Michael T. Bardo

Conditioned place preference: what does it add to our preclinical understanding of drug reward?

Abstract. Rationale: Among the various experimental protocols that have been used to measure drug reward in laboratory animals, conditioned place preference (CPP) has been one of the most popular. However, a number of controversial issues have surrounded the use of this experimental protocol. Objective: The present review provides a theoretical overview of some critical issues relevant to CPP. The advantages and limitations of CPP are also covered. Results: Based on modern and traditional theoretical formulations of Pavlovian conditioning, CPP appears to reflect a preference for a context due to the contiguous association between the context and a drug stimulus. Within this theoretical framework, it seems clear that CPP measures a learning process that is fundamentally distinct from drug self-administration. The main advantages of CPP are that it: (1) tests animals in a drug-free state; (2) is sensitive to both reward and aversion; (3) allows for simultaneous determination of CPP and locomotor activity; (4) is adaptable to a variety of species; (5) typically yields dose-effect curves that are monophasic rather than biphasic; and (6) has utility in probing the neural circuits involved in drug reward. The main limitations of CPP are that it: (1) is subject to interpretation based on the notion of novelty seeking; (2) is cumbersome for providing the graded dose-effect curves needed for answering some pharmacological questions; (3) is difficult to interpret when animals prefer one context prior to drug conditioning; and (4) lacks face validity as an experimental protocol of drug reward in humans. Conclusion: Despite some limitations, CPP provides unique information about the rewarding effect of contextual cues associated with a drug stimulus.

Psychobiology of novelty seeking and drug seeking behavior.

There is considerable evidence that high novelty seekers are at increased risk for using drugs of abuse relative to low novelty seekers. This review examines the potential biological mechanism that may help explain the relationship between novelty seeking and drug seeking behavior. Evidence is summarized to suggest that exposure to novelty activates, at least in part, the same neural substrate that mediates the rewarding effects of drugs of abuse. It is argued that individual differences in response to novelty and drugs may relate to individual differences in the mesolimbic dopamine (DA) system of the brain. Individual differences in both novelty seeking and drug seeking behavior, while under some degree of genetic control, appear to be modifiable by early development experiences and this modification may relate to alterations in activity of the mesolimbic DA system. Within the context of this biological formulation, implications for the prevention and treatment of drug abuse are discussed.

Conditioned place preference using opiate and stimulant drugs: A meta-analysis

A meta-analysis was conducted on the data obtained from published articles that have used the conditioned place preference (CPP) paradigm to assess the rewarding effects of morphine, heroin, amphetamine and cocaine in rats. Using a histogram analysis of the data, significant dose-effect curves were evident with all of the drugs examined, except for cocaine. Analysis of the data also revealed that several methodological variables moderated the effect size for CPP, at least with some of the drugs examined. In particular, the following methodological variables significantly moderated CPP effect size: strain of rat used; housing condition (single or group cages); type of apparatus (2 or 3 compartments); preconditioning test (present or absent); route of drug administration; intervening saline trials (present or absent); conditioning trial duration; and drug compartment (nonpreferred, counterbalanced or white). No significant effect size differences were evident using sex, number of drug trials, or test duration as moderator variables in the analyses. These meta-analytic results may be useful to investigators for maximizing the effect size of drug-induced CPP.

Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty

To assess dopamine efflux during novelty-seeking behavior in rats, fast-scan cyclic voltammetry in the nucleus accumbens was combined with free-choice entry into a novel environment. Cyclic voltammograms, confirmed by in vitro testing, revealed that entry into novel, but not familiar, surroundings increased dopamine efflux in a regionally and temporally distinct pattern. Whereas dopamine failed to change in the core region of the accumbens and overlying neostriatum, an abrupt increase occurred in accumbal shell, a limbic-related area implicated in goal-directed behavior. Although the dopamine response was confined to the brief period of entry into novelty (approximately 8 s duration), a less rapid and more persistent dopamine change (> 20 s duration) occurred in the shell-core transition zone, the so-called shore. These results suggest that novelty mimics other positively reinforcing stimuli in enhancing dopamine transmission in the nucleus accumbens, but the regional and temporal heterogeneity of this effect may represent different aspects of accumbal dopamine function.

Transient increases in catecholaminergic activity in medial prefrontal cortex and nucleus accumbens shell during novelty

Voltammetric recordings with electrochemically modified carbon-fiber electrodes were obtained from specific regions of the forebrain in rats given free-choice access to a novel environment. Entry into novelty increased the catechol signal in the medial prefrontal cortex and shell of the nucleus accumbens by more than 100%, but had no consistent effect in either the neostriatum or accumbal core. In both the medial prefrontal cortex and accumbal shell, moreover, the novelty-induced increase in catecholaminergic activity was detectable only during the initial entry into the novel compartment and did not reappear when animals returned to the familiar environment. These results support increasing evidence for a functional distinction between the accumbal core and shell, with the latter having been linked to brain reward mechanisms. The results also indicate that novelty activates, albeit very transiently, some of the same neurochemical systems believed to play a critical role in the reinforcing effects of certain drugs of abuse.

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 c) 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.

The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release

In two separate experiments, rats were raised in either an enriched condition (EC) or impoverished condition (IC) from 21 to 60 days of age. Experiment 1 assessed amphetamine-stimulated locomotor activity and in vivo dopamine (DA) synthesis and metabolism in the nucleus accumbens (NA) and striatum (Str). In Experiment 2, amphetamine-stimulated DA release in the NA and Str was assessed in vitro. The results showed that EC rats have lower basal levels of locomotor activity than IC rats. However, in the presence of amphetamine, EC rats showed a greater increase in locomotion over IC when compared to their own controls. Concomitant with this behavioral difference, EC rats also showed an enhanced neurochemical response to amphetamine in vivo. That is, relative to IC rats, amphetamine produced a greater synthesis of DA in the Str of EC rats, as well as a greater metabolism of DA in the NA of EC rats. In the in vitro DA release experiment, EC rats had a lower concentration of tissue DA than IC. However, in contrast to the in vivo experiment, there were no significant differences between EC and IC rats in amphetamine-stimulated release of DA in vitro in either the Str or NA. The failure of amphetamine to produce differential neurochemical effects in EC and IC rats in vitro may be because this experiment eliminated either pharmacokinetic effects or neurochemical differences in brain regions outside the NA and Str.

Environmental enrichment attenuates locomotor sensitization, but not in vitro dopamine release, induced by amphetamine

Rats were raised from weanling until young adulthood in either an enriched condition (EC) or isolated condition (IC). Following this, the locomotor and rewarding effects of amphetamine were determined using the conditioned place preference (CPP) paradigm. EC rats were more sensitive to the acute locomotor stimulant effect and rewarding effect of amphetamine relative to IC rats. In contrast, EC rats were less sensitive than IC rats to the locomotor sensitization effect obtained across repeated amphetamine injections. To determine the effect of environmental enrichment on alteration of brain dopamine (DA) function induced by amphetamine, the effect of amphetamine on electrically evoked release of DA and dihydroxyphenylacetic acid (DOPAC) was determined in vitro using tissue slices from the nucleus accumbens and striatum of EC and IC rats. No differences between EC and IC rats in release of DA or DOPAC were evident, suggesting that the environmentally induced difference in sensitivity to the behavioral effects of amphetamine involves a neural mechanism extrinsic to the mesolimbic and nigrostriatal terminal field regions.

Neurobehavioral effects of environmental enrichment and drug abuse vulnerability.

Environmental enrichment during development produces a host of neurobehavioral effects in preclinical models. Early work demonstrated that enrichment enhances learning of a variety of behavioral tasks in rats and these changes are associated with neural changes in various cortical regions. In addition to promoting superior learning, more recent evidence suggests that environmental enrichment also has a protective effect in reducing drug abuse vulnerability. The current review describes some of the most important environment-dependent neural changes in reward-relevant brain structures and summarizes some of the key findings from the extensive literature showing how enrichment decreases the impact of drugs of abuse. Some critical neural mechanisms that may mediate the behavioral changes are postulated, along with some notes of caution about the limitations of the work cited.

Autoradiographic localization of dopamine D1 and D2 receptors in rat nucleus accumbens: resistance to differential rearing conditions.

The radioligands [3H]SCH 23390 and [3H]spiroperidol were used to label dopamine D1 and D2 receptors, respectively, in rat brain slices. Striatal sections were incubated in one of various concentrations of radioligand in the presence or absence of (+)-butaclamol and the resulting labeling was determined by liquid scintillation spectrometry. Scatchard analyses of the data revealed KD values of 1.18 nM for D1 receptors and 0.33 nM for D2 receptors. Tissue sections taken from the entire rostrocaudal extent of the nucleus accumbens, as well as other brain regions, were then processed for autoradiographic analysis of D1 and D2 receptors using a radioligand concentration equal to 1.5 X KD. After apposing the slices to 3H-sensitive film, topographical differences among brain areas were analysed using a quantitative densitometry system which determined the absolute amount of ligand binding relative to calibrated optical density standards. The nucleus accumbens exhibited a rostral-to-caudal density gradient for both D1 and D2 receptors. For D1 receptors, the density was similar across most of the nucleus accumbens, although the most caudal portion examined had a lower density than rostral portions. In contrast, the density of D2 receptors exhibited a more gradual gradient across the entire rostrocaudal extent of the nucleus accumbens. There was no significant rostrocaudal density gradient of either D1 or D2 receptors in either the olfactory tubercle or caudate-putamen in the same tissue sections. A lateral-to-medial gradient of D2 receptors was also present in the nucleus accumbens. That is, while there was no difference in the density of D1 receptors between the lateral core and medial shell subdivisions, the shell had a lower density of D2 receptors than did the core. The density of D1 and D2 receptors in the mesolimbic and nigrostriatal systems was compared in groups of animals raised from 30 to 60 days of age in an impoverished condition, a group-caged condition or an enriched condition. While the brain weight of enriched condition animals was higher than impoverished condition animals, there were no significant differences in the density of D1 or D2 receptors among the different groups. Apparently, the densities of D1 and D2 receptors in the brain are resistant to differential rearing conditions.