Susceptibility to amphetamine-induced place preference is predicted by locomotor response to novelty and amphetamine in the mouse

Rationale It has been demonstrated that major differences between mice of the C57BL/6J and DBA/2J inbred strains for amphetamine-induced place conditioning (preference and avoidance, respectively) are evident in standard housing conditions but abolished by temporary restricted feeding. This gene-experience model may be usefully exploited to dissect behavioral phenotypes related to place conditioning induced by addictive drugs.Objectives This study evaluated a number of behavioral phenotypes related to amphetamine-induced place preference for strain differences (C57BL/6J vs DBA/2J) susceptible to be abolished by temporary food restriction.Methods Mice of the two inbred strains were tested for: (1) conditioned taste aversion and place preference induced by amphetamine within the same dose-range; (2) preference for a novel compartment 24 h after a single exposure to only one of two compartments; (3) amphetamine-induced behavioral sensitization and conditioned hyperactivity; and (4) locomotor activity during exploration of a novel environment.Results The two strains showed consistent taste aversion at doses of amphetamine that promoted opposite strain-dependent place conditioning. Both strains spent more time exploring the novel rather than the known compartment of the place conditioning apparatus. Instead, only mice of the C57 strain showed amphetamine-induced behavioral sensitization and conditioned hyperactivity. However, temporary food restriction did not affect strain differences for these phenotypes. Finally, C57 mice were more active than DBA in a novel environment and restricted feeding abolished this strain-dependent difference.Conclusions These results relate individual differences for amphetamine-induced place conditioning with locomotor response to amphetamine and novelty.     

Haloperidol-induced catalepsy is modulated by the development of tolerance to amphetamine-induced anorexia

The effect of the development of tolerance to amphetamine-anorexia on both amphetamine-induced and haloperidol-induced motor effects was investigated. The animals in experiment 1 showed an acute anorexic reaction to 3 mg/kg amphetamine, whereas the rats in experiment 2 failed to meet the criterion level of acute anorexia. During initial training rats received 13 injections of saline or 3 mg/kg amphetamine intraperitoneally (i.p.) every other day. In both experiments, for one group each amphetamine injection was followed 20 min later by 30 min access to milk (CONT groups). In a second group, each amphetamine injection was followed 24 h later by 30 min access to milk (NONCON groups) and a third group received only saline injections and milk (controls). As expected, in experiment 1 originally anorexic animals in the CONT group developed tolerance, whereas the NONCON and control groups displayed no tolerance to amphetamine-anorexia. The NONCON group showed sig nificantly more stereotypy than either the CONT or control group. Furthermore, following 1.25 mg/kg haloperidol the CONT animals were less cataleptic than the NONCON and control groups which did not differ. In experiment 2, at the end of training the rats in all groups displayed no anorexia following amphetamine injection; they consumed an amount of milk equivalent to that normally consumed under no-drug conditions. Neither was there a difference in the amount of catalepsy between groups following injection of 1.25 mg/kg haloperidol.     

Restoration of amphetamine-induced locomotor sensitization in dopamine D1 receptor-deficient mice

Rationale and objectives  

Amphetamine-induced sensitization is thought to involve dopamine D₁ receptors. Using mice lacking dopamine D₁ receptors (D₁^−/−), we found that they exhibited blunted sensitization to low doses of amphetamine, while others using different treatment and testing regimens reported inconsistent results. We investigated whether experimental variables, alteration in gene expression or cholinergic input played a role in amphetamine-induced responses.     

Environment-dependent sensitization to amphetamine-induced circling behavior

Sensitization to amphetamine-induced circling behavior in nonlesioned, female rats was studied. Experiments were designed to determine the effects of time spent in the test environment prior to and following the administration of amphetamine and of the time between injections of amphetamine on the environment-dependent nature of the sensitization process. One group of rats was allowed to habituate to the test apparatus prior to injection of the drug. In this group, the drug was administered in the apparatus and the rats remained there for the duration of drug action. Another group of rats was placed in the apparatus only during the time of peak drug action. These rats were administered amphetamine in their home cages and were not allowed time to habituate to the test apparatus. Amphetamine was administered 2 times and injections were separated by either 1 or 7 days. To determine if the sensitization was dependent on the environment in which the drug was previously experienced, one-half of each of these groups of rats were kept in their home cages following the first injection of amphetamine and experienced the effects of the second injection of amphetamine in the test apparatus. The other half experienced the effects of both injections of amphetamine in the test apparatus. Sensitization was found to occur only in rats that experienced the effects of the first drug injection in the test environment.     

Memory processes governing amphetamine-induced psychomotor sensitization.

We investigated how, under certain circumstances, the expression of psychomotor sensitization comes to be context-specific. Rats that had previously sustained 6-hydroxydopamine-induced unilateral dopamine depletion received repeated injections of d-amphetamine (AMPH) or saline in group-specific environments, and rotational behavior was measured as an index of psychomotor activation. Following these treatments some groups were given electroconvulsive shock (ECS), when memories of the drug experience were reactivated (and therefore vulnerable to disruption), in order to produce retrograde amnesia. Animals given an AMPH challenge in the environment in which they received drug treatments (Paired) expressed robust sensitization. Animals given an AMPH challenge in a context that was never paired with drug administration (Unpaired) did not express sensitization. A saline challenge in the AMPH paired context produced a conditioned rotational response (CR). ECS had no effect in Control animals, no effect on the expression of sensitization in Paired animals, and no effect on the expression of the CR in Paired animals. However, ECS did affect Unpaired groups: unlike Unpaired animals given sham ECS, Unpaired animals given ECS expressed robust sensitization. Thus, without ECS, the expression of sensitization must have been suppressed in the Unpaired animals (who had the same drug history as Paired animals), and ECS released this otherwise suppressed sensitization. Based on these and other findings, we propose that three memory mechanisms regulate context-specificity of AMPH sensitization: (1) Repeated drug administration induces sensitization of the neural substrate that mediates the unconditional response (UR) to the drug, a form of non-associative learning; (2) An inhibitory process can block the expression of neural sensitization in contexts where the drug is not expected, a process we speculate may involve a form of inhibitory occasion-setting; (3) An excitatory conditioned response (CR) can amplify the sensitized response in a context where the drug is expected. It is suggested that the ability of drug-associated contexts to modulate the expression of neural sensitization via occasion-setting may combine with the ability of a drug-associated context to produce conditioned responses, together providing powerful associative control over not only behavioral sensitization, but in addicts, over craving and relapse.     

Susceptibility to cardiac ischemia/reperfusion injury is modulated by chronic estrogen status

The purpose of this study was to test whether the susceptibility of the heart to ischemia/reperfusion injury is modulated by the chronic estrogen status, i.e., increased with estrogen deficiency and attenuated by pharmacologic estrogen supplementation. In addition, the study tested whether estrogen-dependent changes in mechanical function are associated with alterations of cardiac high-energy phosphate metabolism. Rats were ovariectomized, not ovariectomized, or ovariectomized and treated with subcutaneous estrogen pellets (1.5 mg/21 d) (n = 8-11 per group). Three weeks later, hearts were isolated and perfused isovolumically under constant perfusion pressure conditions. Hearts were subjected to 15 min of total global ischemia (37 degrees C) and 30 min of reperfusion. Simultaneous [31P] nuclear magnetic resonance spectra were recorded throughout this protocol to monitor changes in ATP, phosphocreatine, and inorganic phosphate content. Whereas preischemic values for heart rate, end-diastolic pressure, and coronary flow were not different among groups, left ventricular developed pressure was slightly but significantly decreased in the estrogen-treated group (p < 0.05). However, treated hearts showed improved recovery of left ventricular developed pressure on reperfusion (89 +/- 4% in control rats, 70 +/- 8% in ovariectomized hearts, and 114 +/- 9% of preischemic values in estrogen-treated rats). However, changes in ATP, phosphocreatine, and inorganic phosphate during ischemia were as previously described and were unaffected by chronic estrogen status. In conclusion, in the isolated buffer-perfused rat heart, estradiol treatment caused improved functional recovery after ischemia/reperfusion injury. This improvement, however, did not include preservation of high-energy phosphate metabolism. Other potential mechanisms include an anti-oxidant activity of 17beta-estradiol-and estrogen-induced alterations in glucose metabolism.     

Locomotor effects of amperozide. Antagonism of amphetamine-induced locomotor stimulation

Amperozide given subcutaneously (0.25 mg/kg) depressed amphetamine-induced locomotor activity by 40%. In the absence of amphetamine (1.5 mg/kg), this dose of amperozide had no effect on locomotor activity during the 60 min test period. Amperozide (0.1-1 mg/kg) dose-dependently decreased the locomotor activity of mice as measured in motron boxes. Only doses of amperozide greater than 0.25 mg/kg resulted in statistically significant (p less than 0.05) decreases in motor activity. Pretreatment of mice with flumazenil (10 mg/kg p.o., 30 min) or bicuculline (2 mg/kg i.p., 10 min) had no effect on amperozide (1 mg/kg)-induced hypomotility. These doses of the drugs had no effect per se. These results suggest that dopaminergic mechanisms might be involved in the amperozide-induced hypomotility.     

Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration

To begin to characterize the temporal profile of behavioral sensitization to the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA), rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, followed by a challenge injection of MDMA (2.5 mg/kg) either 15 or 100 days later. Because we found previously that contextual drug associations are important for the expression of behavioral sensitization to MDMA following relatively short withdrawal periods, rats received the repeated injections either in their home cages (unpaired group) or in the activity monitors that were used for testing sensitization on challenge day (paired group). Locomotor sensitization was evident at 15 days of withdrawal but only in the paired MDMA-treated group. Interestingly, however, sensitization was apparent at 100 days of withdrawal in both paired and unpaired rats but the form of sensitization differed between groups. Thus, sensitization in paired rats was expressed as an increase in stereotypy, whereas sensitization in unpaired rats was expressed as an increase in locomotion, paralleling locomotion levels in paired animals at 15 days of withdrawal. These results suggest that the neural changes that underlie behavioral sensitization to MDMA are quite enduring but involve an interaction between withdrawal time and the context of drug administration.     

Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

Introduction

Muscarinic M₅ receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M₅ receptors modulate their activity. Previous studies showed that M₅ receptor knockout (M ₅ ^?/? ) mice are less sensitive to the reinforcing properties of addictive drugs.

Materials and methods

Here, we investigate the role of M₅ receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M ₅ ^?/? mice backcrossed to the C57BL/6NTac strain.

Statistical analyses

Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M ₅ ^?/? mice, while the effects of cocaine were similar in M ₅ ^?/? and wild-type mice.

Results

Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M ₅ ^?/? mice.

Discussion

The different effects of amphetamine and cocaine in M ₅ ^?/? mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M₅ receptor. These results support the concept that the M₅ receptor modulates effects of addictive drugs.     

Nitric oxide synthase inhibition blocks amphetamine-induced locomotor activity in mice.

Effects of N(G)-nitroarginine methyl ester (L-NAME), a nonspecific inhibitor of nitric oxide (NO) synthase, on amphetamine-induced locomotor activity were investigated in Swiss-Webster mice. Locomotor activity was measured for 30 min immediately following amphetamine (1, 2 and 4 mg/kg, i.p.) or saline treatments. L-NAME (15 and 30 mg/kg) and a combination of L-arginine (1000 mg/kg) and L-NAME (30 mg/kg) were injected 30 min before amphetamine (2 mg/kg) to other groups of the mice. L-Arginine was injected 30 min before L-NAME treatment when they were combined. L-NAME (30 mg/kg) and L-arginine (1000 mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of amphetamine. Amphetamine caused a dose-dependent increase in locomotor activity of the mice. L-NAME blocked the amphetamine-induced locomotor stimulation dose dependently. L-Arginine pretreatment prevented the inhibitory effects of L-NAME on amphetamine-induced locomotor stimulation. L-NAME and L-arginine did not cause any significant change in locomotor activity in mice not treated with amphetamine. These results suggest that amphetamine-induced locomotor stimulation in mice is modulated by NO.     

Limitations to the generality of cocaine locomotor sensitization

Repeated exposure to cocaine often leads to tolerance to effects on operant behavior, whereas sensitization often develops to effects on locomotor activity. The purpose of the present set of experiments was to examine if locomotor sensitization to cocaine would develop in the presence or absence of an operant contingency in rats. In Experiment 1, rats lever pressed on an FR schedule of reinforcement, and were administered chronic cocaine. Tolerance to effects of cocaine on lever pressing developed in most subjects. No subjects developed locomotor sensitization even when the operant contingency was removed. Experiment 2 examined effects of chronic cocaine administration in rats with no exposure to an operant contingency. Tolerance developed to locomotor effects of cocaine in some subjects, but none developed sensitization. In Experiment 3, rats were exposed to a shorter drug regimen, and given time off before a sensitization-test session. Some, but not all subjects showed locomotor sensitization during the test session. The present results, therefore, show that locomotor sensitization to cocaine is not an inevitable consequence of repeated exposure to the drug.     

Characteristics of "reverse tolerance" to amphetamine-induced locomotor stimulation in mice

The characteristics of chronically administered amphetamine on the locomotor and anticonvulsant effects were studied in adult CF-1 mice. The influence of dose of the drug and interdose interval on the development of "reverse tolerance" to the locomotor stimulation was investigated, in addition to the selectivity of the response and the persistence of the change in pharmacodynamics. Once-daily treatment with 6 mg/kg amphetamine for 4 weeks resulted in a 2-3 fold increase in locomotor activity. The increase in responsiveness, however, was limited to the first period of 2 weeks and there was no subsequent change in pharmacodynamics during the last 2 weeks of treatment. After 36 days of withdrawal, the response had not returned to that of control, illustrating the persistence of the effect. The results of varying the interdose interval indicated that "reverse tolerance" occurred even when the interval was as long as 14 days. These results represent additional evidence of the persistence of the phenomenon. Selectivity of the changes in the CNS was illustrated by the cross-reactivity with a motor-stimulant dose of cocaine but not with that of morphine. Selectivity was also demonstrated by the failure of "reverse tolerance" to develop to the anticonvulsant effects of amphetamine, which also appear to be mediated dopaminergically.     

Meal schedule influences food restriction-induced locomotor sensitization to methamphetamine

Rationale  

Traditional protocols for inducing sensitization to psychostimulants use an intermittent or “binge”-like drug administration, and binge eating behavior is comorbid with drug abuse in humans. Food restriction increases the reinforcing properties and self-administration of many drugs of abuse.     

Environmental modulation of both locomotor response and locomotor sensitization to the dopamine agonist quinpirole

The study tested whether differences in locomotor activation during chronic treatment result in differential behavioral sensitization induced by the D2/D3 dopamine agonist quinpirole. One group of rats received repeated injections of quinpirole in their home cage and another group received this treatment in an alternate environment of similar size. In the home cage, quinpirole induced less locomotion than in the non-home environment. When tested in activity monitors at the end of chronic treatment, the home cage group showed less sensitized locomotion to quinpirole than the non-home cage rats. Thus, the extent of locomotor sensitization to quinpirole appears to be related to the amount of locomotion characteristic of the training environment. Such differential sensitization may reflect a modulation of the hierarchy of expression of quinpirole-enhanced hyperactivity via a non-associative process.     

Drug interactions on spontaneous locomotor activity in rats. Neuroleptics and amphetamine-induced hyperactivity

The locomotor activity of female rats was recorded during 10-min sessions in a circular open-field apparatus after the administration of vehicle or drug. Dose-response curves were obtained for seven neuroleptic drugs both alone (spontaneous activity) and in combination with 1.0 mg/kg of d-amphetamine. Haloperidol, pimozide, loxapine, thiothixene, molindone and chlorpromazine all produced graded decreases in spontaneous locomotor activity. Haloperidol, pimozide, loxapine, thiothixene and molindone also produced graded reversals of the hyperactivity produced by d-amphetamine, while chlorpromazine did not. Clozapine neither altered spontaneous activity nor reversed the hyperactivity produced by d-amphetamine. The data indicate that measures of locomotor activity provide important additional information about the actions of neuroleptics and do not necessarily mirror the actions of these drugs on other measures of performance such as lever-pressing for brain stimulation.     

The expression of locomotor sensitization to apomorphine is dependent on time interval between injection and testing

This study examined the onset of locomotor sensitization induced by apomorphine as a function of the temporal delay between drug injection and testing. In experiment 1, rats received three daily administrations of 2.0 mg/kg apomorphine or vehicle either immediately (0 min) or 20 min before being placed into the test environment for 20 min test sessions. Apomorphine given immediately before testing induced a stimulant effect during the first session and sensitization by the second session. However, when testing was delayed 20 min, apomorphine induced stimulant effects only after the third injection. In experiment 2, separate groups received a single 2.0 (mg/kg) apomorphine/vehicle injection immediately before being placed into the test environment for 60 min. In this experiment, apomorphine induced a stimulant effect at 0-20 and 20-40 min. However, the 20-40 interval increase in locomotion was relative to the low level of activity in the vehicle group and was not greater than the 0-20 min locomotion of the vehicle group. Thus, sensitization depends both on peak drug concentration and habituation state of the control group. The variable post-injection delays could be a useful method to study sensitization because it can avoid ceiling effects and changing baselines in the control groups.     

Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization.

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A(2A) receptors in psychostimulant-induced locomotor sensitization using an A(2A) receptor knockout (A(2A) KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A(2A) KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D(1) agonist SKF81297 (2.5 mg/kg) or the D(2) agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A(2A) KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A(2A) KO and WT mice, suggesting normal D(1) and D(2) receptor responsiveness. Finally, at the cellular level A(2A) receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A(2A) KO mice suggests a critical role of the A(2A) receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A(2A) adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure.     

Medial septal lesions in rats enhance locomotor sensitization to amphetamine

Rationale: The mesolimbic dopamine (DA) system appears to play a major role in the locomotor activating and sensitizing effects of several addictive drugs. However, less is known about the neural structures that may modulate this system. Objective: We examined the effects of medial septal lesions on the locomotor activating and sensitizing effects of amphetamine in between-subjects (experiment 1) and within-subjects (experiment 2) experiments. Results: Repeated injections of 0.6 mg/kg (experiment 1) or 1.0 mg/kg (experiment 2) amphetamine over six sessions produced more locomotion in the lesioned rats than in the sham-operated controls. This repeated exposure to amphetamine subsequently increased the locomotor response to 0.2 mg/kg (experiment 2) and 0.4 mg/kg (both experiments) amphetamine in the lesioned rats, such that these sensitized, lesioned rats moved more in response to these doses than unsensitized, lesioned rats and sensitized controls did. Both experiments also indicated that this prior sensitization enhanced the locomotor response to 0.4 mg/kg amphetamine more in the lesioned rats than in the control rats when compared with the response produced by saline following sensitization or by the same dose of amphetamine prior to sensitization. In contrast, prior exposure to amphetamine decreased the locomotor response to 4.0 mg/kg amphetamine in the lesioned rats (experiment 1). Conclusions: Although medial septal lesions occasionally enhance locomotor responses to moderate doses of amphetamine prior to sensitization, a main effect of these lesions is to further enhance the effects of locomotor sensitization to amphetamine. Implications for drug addiction are discussed. Received: 26 August 1998 / Final version: 23 April 1999