Hans S. Crombag

Neural and Behavioral Plasticity Associated with the Transition from Controlled to Escalated Cocaine Use

BACKGROUNDnRats given extended access to cocaine develop several symptoms of addiction, including a gradual escalation of drug intake, whereas rats given limited access do not. We asked here whether extended access to cocaine also produces drug-induced sensitization, a form of neurobehavioral plasticity implicated in addiction.nnnMETHODSnRats were given limited (1 hour/session) or extended access (6 hours/session) to self-administered cocaine. Following a period of abstinence, rats were selected at random for assessment of their psychomotor response to cocaine or drug-seeking during extinction or for anatomic studies.nnnRESULTSnWhen re-exposed to cocaine, rats allowed extended drug access showed greater drug-seeking behavior and were hypersensitive (sensitized) to the psychomotor activating effects of cocaine compared with rats given limited access. Extended access to cocaine was also associated with a greater increase in the density of dendritic spines on neurons specifically in the core of the nucleus accumbens (and not in the shell or medial or orbital frontal cortex).nnnCONCLUSIONSnThe transition from stable to escalated cocaine use, a hallmark of addiction, is associated with especially robust behavioral sensitization and synaptic reorganization in the core of the nucleus accumbens.

Biological Basis of Sex Differences in the Propensity to Self-administer Cocaine

Women are at greater risk for cocaine addiction than are men, and female rats similarly show a greater propensity to self-administer cocaine than do male rats. This could be due to the intrinsic sex differences in brain organization, to the activational effects of circulating gonadal hormones, or both. For example, estradiol enhances dopamine release in the striatum and nucleus accumbens, and facilitates the behavioral sensitization induced by repeated cocaine exposure. We report here that independent of circulating gonadal hormones, female rats acquire cocaine self-administration behavior more rapidly, and they self-administer more cocaine at a faster rate than do male rats. This indicates that there is an intrinsic difference between male and female subjects in the neural systems mediating drug-seeking behavior due to sexual differentiation of the brain. Furthermore, we find that the administration of estradiol to gonadectomized female subjects greatly facilitates the acquisition of cocaine self-administration. These data demonstrate that both intrinsic sex differences in brain organization and the actions of circulating estradiol contribute to increased vulnerability for cocaine use in female subjects.

Modulation of the Induction or Expression of Psychostimulant Sensitization by the Circumstances Surrounding Drug Administration

The conditions necessary to induce psychomotor sensitization and to promote its expression are not well understood. Two examples are reviewed here of how the circumstances surrounding drug administration (set and setting) can powerfully modulate the sensitization produced by psychostimulant drugs, such as amphetamine or cocaine. In the first example it is suggested that repeated exposure to psychostimulant drugs may induce neural sensitization (i.e., produce relevant adaptations in the nervous system). The circumstances surrounding drug administration may determine, however, whether neural sensitization is expressed in behavior. In the second example it is suggested that the circumstances surrounding drug administration may determine whether sensitization is induced at all, or at least the rate and extent of sensitization produced by a given dose of a drug. It is concluded that psychomotor sensitization is not an inevitable consequence of exposure to psychostimulant drugs, but is the result of interactions amongst the pharmacological actions of drugs and the circumstances surrounding drug administration.

The role of contextual versus discrete drug-associated cues in promoting the induction of psychomotor sensitization to intravenous amphetamine

The environmental context in which psychostimulant drugs are administered can have a large effect on both their acute psychomotor activating effects and their ability to induce the psychomotor sensitization associated with repeated drug administration. For example, the acute effects of amphetamine and the development of psychomotor sensitization to amphetamine and cocaine are enhanced when they are administered in a distinct and relatively novel test environment, relative to when they are given in the home cage, in the absence of any environmental stimuli predictive of drug administration. The experiments reported here were designed to further examine this phenomenon and to test the hypothesis that the ability of a distinct context to promote robust psychomotor sensitization is due to its ability to reliably signal (cue) drug administration. Specifically, we compared the ability of contextual cues (a distinct test environment) and discrete cues (light, tone and/or odor), which both reliably predict drug administration, to promote the induction of sensitization. The psychomotor stimulant effects (rotational behavior) of repeated intravenous infusions of 0. 5 mg/kg amphetamine were assessed in rats for whom drug treatments were signaled either: (1) by placement into a distinct test environment; (2) by presentation of discrete cues; or (3) rats for whom drug treatments were given in the home environment in the absence of any environmental cues. Amphetamine produced robust sensitization when given in association with placement into a distinct test environment. The same treatment failed to produce sensitization when the drug was given unsignaled in the animals home cage. Most importantly, signaling drug administration by presenting discrete cues was not sufficient to promote the robust sensitization seen when treatments were given in a distinct test environment. These results confirm that the induction of psychomotor sensitization can be powerfully modulated by environmental context and further establish that, although contextual stimuli associated with a distinct test environment promote robust sensitization, discrete cues that merely predict drug administration do not have this property. Possible reasons for the difference in the ability of contextual versus discrete environmental cues to promote sensitization are discussed.

Signalled versus unsignalled intravenous amphetamine: large differences in the acute psychomotor response and sensitization

Both the acute psychomotor response and the development of sensitization to amphetamine are attenuated if i.p. injections are given in the cage where animals live (HOME), relative to when injections are given in a novel (NOVEL), but otherwise physically identical cage. It was suggested that this effect of environment on sensitization may be due to the relative availability of cues predictive of drug administration in the two conditions. It was hypothesized, therefore, that removal of all environmental cues predictive of drug administration would attenuate the development of sensitization even further. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated unsignalled intravenous (i.v.) infusions of 1.0 mg/kg amphetamine given in a HOME environment with those of signalled i.v. infusions given in a NOVEL environment. It was found that signalled i.v. amphetamine administration (NOVEL) produced a large acute psychomotor response, and repeated administrations resulted in a significant increase in psychomotor response (i.e., sensitization). In contrast, the same treatment in the HOME condition produced only a very small acute response and no sensitization. Indeed, the magnitude of the psychomotor response to an amphetamine challenge varied approximately 23-fold as a function of past drug history and environmental condition. It is suggested that this paradigm provides a powerful new model to study how environmental factors modulate responsiveness to psychoactive drugs.

The Ability of Environmental Context to Facilitate Psychomotor Sensitization to Amphetamine Can Be Dissociated from Its Effect on Acute Drug Responsiveness and on Conditioned Responding

Doses of amphetamine or cocaine that fail to induce psychomotor sensitization when given to a rat in its home cage can produce robust sensitization if given immediately following placement into a relatively novel, distinct environment. A drug-associated context can serve as a conditioned stimulus, and therefore may promote robust sensitization by facilitating associative learning processes. We examined this hypothesis by habituating rats to the test environment for 1 or 6–8 hr prior to each drug injection, which degrades the ability of environmental context to serve as an effective conditioned stimulus. When 0.5 mg/kg of amphetamine was administered intravenously immediately after placement into a distinct environment there was a large acute psychomotor response (rotational behavior) on the first test day, and robust sensitization developed with repeated daily injections. When the same treatment was administered in the home cage, there was a small acute response and no sensitization developed. The enhanced acute response seen in the distinct environment was significantly attenuated by 1 hr of habituation to the test environment, and completely abolished by 6–8 hr of habituation. Also, as little as 1 hr of habituation completely prevented the development of a conditioned rotational response. In contrast, neither 1 nor 6–8 hr of habituation had any effect on the ability of amphetamine to induce robust behavioral sensitization. It is concluded that the ability of a distinct environment to facilitate sensitization to amphetamine can be dissociated from its effect on acute drug responsiveness and from the ability of drug-associated environmental stimuli to elicit a conditioned response. Possible mechanisms by which a distinct environment facilitates sensitization are discussed.

Susceptibility to Amphetamine-Induced Locomotor Sensitization Is Modulated by Environmental Stimuli

We have previously reported that intravenous (I.V.) administrations of 0.5–1.0 mg/kg of amphetamine in the absence of any environmental stimuli predictive of drug administration failed to induce psychomotor sensitization whereas the same drug did produce robust sensitization when given in association with environmental novelty. These results were obtained by studying rotational behavior in animals with a unilateral 6-OHDA lesion of the mesostriatal dopamine system. The purpose of this study was to determine if environmental novelty has a similar effect on sensitization to the locomotor activating effects of amphetamine in neurologically intact rats. Rats were implanted with I.V. catheters and divided in four groups. Two groups were housed in locomotor activity cages and given seven consecutive I.V. infusions of either saline (SAL-HOME group) or 0.375 mg/kg of amphetamine (AMPH-HOME group), using a remotely activated delivery system. Simultaneously, the other two groups were transported to the test cages and given the same treatment (SAL-NOVEL and AMPH-NOVEL groups). After one week withdrawal, all groups were given an amphetamine challenge (0.375 mg/kg, I.V.). Amphetamine sensitization developed when the drug was administered under NOVEL conditions, as indicated by a progressive increase in ampheatmine-induced locomotor activity over test sessions and by a greater response to the amphetamine challenge in the AMPH-pretreated versus the SAL-pretreated group. In contrast, no sensitization was observed under HOME conditions. Similar results were obtained with the analysis of vertical activity.

Cocaine-induced psychomotor activity is associated with its ability to induce c-fos mRNA expression in the subthalamic nucleus: effects of dose and repeated treatment

Factors that modulate the psychomotor activating effects of amphetamine and cocaine, such as environmental novelty and dose, also regulate the ability of these drugs to induce c‐fos mRNA expression in the subthalamic nucleus (STN). We hypothesized therefore that engagement of the STN may be important for stimulant‐induced psychomotor activation. To further test this hypothesis we examined whether repeated treatment with cocaine, which enhances its psychomotor activating effects (i.e. produces behavioural sensitization), also enhances its ability to induce c‐fos expression in the STN. In addition, given that STN activity is thought to be influenced by preproenkephalin mRNA‐containing (ENK+) neurons in the caudate–putamen, we also examined whether repeated cocaine treatment alters c‐fos expression in ENK+ cells. We report that: (i) cocaine pretreatment enhances the ability of a cocaine challenge to induce c‐fos mRNA expression in the STN, and this effect is most robust at challenge doses where behavioural sensitization is observed; (ii) the ability of cocaine to induce c‐fos in the STN is independent of the ability of cocaine to engage ENK+ cells. These results support the idea that the STN is involved in stimulant‐induced psychomotor activation and sensitization, but suggest that stimulant‐induced engagement of the STN is not dependent on ENK+ cells in the caudate–putamen. These findings may have implications concerning the neurobiological mechanisms underlying the behavioural effects of psychostimulant drugs.

The rate of intravenous cocaine or amphetamine delivery does not influence drug-taking and drug-seeking behavior in rats.

We studied the influence of rate of intravenous infusion of cocaine or amphetamine on drug-taking and seeking behavior. First, drug-naive rats were tested for acquisition of self-administration of increasing doses of amphetamine or cocaine infused over 5 or 100 s. Second, self-administration of cocaine or amphetamine infused over 5-100 s was assessed on fixed or progressive-ratio (PR) reinforcement schedules. Finally, the ability of a single 5 or 100 s amphetamine or cocaine infusion to reinstate extinguished drug seeking was assessed. Although slower infusion rates produced a small effect on drug taking under continuous-reinforcement conditions, infusion rate did not alter drug taking on intermittent or PR reinforcement schedules, or the ability of cocaine or amphetamine to reinstate drug seeking. Taken together, our results suggest that variation in drug delivery rate over a range that we previously found alters the induction of behavioral sensitization, gene-expression and striatal dopamine activity, does not markedly alter drug-taking or seeking behavior.

Drugs, Environment, Brain, and Behavior

The effects of psychoactive drugs are not just a function of their pharmacological actions, but are due to complex interactions among pharmacological, psychological, and environmental factors. We discuss here how drug-environment interactions determine the likelihood that addictive drugs produce a persistent form of neurobehavioral plasticity (sensitization) thought to be involved in the pathophysiology of addiction and relapse.