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Am J Physiol Regul Integr Comp Physiol 293: R1452-R1458, 2007. First published June 13, 2007; doi:10.1152/ajpregu.00048.2007
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WATER AND ELECTROLYTE HOMEOSTASIS

Centrally administered vasopressin cross-sensitizes rats to amphetamine and drinking hypertonic NaCl

Shawna M. McBride and Francis W. Flynn

Graduate Neuroscience Program and Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming

Submitted 23 January 2007 ; accepted in final form 12 June 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Prior sodium restriction cross-sensitizes rats to the psychomotor effects of amphetamines and vice versa. Repeated central injections of vasopressin (VP) induce a psychomotor sensitization similar to amphetamine sensitization and repeated sodium deficiency. Thus brain VP signaling may be a common mechanism involved in mediating these two motivational systems. In experiment 1, we tested the hypothesis that rats previously sensitized to central VP would show enhanced psychomotor responses to amphetamine. Rats were administered saline, VP (50 ng), or amphetamine (1 mg/kg or 3 mg/kg) on days 1 and 2, and given saline or amphetamine on day 3. Amphetamine produced psychomotor arousal in all groups. However, amphetamine on day 3 elicited a significantly greater psychomotor response in rats that had prior injections of amphetamine or VP than in rats previously treated with saline. In experiment 2, the hypothesis that prior experience with central VP would cross-sensitize rats to drinking hypertonic sodium (NaCl) solutions was tested. Rats were administered VP (50 ng) or saline for 3 days. On the fourth day, nondeprived rats were given access to 0.3 M NaCl and water for 1 h. Control and saline-treated rats only drank 1 ml of 0.3 M NaCl, but rats previously exposed to central VP drank significantly more hypertonic saline (4 ml). These results show that prior experience with central VP cross-sensitizes rats to the psychomotor stimulant effects of amphetamine and the ingestion of concentrated NaCl solutions. This pattern of cross-sensitization links central VP signaling, amphetamine, and sodium deficiency, and therefore it may play a role in the cross-sensitization between sodium appetite and amphetamines.

behavioral sensitization; psychomotor stimulant; saline solution

BEHAVIORAL SENSITIZATION IS a long-lasting increase in the response to a stimulus with repeated exposures (6, 35, 52, 60). Sensitization occurs in response to repeated exposure to sodium deficiency, amphetamine, and repeated activation of brain vasopressin (VP) pathways. Sodium deficiency arouses the ingestion of concentrated NaCl solutions, and repeated experience with sodium deficiency sensitizes rats to drinking hypertonic NaCl. More specifically, the ingestion of hypertonic NaCl progressively increases with additional experiences with sodium deficiency and causes a sustained, increased preference for hypertonic NaCl that is observed even months after the last experience with sodium deficiency, at a time when the rats are sodium replete (6, 13, 35, 46, 52). Sensitization to amphetamine is manifested in the progressive increase in psychomotor arousal with repeated amphetamine administration, again with persistent effects observed months after treatment if amphetamine is readministered (17, 35, 52, 61). Last, central injections of VP sensitize the brain to subsequent injections of VP or activation of VP pathways, with each additional activation of the VP pathway causing more severe psychomotor responses (2, 3, 13, 63).

Cross-sensitization occurs when sensitization to one substance can potentiate responses to another substance. In a series of experiments, Bernstein and colleagues (6) showed that behavioral responses to amphetamine were enhanced by a prior history of sodium deficiency and vice versa. One system that has been implicated in both sodium and amphetamine sensitization is the mesolimbic dopamine system, which is involved in mediating motivation and reward responses (25, 29, 52, 62). In fact, sodium deficiency produces alterations in the nucleus accumbens that mimic the effects of amphetamine (44). These results suggest that in adult rats the sensitization to repeated sodium deficiency and sensitization to amphetamine may have common underlying mechanisms. Thus an animal sensitized to amphetamine is also primed to be sensitized to other substances that utilize the dopaminergic system, including sodium appetite and vice versa.

The effects of sodium deficiency on behavioral responses to amphetamine can have an early-life onset as well. Offspring of dams maintained on a low-sodium diet during pregnancy and weaning show enhanced behavioral responses to amphetamine when tested months later as adults (32). Thus early-life experience with sodium restriction produces long-lasting changes in brain organization that affect the neurobehavioral response to amphetamine in offspring.

The neural bases for sodium appetite have been extensively studied in the rat, and the results show that several brain neurochemical systems, including the renin-angiotensin system, are involved in the arousal of NaCl appetite. In addition, the neurohypophyseal hormones, oxytocin and VP, are associated with the control of sodium balance (14). More specifically, many treatments that arouse the ingestion of sodium solutions also stimulate the release of VP into the blood (15, 18, 22, 47, 55). In addition to a peripheral release, sodium deficiency stimulates the central release of VP, and this centrally released VP plays a role in the arousal of sodium appetite (13). These results suggest that VP is released centrally to modulate ingestive behavior stemming from sodium deficiency.

Brain VP is also linked to other forms of behavioral sensitization, including sensitization to psychomotor stimulants. Injections of cocaine activate VP signaling and result in a subsequent reduction in VP concentrations in multiple brain areas, including the septum, nucleus accumbens, and hippocampus, without affecting plasma levels of VP (48).

Because central injections of VP lead to sensitization and because brain VP is released in response to sodium deficiency and in response to psychomotor stimulants, one possible underlying mechanism linking cross-sensitization between sodium appetite and amphetamine is brain VP. We therefore hypothesized that if brain VP plays an underlying role in the behavioral sensitization observed following repeated sodium deficiencies and repeated amphetamine administration and in the cross-sensitization of sodium deficiency and amphetamine, then: 1) intraventricular injections of VP should enhance the behavioral response to amphetamine and 2) repeated central injections of VP should produce an enhancement of sodium intake, similar to that observed following repeated experiences with sodium deficiency.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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Subjects

Male rats were bred at the University of Wyoming (Charles River strain, 300–450 g, ~6 mo old) and were housed in individual, suspended, steel-mesh cages in a temperature-controlled colony room with a 12:12 h light:dark cycle. All rats were given ad libitum access to Purina rat chow and tap water except when indicated. This study was approved by the University of Wyoming Animal Care and Use Committee and complied with federal regulations.

Surgery

Rats were anesthetized with a mixture of ketamine HCl and acepromazine maleate (0.07 ml/100 g ip) and were secured in a stereotaxic device by using blunt earbars. The skull was exposed and leveled. A midline incision was made, and a hole was drilled through the skull at 0.9 mm posterior to the bregma and 1.8 mm lateral to the midline. The dura was cut, and a sterilized, stainless-steel guide cannula (26 gauge; Plastics One, Roanoke, VA) was lowered 4.5 mm from the dura. The guide cannula was anchored to four jewelry screws in the skull by using dental acrylic. The cannula was then sealed with an obturator. Following surgery, antibiotic ointment was applied to the surgical area and rats were allowed to recover for a minimum of 3 days. During recovery, rats had ad libitum access to Purina chow and tap water.

Intraventricular injections of angiotensin II reliably stimulate water intake, and an angiotensin II drinking test was used to determine the placement and patency of the cannula. Food was removed from the rat's cages. Rats were removed from the home cage, administered an intraventricular injection of angiotensin II (50 µg/3 µl; Sigma, St. Louis, MO), and returned to the cage. Water intake was measured for 20 min, and rats were determined to have correct placement of a patent cannula if they drank >5.0 ml of water following the angiotensin II injection (13, 14). The experiments began 1–2 wk later.

Experiment 1: Cross-Sensitization of Brain VP and Amphetamine

Rats were administered a total of three injections on three successive days. Injections were administered at the same time each day. Unless indicated (treatment groups 8, 9, and 10), the first two injections (isotonic saline or 50 ng VP) were administered into the lateral ventricle and the third injection was administered intraperitoneally [saline or D-amphetamine sulfate (1 mg/kg or 3 mg/kg; Sigma, St. Louis, MO)]. Rats were randomly assigned to 1 of 10 treatment groups (n = 5 per group): 1) control (no treatment), 2) saline-saline-saline (S-S-S), 3) saline-saline-1 mg/kg amphetamine (S-S-A1), 4) saline-saline-3 mg/kg amphetamine (S-S-A3), 5) VP-VP-saline (VP-VP-S), 6) VP-VP-1 mg/kg amphetamine (VP-VP-A1), 7) VP-VP-3 mg/kg amphetamine (VP-VP-A3), 8) VP-VP-VP (VP-VP-VP; all injections icv), 9) 1 mg/kg amphetamine-amphetamine-amphetamine (A1-A1-A1; all injections ip), and 10) 3 mg/kg amphetamine-amphetamine-amphetamine (A3-A3-A3; all injections ip).

Rats were removed from home cages and were placed in clear plastic chambers (23 cm x 24 cm x 22 cm). After rats were acclimated to the testing chambers, baseline measurements were taken for 10 min before treatment. Rats were then removed from the chamber, administered their assigned injection, and returned to the testing chamber for 30 min. An experimenter scored each rat's behavior at baseline (10 min) and following injections (30 min). Behaviors were scored every 1 min as 1) normal behavior: resting, drinking, eating, and exploration or 2) abnormal behavior. Abnormal behaviors associated with central VP injections included severe motor disturbances [convulsions, barrel rotations (rotation along the long axis of the body)], sprawled-out posture with hind-limb extension and motor difficulty, and excessive scratching (13, 27, 63). Abnormal behaviors associated with amphetamine administration included excessive locomotion and motor stereotypy (61). The frequency of normal and abnormal behaviors was then tabulated and expressed as a percentage of the total behavior (13). This was repeated on 3 days. The percent of abnormal behavior was analyzed by using one-way ANOVAs. Significant main effects were further analyzed by using post hoc least significant difference tests.

The 50-ng dose of VP was chosen because it is known to elicit mild behavioral abnormalities in rats and leads to a progressive increase in abnormal behaviors with repeated treatments, indicating sensitization (13). The two doses of amphetamine used were chosen because they are consistent with those typically used to show psychomotor effects of amphetamine and cross-sensitization to NaCl in adult rats (6, 61).

Experiment 2: Cross-Sensitization of Brain VP and Sodium Ingestion

Brain VP signaling is linked to both sodium appetite (13, 14) and motor sensitization (2, 3). It was of interest to determine if repeated injections of VP would also sensitize rats to drinking hypertonic NaCl. Rats used in experiment 1 served as subjects for experiment 2. Fluid-intake testing was conducted 24 h after the last intraventricular injection in rats from three treatment groups (n = 4 per group): 1) control, 2) S-S-S, and 3) VP-VP-VP. As described above, rats were administered a total of three intraventricular injections on successive days with injections administered at the same time each day. Testing was done 24 h after the last intraventricular injection, because central injections of VP elicit motor disturbances that might have interfered with drinking. Rats were given a 1-h fluid-intake test to examine differences in sodium and water ingestion (14). Two calibrated glass bottles, one containing deionized water (dH2O) and one containing 0.3 M NaCl, were attached to the front of each cage and were placed on opposite sides to prevent mixing of solutions, and food was removed. After 1 h, intake was measured to the nearest milliliter. Intake of water and NaCl were compared by using separate, one-way ANOVAs with post hoc least significant difference tests. For all results, data were expressed as means ± SE, and data were analyzed by using SPSS software, with a P value <0.05 considered significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Experiment 1: Cross-Sensitization of Brain VP and Amphetamine

Sensitization to repeated injections of VP and amphetamine. Figure 1, top shows the progressive daily increase in abnormal behavior in VP-VP-VP rats. Central VP administration on day 1 elicited little abnormal behavior. However, abnormal behavior progressively increased with each successive VP treatment. Rats administered intraventricular VP injections showed a sensitization to VP, as shown by an increase in abnormal behavior over the 3-day period. The amount of abnormal behavior significantly increased with each successive injection of VP [F(2,41) = 17.9, P < 0.001; day 1 compared with day 2, P < 0.001; day 2 compared with day 3, P < 0.005; and day 3 compared with day 1, P < 0.001]. Abnormal behavior associated with the VP injections included severe motor disturbances such as convulsions or barrel rotations, sprawled-out posture with hind-limb extension and motor difficulty, and excessive scratching, which increased in severity and duration with multiple injections.


Figure 1
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  		Fig. 1. Sensitization to daily injections of vasopressin (top), 1 mg/kg amphetamine (middle), and 3 mg/kg amphetamine (bottom). Percent of abnormal behavior (mean ± SE) significantly increased across days 1–3 (*P < 0.05; **P < 0.005; #P < 0.001).

 
Like the increase in abnormal behavior seen following VP injections, repeated daily injections of 1 mg/kg amphetamine (A1-A1-A1) also led to a progressive and significant increase in abnormal behavior (Fig. 1, middle). The first injection of 1 mg/kg amphetamine elicited the least amount of abnormal behavior, and the occurrence of abnormal behavior increased with each successive daily injection [F(2,14) = 56.6, P < 0.001; day 1 compared with day 2, P < 0.001; day 2 compared with day 3, P < 0.003; and day 3 compared with day 1, P < 0.001].

The higher dose of the amphetamine, 3 mg/kg (A3-A3-A3), resulted in a similar pattern of abnormal behavior (Fig. 1, bottom). The frequency of abnormal behaviors increased significantly from day 1 to day 3 [F(2,14) = 8.9, P < 0.004; day 1 compared with day 2, P < 0.05; day 2 compared with day 3, P < 0.05; and day 3 compared with day 1, P < 0.001]. Abnormal behaviors observed after amphetamine treatment included excessive locomotion and motor stereotypy.

Cross-sensitization between brain VP and amphetamine. Figure 2 shows the percent of abnormal behavior on the third test day. No abnormal behavior was observed in control rats or in rats administered isotonic saline on day 3 after having received two daily injections of isotonic saline or VP. VP elicits abnormal behavior (Fig. 1), but the observation that saline-treated rats show no abnormal behavior after two prior VP injections indicates that abnormal behavior was not being conditioned to the injection routine.


Figure 2
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  		Fig. 2. Percent of abnormal behavior (mean ± SE) on day 3. Left: groups treated with saline or 1 mg/kg amphetamine injection on day 3. Right: percent of abnormal behavior displayed by rats treated with saline or 3 mg/kg amphetamine on day 3. S, saline; VP, vasopressin; A1, 1 mg/kg amphetamine; A3, 3 mg/kg amphetamine. aSignificantly greater than control, S-S-S, and VP-VP-S groups, P < 0.001; bSignificantly greater than S-S-A1 or S-S-A3, P < 0.001; cA1-A1-A1 was significantly greater than VP-VP-A1, P < 0.01; NS, no significant difference.

 
The comparison that provides evidence for cross-sensitization is between rats that received saline injections prior to an amphetamine injection (S-S-A1) and rats that received VP injections prior to an amphetamine injection (VP-VP-A1). VP-VP-A1 rats showed significantly greater abnormal behavior than S-S-A1 rats (P < 0.001). In fact, rats given saline before an amphetamine injection showed the same amount of abnormal behavior as day 1 naïve rats treated with amphetamine (A1-A1-A1-day1; Fig. 1). A prior history with either VP or 1 mg/kg amphetamine potentiated the psychomotor response to amphetamine on day 3. Amphetamine on day 3 elicited significantly more abnormal behavior if the rats had two prior injections of VP or amphetamine than if saline was administered on the two prior days (P <0.001). The third injection of A1 elicited more abnormal behaviors in rats with a history of 1 mg/kg amphetamine injection than in rats with the history of VP injection (P < 0.01). Thus a prior history with central injections of VP sensitized rats to 1 mg/kg amphetamine but was less effective than 1 mg/kg amphetamine.

The same pattern of results was obtained in rats treated with 3 mg/kg amphetamine (Fig. 2). The ANOVA revealed significant differences in abnormal behavior on day 3 between groups [F(5,24) = 494, P < 0.0001]. On day 3, rats in the control, S-S-S, or VP-VP-S groups displayed no abnormal behavior following the treatment. Rats that were administered their initial dose of 3 mg/kg amphetamine on day 3 (S-S-A3) exhibited significantly more abnormal behavior than rats in the control, S-S-S, and VP-VP-S groups (P < 0.001). However, the S-S-A3 group had less abnormal behavior compared with rats treated previously with VP or amphetamine (P < 0.001). A3-A3-A3 rats displayed significantly more abnormal behavior than S-S-A3 rats (P < 0.001). Similarly, two prior injections of VP produced the same sensitization to 3 mg/kg amphetamine as did two prior injections of 3 mg/kg amphetamine. VP-VP-A3 rats displayed significantly more abnormal behavior than did S-S-A3 rats (P < 0.001). Furthermore, because there were no significant differences in the occurrence of abnormal behavior in rats administered amphetamine on day 3 after two prior injections of VP (VP-VP-A3) or amphetamine (A3-A3-A3; P = 0.1), prior injections of VP produced the equivalent sensitization to 3 mg/kg amphetamine as did prior injections of amphetamine. As stated above, excessive locomotion and motor stereotypy were observed after amphetamine treatment, similar to other studies (61).

Experiment 2: Cross-Sensitization of Brain VP and Sodium Ingestion

Fluid intake (0.3 M NaCl and water) of rats that had a prior history with three successive days of saline or VP injections was measured on day 4. Figure 3 shows that there were no significant differences in water intake between the three groups [control, S-S-S, and VP-VP-VP; F(2,11) = 0.8, P > 0.5]. Additionally, the rats in the control and S-S-S groups consumed similar volumes of 0.3 M NaCl during the 1-h testing period. In contrast, rats administered central injections of VP for three consecutive days (VP-VP-VP) and tested on the fourth day consumed significantly more 0.3 M NaCl than rats that received either no treatment or isotonic saline injections [F(2,11) = 6.2, P > 0.02; P’s < 0.01]. Rats with the prior VP history drank an average of 4.25 ml of NaCl, ~3 ml more than control rats. Thus a prior history with central injections of VP sensitized rats to drinking hypertonic NaCl solution.


Figure 3
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  		Fig. 3. Need-free intake of deionized water and 0.3 M NaCl (in ml; means ± SE) on day 4 by rats in the no treatment (control), 3-day saline treatment (S-S-S), and 3-day VP treatment (VP-VP-VP) groups. Significantly greater than control and saline groups, *P < 0.01.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The objective of the present experiments was to examine the common involvement of brain VP signaling in mediating behavioral sensitization to amphetamine and drinking concentrated NaCl solutions. This involvement was assessed by using a behavioral, cross-sensitization procedure. Previous studies have shown that both repeated VP treatments and repeated amphetamine treatments lead to enhanced motor activity that is dose dependent, with increased doses causing increased or altered motor responses (14, 37, 38, 61). In this paper, we used the increased responsiveness to different substances on successive days as an assay for sensitization, and although there were qualitative differences between abnormal behaviors associated with VP and amphetamine treatment, both treatment regimens led to a progressive increase in the abnormal behavior observed with multiple-day treatments. In fact, behavioral sensitization to a variety of substances (nicotine, ethanol, psychomotor stimulants, sodium deficiency) is manifested in different behaviors, but the similarity between all of these is the persistent and increased behavior observed with multiple applications, suggesting that a common neural system is involved in reinforcement of behaviors (9, 12, 33, 61). Behavioral sensitization, as defined, is an enduring increase in the strength of a response to a stimulus on repeated exposures, and cross-sensitization occurs when sensitization to one substance potentiates responses to another substance (6). In other words, sensitizing an animal to one substance sensitizes the animal to another substance by affecting the same neural substrate involved in mediating the response.

Many experiments have shown that there is a cross-sensitization between similar classes of stimuli, including a cross-sensitization between psychostimulant drugs such as amphetamine and cocaine (20, 23, 34, 49, 58). However, the idea that different classes of stimuli may cross-sensitize one another is fairly new. Sodium deficiency leading to sensitization to hypertonic sodium solutions, for example, may be a previously unsuspected factor affecting amphetamine sensitization and possibly sensitization to other psychostimulant drugs.

The present experiments demonstrate that prior activation of brain VP pathways enhances behavioral responses to both amphetamine and sodium solutions. Specifically, rats that received an amphetamine injection after two prior VP injections were more responsive to amphetamines than rats with no prior history of central VP injections. As expected, successive injections of amphetamine produced a progressive increase in psychomotor arousal. The third injection of amphetamine elicited a greater response than that of a single injection. Prior injections of VP mimicked the effects of prior amphetamine injections. That is, the psychomotor arousal produced by the first injection of amphetamine in rats with the prior history of VP injections was as severe as that produced by the third injection of amphetamine. Rats that had not received a sensitizing VP regimen had significantly lower abnormal behavior compared with rats given previous VP treatments and then amphetamines. The observation that a prior history with central VP cross-sensitized rats to amphetamine suggests that central VP signaling is one, of perhaps several, neurochemical systems that underlie sensitization to psychomotor stimulants, such as amphetamine.

Brain VP is also linked to other forms of behavioral sensitization, including sensitization to cocaine. Injections of cocaine activate VP signaling and result in a subsequent reduction in VP concentrations in multiple brain areas, including the septum, nucleus accumbens, and hippocampus, without affecting plasma levels of VP (48). Furthermore, VP-deficient Brattleboro rats do not develop a sensitization to cocaine. However, VP replacement can restore behavioral sensitization to cocaine in Brattleboro rats. The authors (36) suggested that VP may play a general role in the development of behavioral sensitization.

A form of behavioral sensitization occurs following repeated experiences with sodium depletion (12, 45, 46). Repeated sodium depletions cause a progressive increase in need-induced sodium intake and long-lasting, enhanced preference for hypertonic NaCl (46). The need-free sodium appetite that develops can be considered a behavioral sensitization to drinking hypertonic NaCl. Several possible underlying mechanisms contributing to the enduring need-free NaCl ingestion in rats with a history of multiple sodium depletions have been evaluated. For example, sodium depletion in rats leads to elevated levels of renin, angiotensin II, and aldosterone, which arouse a sodium appetite; however, hormone levels return to baseline levels shortly after the acute sodium depletion (46). Additionally, the enhanced drinking of hypertonic NaCl after sodium depletions is unchanged by treatments that inhibit angiotensin-converting enzyme or by aldosterone antagonists (31). Therefore, the renin-angiotensin-aldosterone system is not involved in the behavioral sensitization to drinking hypertonic NaCl following repeated experiences with sodium deficiency (46). Analysis of brain concentrations of dopamine, its metabolites, and serotonin showed that monoaminergic systems are altered by sodium depletion. However, whereas the drinking of NaCl increased with repeated sodium depletions, monoamine concentrations within the forebrain did not (16). Hence the neurochemical systems underlying behavioral sensitization to sodium solutions remain unidentified.

Sodium deficiency activates central vasopressinergic pathways, and blockage of brain V1 receptors attenuates salt appetite (13). Additionally, repeated activation of brain VP pathways sensitizes the brain (24). The present results demonstrate that brains sensitized to VP by prior intraventricular injections of VP facilitate the drinking of hypertonic NaCl. Sodium-replete rats previously treated with central VP injections drank significantly (~3 ml) more 0.3 M NaCl compared with control animals that drank little. The rats that received VP treatment drank an average of 4 ml of hypertonic NaCl in 1 h, which is just less than what rats with a prior history of sodium deficiency drink (45). The enhanced drinking of hypertonic NaCl following repeated injections of VP is not related to any possible effects of VP signaling on the hydrational status of the rat. Intraventricular injections of VP for 5 days have no effect on urine volume, urinary sodium, or urinary potassium compared with control subjects (21). Thus both repeated central injections of VP and repeated experience with sodium deficiency facilitate the need-free ingestion of hypertonic NaCl. Hence repeated exposure to sodium deficiency and the activation of central VP pathways (13) may contribute to the behavioral sensitization to drinking hypertonic NaCl. Interestingly, prior treatment with amphetamine also augments the ingestion of hypertonic NaCl. Rats that had a prior history of amphetamine treatment that were then made sodium deficient drank more hypertonic NaCl than did sodium-deficient rats with no prior amphetamine experience (6).

More commonly, a system involving dopamine neurons in the midbrain and their projections to the nucleus accumbens and further connections with the striatum and limbic system nuclei is thought to underlie behavioral sensitization (35, 40, 41, 60). Drugs, such as amphetamine, may express their actions over neural systems that evolved for the expression and mediation of responses to physiological challenges (25). Indeed, evidence links the dopamine system and sodium appetite. First, studies show a cross-sensitization between sodium depletion and amphetamine (6). Second, sodium restriction produced changes in dendritic morphology of nucleus accumbens neurons like that found following amphetamine treatment (42–44). VP acting centrally as a neurotransmitter is poised to influence the mesolimbic dopamine system and to alter sensitivity to amphetamines and sodium. VP-immunoreactive fibers and terminals are found in the nucleus accumbens (1, 51), and a high density of VP receptor binding sites is present in the shell of the nucleus accumbens and an area between the shell and core (26, 56, 59). Also, VP stimulates dopamine release from the striatum (57). Thus brain VP may ultimately exert its actions by affecting the dopamine system, which has already been linked to behavioral sensitization (35).

The present experiments focused on the role of central VP signaling because central VP release is common to both sodium-deficient states and psychostimulant use (13, 48). Additionally, centrally released VP is poised to influence areas in the brain associated with behavioral sensitization, such as the mesolimbic dopamine system where high densities of vasopressin receptors are found (26, 56, 59). One interpretation of the present results, therefore, is that central VP pathways are an important component of behavioral sensitization to sodium and amphetamine and may underlie the cross-sensitization between these two substances. An alternative interpretation of the data could be that the stimuli used in this experiment, central VP injections and amphetamine treatment, cause a general stress response and activation of the hypothalamic-pituitary-adrenal axis. Cross-sensitization between amphetamines and stress is well known (30) and corticotropin-releasing hormone (CRH) is released in response to administration of psychostimulants (4, 5, 39). Furthermore, extrahypothalamic CRH increases dopamine neurotransmission in the nucleus accumbens and may contribute to the reinforcing effects of cocaine (19). Central injections of CRH and experimental stressors increase salt intake in several species as well (7, 8, 28, 50, 53, 54). However, VP is also released both centrally and peripherally as part of the stress response and could therefore contribute equally to these behaviors if they are the result of a stressor (10, 11). Additionally, although CRH may be involved in the phenomena of behavioral sensitization, our data show that brain VP is an important factor in activating areas of the brain associated with behavioral sensitization.

In conclusion, homeostatic challenges such as sodium deficiency and drugs of abuse interact to enhance the responsiveness of one another. The cross-sensitization between sodium appetite and amphetamines suggests that a common neural mechanism or system is involved. Our findings that the administration of exogenous VP sensitizes rats to amphetamine and drinking hypertonic sodium solutions suggests that brain VP is involved in the behavioral sensitization to both challenges. VP signaling, in turn, may be exerted through the dopamine system, a system involved in mediating motivational and reward responses. Understanding the relationship between natural challenges and drugs of abuse may help identify the neural pathways involved in the enhanced behavioral responses to these substances with multiple applications and previously unsuspected connections between such disparate motivational challenges.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institutes of Health awards RO1-DK-50586 and P20-RR-15640 to F. W. Flynn.


   ACKNOWLEDGMENTS
 
We thank Gwendolen Haley, Devin Adams, and Don Pratt for technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: F. W. Flynn, Neuroscience Program, Dept, 3166, 1000 E. Univ. Ave., Laramie, WY 82071 (e-mail: flynn{at}uwyo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 METHODS
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 DISCUSSION
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 REFERENCES
 

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