible for more transient drug effects.

Induction of a salt appetite, a strong natural motivator, is also associated with sensitization (Sakai, Fine, Epstein and Frankmann, 1987). Salt appetite, the innate response to sodium need, is expressed as eager ingestion of NaCl. Salt appetite is strongly enhanced in rats with a history of prior episodes of sodium depletion and such experiences have been reported to have additional long-term effects on behavior. Thus, the experience of sodium depletion can lead to durable, possibly life-long, changes in behavioral responses to salt.

Sensitization to drugs, such as amphetamine, is associated with alterations in the morphology of neurons in the nucleus accumbens, a brain region critical to motivation and a major target of the mesolimbic dopamine system. Robinson and Kolb (1997) recently reported that repeated amphetamine treatments, using a delivery schedule known to support sensitization of locomotor activation, alter the morphology of neurons in the nucleus accumbens, a brain region believed to play an important role in motivated behaviors and responses to drugs of abuse. Drug treated animals were found to have a significantly greater number of dendritic branches and more dendritic spines than untreated controls. These findings are indicative of changes in synaptic connectivity and such persistent synaptic alterations may underlie the behavioral sensitization induced by these drugs.

We examined whether a strong natural motivator, sodium depletion and associated salt appetite, also lead to alterations in neurons in nucleus accumbens. To induce a salt appetite, animals received sodium-depleting treatments with the diuretic furosemide and were maintained overnight on distilled water and sodium free chow. Golgi-impregnated medium spiny neurons from the shell of the nucleus accumbens of rats that had experienced sodium depletions were examined for patterns and extent of dendritic branching. Rats with a history of sodium depletions were found to have significantly more dendritic branches and spines than controls (Roitman, Na, Anderson, Jones and Bernstein, 2002). Thus, sodium depletion and the induction of salt appetite lead to changes in dendritic morphology in the shell of the nucleus accumbens and the pattern of those changes is similar to that seen after amphetamine sensitization.

The observation of a striking similarity between the effects of sodium depletion history and multiple amphetamine treatments on neuronal morphology in nucleus accumbens led us to examine whether the behavioral effects of sodium depletions were also similar, that is whether they led to sensitization to the psychostimulant effects of amphetamine. Rats received a single injection of amphetamine (d-Amphetamine sulfate; 2 mg/kg, IP) and were placed in an open field where their locomotor activity was recorded. Those rats with a history of sodium depletions displayed significantly more rearing behavior (but not horizontal locomotion) than controls. Thus, the induction of a strong sodium appetite appears to sensitize not only salt appetite but also some of the psychomotor stimulant effects of amphetamine (Roitman et al, 2002). These effects were evident after at least a week had elapsed to allow rats to recover from any residual sodium deficit. Therefore the findings point to effects not of an ongoing need or challenge, but of the animals’ prior history of deprivation. They provide striking evidence that the increases in dendritic length and synapse number, provoked by sodium depletions, may have behavioral consequences beyond the realm of responses to salt. Thus, neuronal alterations common to salt and drug sensitization may provide a general mechanism for enhanced behavioral responses to subsequent exposures to these challenges.

Q. Sham-drinking of salt was reportedly blunted by DA-antagonists; were your observations related to those findings?
A. Yes.

Q. What sort of response might be seen if the rats were water-deprived, but sodium-replete?
A. That’s unknown.

Q. If the rats had no cues that the drug was in a specified place, would they want to go there?
A. In the Conditioned Place Preference paradigm drugs are given during conditioning, but not during testing. This set-up is different from a Drug Self Administration paradigm where cues can provide information about whether or not drugs are “available”.

Q. How do your results compare- anatomically- with the food-deprivation studies done in primates?
A. In both cases, changes occur in the nucleus accumbens.

Q. Do Amphetamines reduce salt intake in sodium-deprived rats?
A. It’s unknown.

Q. Can antagonists block conditioned taste aversions or context-place-preferences?
A. Dopamine antagonists can block conditioned taste aversions.

Q. Can you describe how the drug‘s route-of-administration might influence the animals’ preferences?
A. Route-of-administration plays a big role in many studies, but not in this case since the rats formed aversions to drugs that they had self-administered.

Q. Is it possible that the rat’s first administration is aversive, but that later ones become preferred?
A. No; our evidence does not support this possibility.

Q. Could your amphetamine doses have been toxic?
A. It is true that DA can cause a loss of axonal inputs (pruning), so toxicity cannot be ruled out.

Q. What about other DA-neuronal fields?
A. We have only examined the medium spiny neurons in the nucleus accumbens. Robinson and Kolb found similar changes in the prefrontal cortex after amphetamine sensitization.

Q. Can you get increases if the rats are not Na+-depleted (i.e., need-free Na+)?
A. The literature regarding need-free rats is inconsistent; some papers report increases- while others do not.

Q. Are your results parallel with Bart Hoebel’s model of sugar-addicted rats?
A. Yes; our results are strikingly similar.

Q. Is sensitization a form of conditioned preference?
A. Maybe- in some ways.

Q. What motivated you to examine the relationship between Na+-ingestion and DA?
A. Part of the rationale came from Randall Sakai, who suggested that Na+-sensitization was not ‘learning'; rather, he believed it was driven primarily by Na+-deprivation. Now it seems that, at least in our model, both Na+-deprivation and Na+-ingestion are important.


  1. Pierce RC, Kalivas PW (1997). A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev 25:192-216.
  2. Robinson TE, Kolb B (1997). Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491-7.
  3. Roitman MF, Na E, Anderson G, Jones TA & Bernstein IL (2002). Induction of a salt appetite alters dendritic morphology in nucleus accumbens and sensitizes rats to amphetamine. J Neurosci 22:RC225 (1-5).
  4. Sakai RR, Fine WB, Epstein AN, Frankmann SP (1987) Salt appetite is enhanced by one prior episode of sodium depletion in the rat. Behav. Neurosci. 101, 724-31.