Louk J. M. J. Vanderschuren

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization : a critical review of preclinical studies

Abstractu2002Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and µ-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. Conclusions: The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

Drug‐induced reinstatement of heroin‐ and cocaine‐seeking behaviour following long‐term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug‐seeking behaviour following long‐term extinction of intravenous (i.v.) drug self‐administration (an animal model for craving) and long‐term behavioural sensitization. Rats were allowed to self‐administer heroin (50 μg/kg per inj., 14 daily sessions), cocaine (500 μg/kg per inj., 10 daily sessions) or saline. Following a 3‐week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on non‐reinforced drug‐seeking behaviour. In addition, the occurrence of long‐term behavioural sensitization in rats with a history of heroin or cocaine self‐administration was determined. Heroin‐seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self‐administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine‐seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self‐administration. In other words, the induction of drug‐seeking behaviour following a prolonged drug‐free period was found to be associated with the expression of long‐term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug‐seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug‐induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.

A Single Exposure to Amphetamine Is Sufficient to Induce Long-Term Behavioral, Neuroendocrine, and Neurochemical Sensitization in Rats

Repeated treatment with psychostimulant drugs causes long-lasting behavioral sensitization and associated neuroadaptations. Although sensitization induced by a single psychostimulant exposure has also been reported, information on the behavioral and neurochemical consequences of a single psychostimulant exposure is sparse. Therefore, to evaluate whether behavioral sensitization evoked by single and repeated psychostimulant pretreatment regimens represent the same neurobiological phenomenon, the time-dependent expression of behavioral, neurochemical, and neuroendocrine sensitization after a single exposure to amphetamine was investigated in rats. A single exposure to amphetamine (5 mg/kg, i.p.) caused context-independent sensitization of the locomotor effects of amphetamine, which intensified over time. Thus, sensitization to amphetamine was marginal at 3 d after treatment and more evident after 1 week, whereas 3 weeks after treatment, profound sensitization, as well as cross-sensitization, to cocaine was observed. Amphetamine pretreatment caused an increase in the electrically evoked release of [3H]dopamine from nucleus accumbens, caudate putamen, and medial prefrontal cortex slices and of [14C]acetylcholine from accumbens and caudate slices. The hyperreactivity of dopaminergic nerve terminals appeared to parallel the development of locomotor sensitization, i.e., whereas hyperreactivity of accumbens dopaminergic terminals increased between 3 d and 3 weeks after treatment, the hyperreactivity of medial prefrontal dopaminergic terminals decreased. Pre-exposure to amphetamine also sensitized the hypothalamus–pituitary–adrenal axis response to amphetamine at 1 and 3 weeks, but not at 3 d after treatment. Because these data closely resemble those reported previously for repeated amphetamine pretreatment, it is concluded that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical, and neuroendocrine sensitization in rats.

Critical Involvement of Dopaminergic Neurotransmission in Impulsive Decision Making.

BACKGROUNDnImpulsive decision making, apparent as intolerance for reinforcement delay, is prominent in attention-deficit/hyperactivity disorder. Commonly prescribed for this condition, amphetamine (Adderall), reduces impulsive decision making; however, the neuropharmacologic mechanism of this effect of amphetamine is unclear.nnnMETHODSnWe investigated the involvement of dopaminergic and noradrenergic neurotransmission in impulsive decision making in rats, using a delayed reward task.nnnRESULTSnAmphetamine and methylphenidate decreased impulsive decision making, which was mimicked by the selective dopamine reuptake inhibitor GBR 12909 but not by the noradrenaline reuptake inhibitor desipramine. Impulsive choice was increased by the dopamine D1 receptor antagonist SCH-23390 but not the dopamine D2 receptor antagonist eticlopride. The effect of amphetamine on impulsive choice was attenuated by pretreatment with eticlopride, whereas amphetamine retained its effect on impulsivity in the presence of SCH-23390. The alpha2 adrenoceptor agonist clonidine increased impulsivity, but the alpha1 adrenoceptor agonist phenylephrine did not affect impulsive decision making.nnnCONCLUSIONSnThese data demonstrate an important role for dopaminergic neurotransmission in impulsive decision making, whereby tolerance to delay of reinforcement depends on dopamine D1 receptor activation. Activation of dopamine D2 receptors appears to mediate the beneficial effects of amphetamine on impulsive behavior. Noradrenergic neurotransmission may play a minor role in impulsive choice.

Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration

Abstractu2002n Rationale: The neurobiological mechanisms underlying the persistence of drug craving in detoxified addicts are still poorly understood. Objective: The present study was designed to evaluate dopaminergic mechanisms in drug-seeking behaviour following long-term (>3 weeks) extinction of IV drug self-administration in rats. Methods: To that end, we studied the effects of direct and indirect dopamine (DA) agonists on reinstatement of previously extinguished responding for heroin (50 μg/kg per injection; 14–15 daily 3-h sessions) and cocaine (500 μg/kg per injection; 10–11 daily 2-h sessions). Results: In animals with a cocaine history, priming with cocaine, the selective DA reuptake inhibitor GBR-12909 and the DA D2 receptor agonist quinpirole resulted in robust and selective reinstatement of non-reinforced nose poking behaviour in the previously drug-paired hole. In contrast, the D1 agonist SKF-82958 failed to reinstate responding and the non-selective DA agonist apomorphine even suppressed responding in these animals. In heroin-trained rats, heroin and GBR-12909 strongly reinstated responding, whereas all direct DA agonists were ineffective. Again, the two highest doses of apomorphine decreased responding in these animals. In a parallel study, the ability of DA ligands to express behavioural sensitization in animals pretreated with amphetamine or morphine was evaluated. Interestingly, all agonists that reinstated responding in the present study caused expression of locomotor sensitization and vice versa. Conclusions: The differences between direct and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour long after detoxification. Moreover, the results show an important role of D2 receptor activation in the persistence of cocaine- but not heroin-seeking behaviour. Finally, the results from both studies suggest a relationship between drug-induced reinstatement and drug hyperresponsiveness in long-term abstinent rats.

Relapse to Cocaine- and Heroin-Seeking Behavior Mediated by Dopamine D2 Receptors Is Time-Dependent and Associated with Behavioral Sensitization ☆

The sensitizing properties of drugs of abuse have been proposed to play an important role in the persistence of drug seeking behavior. We decided to evaluate the temporal relationship of dopamine D2 receptor-mediated drug seeking behavior and behavioral sensitization in animals with a history of cocaine and heroin self-administration. During early phases of withdrawal (<1 week), activation of dopamine D2 receptors with quinpirole resulted in robust, dose-dependent, reinstatement of (non-reinforced) responding in both cocaine- and heroin-trained rats. Cocaine and heroin seeking induced by quinpirole was associated with a dramatic enhancement of the psychomotor stimulant effects of the D2 agonist, indicating that sensitization to D2-mediated events had developed. During the late phase of withdrawal (>3 weeks), reinstatement of cocaine seeking by quinpirole was still apparent, but less robust. In heroin-trained rats, increases of responding were no longer observed. Interestingly, behavioral sensitization to quinpirole was still observed in cocaine-trained rats, but was absent in heroin-trained rats. Thus, it appears that dopamine D2 receptors have a time-dependent role in relapse to cocaine and heroin seeking which is strongly associated with a behaviorally sensitized state.

Psychostimulant-Induced Behavioral Sensitization Depends on Nicotinic Receptor Activation

Animal studies have shown that nicotine and psychostimulant drugs (amphetamine and cocaine) share the property of inducing long-lasting behavioral and neurochemical sensitization, which is thought to contribute to their addictive properties. Neuroplasticity subserving learning and memory mechanisms is considered to be involved in psychostimulant-induced sensitization and addiction behavior. Because nicotinic receptors in the brain play a role in the storage of drug-related information underlying reinforcement learning, we evaluated the possibility that activation of central nicotinic receptors may underlie psychostimulant-induced sensitization. Repeated exposure of rats to nicotine profoundly enhanced the psychomotor effects of nicotine and amphetamine 3 weeks after nicotine pretreatment. Moreover, the nicotinic receptor antagonist mecamylamine completely blocked the induction, but not the long-term expression, of behavioral sensitization to amphetamine in amphetamine-pretreated rats. Mecamylamine also prevented the development of cocaine-induced behavioral sensitization. Behavioral sensitization induced by nicotine, amphetamine, or cocaine was associated with an increase in the electrically evoked release of [3H]dopamine from nucleus accumbens slices. Coadministration of mecamylamine during pretreatment with nicotine, amphetamine, or cocaine prevented the development of this long-term hyperreactivity of nucleus accumbens dopamine neurons. Similarly, the high-affinity non-α7 subtype nicotinic receptor antagonist dihydro-β-erythroidine prevented the development of amphetamine-induced behavioral and neurochemical sensitization. These data indicate that nicotinic receptor activation (by endogenously released acetylcholine) is a common denominator initiating neuroplasticity involved in the development of amphetamine, as well as cocaine-induced sensitization.

Ethanol, like psychostimulants and morphine, causes long-lasting hyperreactivity of dopamine and acetylcholine neurons of rat nucleus accumbens: possible role in behavioural sensitization.

Abstract Repeated treatment of rats with ethanol (1u2005g/kg, once daily for 15 days) enhanced the locomotor effect of morphine, 3 weeks post-treatment. This ethanol-induced long-term behavioural sensitization to morphine was associated with an increase in the electrically evoked release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) from nucleus accumbens slices. A similar enhanced responsiveness of accumbal dopaminergic and cholinergic neurons to depolarization was apparent 3 weeks after repeated morphine, amphetamine or cocaine administration. Prior ethanol exposure also caused a long-term enhancement of electrically evoked release of [3H]DA and [14C]ACh from slices of the caudate-putamen. Unlike the locomotor effect of morphine, that of amphetamine was not enhanced in ethanol-pretreated rats. These data indicate that ethanol administration may cause long-term behavioural sensitization associated with adaptive changes in dopaminergic and cholinergic neurons of rat nucleus accumbens and caudate-putamen. Furthermore, an enhanced reactivity of nucleus accumbens dopaminergic nerve terminals and dopamine-sensitive cholinergic neurons appears to be a common long-term neuroadaptive effect of distinct types of addictive drugs. However, since repeated ethanol exposure did not cause a long-term increase in the locomotor effect of amphetamine, these neuroadaptations may not always be sufficient to cause long-lasting behavioural (cross-)sensitization.

Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen

Abstract The development of behavioural sensitization is thought to depend on the dose and temporal pattern of drug treatment. Previous studies have shown that two distinct morphine pretreatment regimens cause different long-term neuroadaptations in rat striatum. Therefore, in the present study the ability of these pretreatment regimens to induce long-term behavioural sensitization was investigated. One pretreatment regimen, termed “chronic”, consisted of three daily injections, for 5 days, with escalating doses (10–50u2005mg/kg) of morphine, and the other, termed “intermittent”, of 14 daily injections with morphine (10u2005mg/kg). Both intermittent and chronic morphine pretreatment caused sensitization to the locomotor effects of morphine, 3 weeks post-treatment, although the former induced a far greater level of sensitization. Moreover, 3 weeks post-treatment, intermittent, but not chronic, morphine pretreatment induced cross-sensitization to the locomotor stimulant effects of amphetamine. Behavioural sensitization following intermittent morphine pretreatment was clear-cut both 1 day and 3 weeks post-treatment, while after 9 weeks, the locomotor effects of morphine were still slightly augmented. It is concluded that intermittent morphine pretreatment is far more effective in inducing long-term behavioural sensitization than chronic morphine pretreatment.

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long‐lasting sensitization. The present study was designed to evaluate whether long‐lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30u2003mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate–putamen, was assessed. In morphine‐pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate–putamen from morphine‐pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long‐lasting behavioural sensitization and associated neuroadaptations.