Sensitization to haloperidol-induced suppression of milk intake: effect of interdose interval

The purpose of this study was to determine the effect of manipulating the interdose interval (IDI) on the suppression of milk intake induced by haloperidol (HAL). Groups of rats were given chronic injections of either HAL (0.625 mg/kg) or saline at IDIs of 1, 2, 7, or 14 days. Dose-response curves were determined at the conclusion of the chronic phase. The results indicated that injections of HAL given at IDIs of 1 or 2 days produced neither tolerance nor sensitization, whereas injections given at intervals of 7 or 14 days produced sensitization. Sensitization was also observed in the control groups, perhaps as a result of the intermittent schedule of HAL injections given during the dose-response tests. Sensitization to HAL was not accompanied by changes in sensitivity to amphetamine. The results of this experiment are consistent with those of other studies in showing that the behavioral effects of neuroleptics are strongly influenced by the schedule of injections. In addition, evidence is presented that sensitization to HAL-induced hypophagia is contingent on behavioral experience under the drug.     

Effects of delaying food availability contingent on ethanol-maintained lever pressing

The effects of delaying food availability 8 s contingent on every, every second, and every fourth lever press maintained by 4, 8, and 16% (v/v) ethanol solutions were examined when food was initially available to rats on a fixed-interval 26-s schedule. The delay contingency decreased ethanol-maintained responding at all ethanol concentrations, with the degree of decrease inversely related to the intermittency of the delay schedule and to the ethanol concentration. Such decreases were not evident in the performance of yoked-control animals which received food coincidentally with experimental animals. Temporal changes in food presentation alone therefore could not account for the decreases produced by the delay contingency.     

Role of behavioral and pharmacological variables in the loss of tolerance to amphetamine hypophagia

 Tolerance to amphetamine-induced hypophagia is lost when drug injections are withdrawn for 4 weeks while milk tests are continued (Wolgin and Hughes 1996). The purpose of this study was to determine whether the loss of tolerance is a function of drug withdrawal per se. Rats made tolerant to amphetamine (2 mg/kg, IP) were assigned to one of three groups. During the next 4 weeks (phase), one group continued to receive amphetamine injections prior to daily milk tests (Before group), one group received drug injections after the milk tests (After group), and one group received injections of saline prior to the milk tests (Saline group). Dose-response tests revealed that the Before group retained tolerance, whereas the After and Saline groups lost tolerance. When retested with chronic injections of amphetamine prior to milk, the After and Saline groups reacquired tolerance more rapidly, and to a greater extent, than non-tolerant controls. These results demonstrate that the loss of tolerance is not due to drug withdrawal per se, but may be due to the unlearning of behavioral strategies previously acquired under the drug. Received: 17 September 1996 / Final version: 10 March 1997     

Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm

We have previously established that chronic cotreatments involving antimuscarinic agents and haloperidol attenuate the development of behavioral hypersensitivity without affecting dopamine receptor proliferation. The antipsychotic agent clozapine also has significant antimuscarinic activity and was coadministered with haloperidol in rats for 2 months to determine if it would similarly attenuate the development of hypersensitivity. Clozapine or chlorpromazine cotreatment, unlike thioridazine cotreatment, did not attenuate the development of haloperidol-induced behavioral hypersensitivity. Clozapine or thioridazine cotreatment also failed to prevent the development of haloperidol-induced D2 receptor proliferation, whereas chlorpromazine cotreatment enhanced D2 receptor proliferation relative to haloperidol-treated animals. Alterations in dopamine biochemistry in the striatum or nucleus accumbens could not explain this dissociation between behavioral hypersensitivity and dopamine receptor proliferation. It is therefore hypothesized that dopamine receptor proliferation is permissive for behavioral hypersensitivity and that factors in addition to alterations in dopamine function contribute to the expression of dopamine hypersensitivity states.     

Sensitization to the motor effects of contingent infusions of heroin but not of κ agonist RU 51599

It has been postulated that behavioral sensitization could reflect drug-induced changes that are central to the development of drug abuse; however, it is still unknown whether behavioral sensitization can arise during a “voluntary” and “self-controlled” consumption of drugs and consequently play a role in drug abuse. For this reason, we studied the possible sensitization of motor activity during ten consecutive intravenous self-administration (SA) sessions of one of the most largely abused opiates the μ agonist heroin [30 μg/infusion (inf)]. We also studied in similar conditions the new κ agonist RU 51599 (6.5, 20 and 100 μg/inf). Heroin and RU 51599 were compared because both drugs are self-administered by rodents, but the reinforcing properties of RU 51599 are very weak compared to those of heroin. At low ratio requirement rats developed SA of both heroin and RU 51599; however, a progressive increase in drug-induced locomotor activity over subsequent sessions was observed only for heroin but not for RU 51599. Sensitization of the motor effects of heroin developed over a period of time during which the intake of the drug was constant. In conclusion, sensitization can develop during the voluntary consumption of an addictive drug such as heroin. These results are in line with the hypothesis that sensitization could play a role in the etiology of drug abuse. Received: 27 December 1997/Final version: 8 May 1998     

Sensitization to the behavioral effects of cocaine: Modification by Pavlovian conditioning

Sensitization to the behavioral effects of cocaine was more pronounced following drug administration in the presence of cues previously associated with cocaine administration than in their absence. Furthermore, sensitization was attenuated by repeated presentations of the usual predrug cues followed only by saline, i.e., sensitization was extinguishable. These findings indicate that Pavlovian conditioning contributes to sensitization, and have implications for treatment of stimulant abuse.     

Development and reversal of sensitization to amphetamine-induced hypophagia: role of temporal,pharmacological, and behavioral variables

This study shows that sensitization can develop to amphetamine-induced hypophagia and examines the stability of this effect following subsequent pharmacological and behavioral experience. Rats given 36 injections of either amphetamine (2.5 mg/kg; Group A) or saline (Group S) at 3-day intervals developed sensitization of hypophagia, as assessed by a shift to the left in the dose-response (DR) function. Group A also displayed sensitization of stereotypy, whereas Group S showed little change except at the highest dose. Subgroups from each group were then given daily injections of amphetamine (2 mg/kg) either before or after access to milk for 4 weeks. Other subgroups were given injections of saline as a control. On a final DR determination, these control groups showed no further changes in milk intake. In contrast, groups given chronic injections of amphetamineafter milk showed a loss of sensitization (DR3=DR1), whereas groups given the drugbefore milk developed tolerance that was limited to the chronic dose. These results demonstrate that (1) sensitization of amphetamine-induced hypophagia and stereotypy can develop independently; (2) sensitization of hypophagia can be reversed, without inducing tolerance, by subsequent daily exposure to the drug; and (3) prior sensitization of hypophagia does not preclude the subsequent development of tolerance if the drug is later given in the context of feeding.     

mCPP-induced hypophagia in rats is unaffected by the profile of dietary unsaturated fatty acids

The n-3 and n-6 polyunsaturated fatty acids (PUFAs) have been shown to modify central serotonergic parameters relevant to ingestive behavior. Evidence suggests an association between the 5-HT(2C) receptor and fat intake. The present research sought to examine the role of the 5-HT(2C) receptor subtype on food intake when diets with different fatty acid compositions are consumed. The effects of 1-(3-chlorophenyl)piperazine (mCPP) on consumption of both low-fat (Experiment 1) and high-fat diets (Experiment 2) differing in their predominant PUFA profiles were compared in rats. Regardless of the PUFA profile, mCPP induced hypophagia within each experiment. Although the present results lend further support to a large body of evidence demonstrating the ability of mCPP to reduce food intake, they do not support the idea that the essential fatty acid composition of the diet can differentially modulate mCPP-induced hypophagia.     

Sensitization of apomorphine-induced stereotyped behavior in mice is context dependent

Rationale: The role of the environment in the sensitization of the stereotyped behavioral effects of apomorphine is unclear, since sensitization of this drug effect has either been difficult to demonstrate or has been shown to occur with a low but not a higher dose of apomorphine. Objectives: The present study was designed to determine whether sensitization of the stereotyped behavioral effects induced by a single dose of apomorphine is dependent on environmental context. Methods: CF-1 mice were pretreated with apomorphine or vehicle under different environmental conditions and tested for stereotyped behavior after apomorphine challenge. Animals were scored positively for stereotyped behavior if they remained stationary and exhibited repetitive head and/or fore-limb movements, and data are reported as the percentage of mice rated as positive for stereotyped behavior. Results: When mice were pretreated with 40 mg/kg apomorphine and later tested in the same environment, the dose–response curve for stereotyped behavior elicited by apomorphine was shifted threefold to the left 48 h after pretreatment, and this sensitization persisted for at least 28 days after pretreatment. Mice pretreated with apomorphine did not have higher brain levels of apomorphine after administration of the test dose of apomorphine. When the pretreatment environment was different from the test environment, mice did not exhibit sensitization to apomorphine. Conclusions: These results show that pre-exposure to a single high dose of apomorphine induces a long-lasting sensitization of apomorphine-induced stereotyped behavior that is context dependent. Since apomorphine directly activates dopamine receptors, these observations suggest that a mechanism located postsynaptic to dopamine neurons may be responsible for sensitization of stereotyped behavior. Received: 12 November 1998 / Final version: 14 April 1999     

Effect of aspirin on haloperidol-induced cataleptic behavior in mice

Haloperidol given intraperitoneally dose-dependently elicited cataleptic behavior, evaluated by high bar and four-cork tests, in mice. The haloperidol-induced cataleptic behavior was reduced dose-dependently after oral treatment with aspirin, a cyclooxygenase inhibitor. The intra-cerebroventricular administration of prostaglandin F2a produced cataleptic behavior of long duration determined by the high bar test. It is suggested that prostaglandins may participate in the induction of cataleptic behavior in part.     

Prior behavioral experience can reverse the effects of morphine

Morphine administration typically decreases responding of squirrel monkeys trained to avoid electric shock. However, the rate-decreasing effects of morphine on avoidance responding were reversed after either concurrent or prior exposure to a condition in which responding was maintained by shock presentation. These findings demonstrate that behavioral experience can play a significant role in determining the behavioral effects of drugs and that specific types of environmental conditions can completely reverse the usual effects those drugs have on behavior.     

Oral desensitisation with food is food-specific and protein-specific

The avoidance of food(s) is the main therapeutic approach to food allergy. Nevertheless, orally- or sublingually-administered food allergens have gained attention and a number of food-allergic children can tolerate gradually increasing amounts of cow's milk and hen's egg. Our purpose is to show that oral desensitisation with food is an allergen-specific therapeutic approach and for this, we describe 4 illustrative children with IgE-mediated food allergy. The first was allergic to cow's milk and hen's egg, the second to cow's milk, hen's egg and fish. Both underwent oral desensitisation to both cow's milk and hen's egg. The third child was allergic to cow's milk, hen's egg and fish and underwent oral desensitisation with cow's milk. The last child was allergic to raw but not to cooked/boiled hen's egg and underwent the oral desensitisation with hen's egg. The first 2 children reached the clinical tolerance to cow's milk after the cow's milk oral desensitisation, but reached the hen's egg tolerance only after the hen's egg oral desensitisation. Moreover, the second child did not tolerate fish after being desensitised to both cow's milk and hen's egg. The third child tolerated cow's milk, but not hen's egg and fish, at the end of the cow's milk oral desensitisation. The fourth child could tolerate the previously not tolerated raw hen's egg after the oral desensitisation with raw hen's egg. In conclusion, we indicate that oral desensitisation with food is allergen specific. The induction of the clinical tolerance to one food is not followed by the tolerance to the other food(s) that the patient is allergic to. To obtain a double or multiple food tolerance, separate desensitisation protocols, one for each food, have to be carried out. Oral desensitisation with food discriminates between raw and cooked proteins.     

Constitutive hyperdopaminergia is functionally associated with reduced behavioral lateralization.

According to the dopamine (DA) hypothesis of schizophrenia and the strong evidence for decreased cerebral lateralization in schizophrenic patients, we postulated that hyperactivity of the dopaminergic system could be associated with a reduced behavioral lateralization in mice. Mice lacking the dopamine transporter (DAT) gene were used as a genetic model of persistent hyperdopaminergia. The DAT null mutation was transferred on C57BL/6JOrl (B6) and DBA/2JOrl (D2) inbred backgrounds for more than 10 generations of backcrossing to derive three DAT strains, B6, D2, and B6xD2(F1). Adult mutant mice of the three DAT strains and their littermates were tested for paw preference using Collins' protocol. Our results demonstrated that, whatever the genetic background, persistent hyperdopaminergia directly impairs the degree of lateralization without affecting the direction. Our results support the degree of lateralization as a good candidate phenotype to further improve genetic analysis of cerebral lateralization in normal and pathological conditions.     

The effect of two behavioral techniques and social context on food consumption.

To test the effect of two behavioral techniques on food consumption, normal weight students ate an evening snack under three conditions: removing serving dishes from the eating area, putting food down between bites, and control. Students ate either alone, with a stranger, or with a friend. Both behavioral techniques reduced the total number of items eaten relative to the control. However, they did not significantly affect total calories consumed. Although the social condition of eating did not differentially affect consumption, there was a high correlation between partners of all types on both calories and items consumed.     

Effects of naltrexone on food preference and concurrent behavioral responses in food-deprived rats

Naltrexone (0.05-5.0 mg/kg, SC) was administered to food-deprived rats prior to a 15-min food-preference test. Total food intake and feeding duration was reduced following administration of the opiate antagonist. However, while naltrexone reduced the consumption of the initially-preferred chocolate-coated cookies, the ingestion of the nonpreferred standard laboratory chow pellets was significantly enhanced. These data cannot be explained in terms of a general anorexic effect and nonspecific suppression of feeding responses. Instead, they indicate that naltrexone reduced preference for the highly palatable cookies, so that a feeding response to the chow pellets emerged. Under the conditions of test-familiarity, naltrexone did not reduce grooming, locomotion or rearing duration. An increase in locomotion may have been secondary to the reduction in feeding. The results agree with previous data from animal and human studies in suggesting that endogenous opioid peptide activity is involved in the palatability of preferred foods.     

Effects of chlordiazepoxide,food familiarization,and prior shock experience on food choice in rats

Chlordiazepoxide (5, 10 mg/kg) increased the time devoted to eating familiar laboratory chow without altering the response to a range of novel, palatable foods which were also available to the food-deprived rats. Prior experience with the same range of alternative foods (food familiarization) radically changed the effect of the drug. After familiarization with these foods, chow was virtually ignored as a food choice, indicating its low relative palatability; chlordiazepoxide then prolonged the time eating the familiarized foods without significantly increasing the response to chow. These results are not consistent with an anti-food neophobia action of chlordiazepoxide. They suggest instead that chlordiazepoxide enhances feeding responses related to food saliency. Footshock, delivered two days before the food choice test affected performance within the test. Its effects were opposite those of chlordiazepoxide, but they competed additively with the drug's effects. These results indicate that chlordiazepoxide's action was not simply to remove any inhibitory effect on feeding produced by fear; instead the drug promoted approach to food antagonizing any deficit in approach associated with fear. These findings are viewed as consistent with an action of chlordiazepoxide to augment the level of feeding motivation. Chlordiazepoxide (15 mg/kg) may act to overcome food neophobia.