Amphetamine-induced Conditioned Place Preference Research Articles

Norepinephrine in the Prefrontal Cortex Is Critical for Amphetamine-Induced Reward and Mesoaccumbens Dopamine Release

Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Noradrenergic transmission in the medial prefrontal cortex (mpFC) has been shown to affect the motor effects of amphetamine, although there is no evidence of its involvement in the rewarding effects of this psychostimulant. The present experiments were aimed at investigating the possibility of a selective involvement of prefrontal cortical norepinephrine (NE) in the rewarding-reinforcing effects of amphetamine. To do so, we evaluated the effects of mpFC NE selective depletion in mice of C57BL/6J inbred strain, a background commonly used in molecular approaches that is known to be highly susceptible to the rewarding effects of the psychostimulant. In a first set of experiments, we demonstrated the absence of amphetamine-induced conditioned place preference in mice bearing prefrontal NE depletion. In a second series of experiments, we demonstrated that the same lesion dramatically reduced amphetamine-induced mesoaccumbens dopamine release as measured by intracerebral microdialysis. These results indicate that noradrenergic prefrontal transmission, by allowing increased dopamine release in the nucleus accumbens induced by amphetamine, is a critical factor for the rewarding-reinforcing effects of this drug.

Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning.

Diazepam in the ventral striatum dissociates dopamine-dependent and dopamine-independent place conditioning.

We have previously shown that diazepam blocks both the formation and the expression of amphetamine-induced conditioned place preference (CPP), but has no effect on the CPP induced by morphine. Because diazepam reduces dopamine activity in the nucleus accumbens, three experiments were conducted in order to investigate whether diazepam selectively blocks the expression of place conditioning dependent on mesolimbic dopamine. The first experiment found that systemic diazepam blocked the expression of conditioned place aversion induced by the kappa-receptor agonist U50-488. The second and third experiments demonstrated that intra-cranial injections of diazepam in the nucleus accumbens blocked the expression of amphetamine CPP but not of morphine CPP. It is concluded that diazepam interferes with mesolimbic dopamine-dependent motivational effects of drugs.

Effects of early handling on amphetamine-induced locomotor activation and conditioned place preference in the adult rat.

Altered hormonal stress responsiveness has been implicated in psychostimulant responsivity, and early handling represents a mild environmental manipulation which alters the hormonal profile following stress exposure. The present experiments examined whether early handling in rats would alter locomotor effects of amphetamine, as well as cross-sensitization of locomotor responsiveness after chronic stress. Conditioned place preference (CPP) for amphetamine was also measured. Handling consisted of daily 15-min isolation periods from days 1-12 postnatally. Novelty- and amphetamine (0, 1.5 mg/kg)-induced locomotion were examined using circular corridors in adult rats that were either restrained repeatedly over 8 days or not disturbed prior to testing. The effects of handling on amphetamine (0, 1, 2, 5 mg/kg) conditioned place preference (CPP) were also examined following 3 days of drug-compartment pairings. Early handling produced a more rapid post-stress recovery in corticosterone levels. Handled animals also exhibited a significant attenuation in amphetamine-induced CPP compared to non-handled controls. Locomotor responsiveness to novelty and amphetamine was not altered by early handling. Although no cross-sensitization was observed, evidence for stress sensitization was seen, but was unaffected by early handling. Handled animals showed an attenuated CPP for amphetamine, data suggesting that sensitivity to the reward value of drugs of abuse in adulthood may be susceptible to relatively minor environmental manipulations early in life. This effect of handling on CPP does not seem to reflect differences in locomotor sensitivity to amphetamine.

Individual differences in novelty-induced activity and the rewarding effects of novelty and amphetamine in rats

Previous work has shown that individual differences in locomotor behavior in an inescapable novel environment predict the locomotor-stimulant effect of amphetamine. Experiment 1 of the present study assessed if novelty-seeking behavior in a free choice situation also predicts the locomotor-stimulant effect of amphetamine. Rats were first assessed for their locomotor response to an inescapable novel environment and then were allowed to choose between this environment (familiar) and a novel environment. Activity in the inescapable novel environment was found to predict subsequent locomotor response to amphetamine, but approach to novelty in the free choice situation did not. In experiment 2, rats were assessed for their approach to novelty in the free choice situation and then assessed for amphetamine-induced conditioned place preference. It was found that rats who spent more time in a novel environment also showed a higher magnitude of amphetamine-induced conditioned place preference. These findings are consistent with the hypothesis that the rewarding properties of novelty and amphetamine may be mediated by a similar brain mechanism.

Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole

Previous studies have shown that antagonists at glutamatergic N-methyl- d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptors can disrupt the development or expression, respectively, of conditioned place preference (CPP) induced by drugs of abuse. The present study examined the effects of inhibition of presynaptic glutamate release by riluzole on the development of morphine- and amphetamine-induced CPP. Morphine (10 mg/kg), d, l-amphetamine (4 mg/kg) and riluzole (4 mg/kg) itself each produced a significant CPP; however, when riluzole was co-administered with morphine or amphetamine during the conditioning sessions, no CPP developed. It is concluded that non-specific disruption of glutamatergic neurotransmission prevents the development of morphine- and amphetamine-induced CPP.

Ascorbate potentiates amphetamine-induced conditioned place preference and forebrain dopamine release in rats.

In order to evaluate the effects of ascorbate, which is known to modulate dopamine neurotransmission, on the reinforcing effects of amphetamine, we coadministered ascorbate and amphetamine during the acquisition of conditioned place preference (CPP) in rats. Our results indicate that 100 mg/kg ascorbate potentiates the CPP induced by 0.5 mg/kg, but not 1.0 mg/kg, amphetamine. A higher dose of ascorbate (500 mg/kg) did not influence the CPP induced by either dose of amphetamine. In vitro release assays revealed that, whereas ascorbate alone (0.01-1.0 mM) did not influence striatal dopamine levels, this vitamin potentiated amphetamine-induced dopamine release in both the nucleus accumbens and neostriatum. Collectively, these results raise the possibility that ascorbate potentiates amphetamine-induced CPP by increasing the ability of this psychostimulant to release dopamine.

Isradipine suppresses amphetamine-induced conditioned place preference and locomotor stimulation in the rat

The locomotor activating and the reinforcing effects of psychomotor stimulants are considered to be correlated with and responsible for the development and maintenance of stimulant addiction. Experiments were conducted to examine the effects of isradipine, the L-type calcium channel inhibitor, on the d-amphetamine-induced (1 mg/kg IP) reinforcement (conditioned place preference) and locomotor stimulation. Isradipine dose-dependently (0.6, 1.2, 2.5 mg/kg IP) attenuated the reinforcing effect of amphetamine. Two higher doses completely blocked the induction of place preference. At these doses isradipine also prevented the increase in the number of intercompartment crosses that was observed in both amphetamine- and vehicle-treated controls. In an acute experiment, isradipine failed to affect locomotor activity on its own either in the place preference boxes or in the open field. Amphetamine increased the open field activity but did not change the number of crosses in the place preference boxes. Only the highest (2.5 mg/kg) dose of isradipine significantly suppressed amphetamine-induced hyperactivity in the open field. The present results suggest that isradipine interferes with amphetamine-derived reinforcement at doses lower than those needed to block the acute locomotor effects of amphetamine. Given the qualitatively similar, previously reported results with verapamil, we conclude that the antireinforcing effects of the L-type calcium channel blockers cannot be exclusively explained by the suppression of psychomotor stimulation. The present results further support the notion that the L-type calcium channel blockers may be effective against stimulant addiction.

Isradipine Suppresses Amphetamine-Induced Conditioned Place Preference and Locomotor Stimulation in the Rat

Isradipine Suppresses Amphetamine-Induced Conditioned Place Preference and Locomotor Stimulation in the Rat

Locomotor and rewarding effects of amphetamine in enriched, social, and isolate reared rats

This study examined the influence of environmental enrichment on the behavioral response to amphetamine. Beginning at 21 days of age, rats were raised in one of three different environmental conditions: a) an enriched condition (EC), in which animals were caged in groups and provided with novel objects daily; b) a social condition (SC), in which animals were caged in groups without any novel objects; and c0 an isolated condition (IC), in which animals were caged individually without any novel objects. At 53 days of age, animals from each environmental condition were assessed for amphetamine-induced changes in locomotor activity and reward using the conditioned place preference (CPP) paradigm. Results from saline-injected control animals indicated that EC animals exhibited less vertical activity than IC animals when exposed to the CPP apparatus. When challenged with amphetamine (0.5 or 2.0 mg/kg), there were no significant differences between SC and IC animals in either locomotor behavior or CPP. However, EC animals exhibited more horizontal and vertical activity following amphetamine than both the SC and IC animals. Similarly, EC animals exhibited a greater magnitude of amphetamine-induced CPP than both the SC and IC animals.