Renewal of drug seeking by contextual cues after prolonged extinction in rats.

Contextual stimuli associated with drug exposure can modulate various effects of drugs, but little is known about their role in relapse to drug seeking. Using a renewal procedure, the authors report that drug-associated contextual stimuli play a critical role in relapse to drug-seeking previously maintained by a heroin-cocaine mixture (speedball). Rats were trained to self-administer speedball, after which drug-reinforced behavior was extinguished over 20 days in the self-administration context or in a different context. On the test day, rats exposed to the drug-associated context, after extinction in a different context, reliably renewed drug seeking. The authors suggest that the renewal procedure can be used to study mechanisms underlying relapse to drug seeking elicited by drug-associated contextual stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Preparative concentration and size fractionation of DNA by porous media using a combination of flow and low electric field strength

Reinstatement of drug-seeking behavior after extinction constitutes a potential animal model of relapse to drug abuse. In a typical reinstatement experiment, previously drug-trained rats undergo extinction during which responding is no longer followed by drug delivery. After significant extinction is observed, rats are then exposed to an event expected to reinstate drug-seeking behavior. Using this procedure, it has been recently reported that footshock stress leads to reinstatement of drug-seeking in heroin-trained, presently drug-free rats. The purpose of the present study was to assess the generality of this effect of stress. Here we report that 15 min of intermittent footshock (0.86 mA; 0.5 s on, with a mean off period of 40 s) reinstated selectively cocaine-seeking behavior after 14 extinction sessions (rats were previously trained on a FR1 TO 20 s to obtain cocaine at a dose of 0.25 mg/infusion). In contrast, under similar experimental conditions, the same stressor did not reinstate food-seeking in food-trained rats after seven extinction sessions (rats were previously trained on a FR1 TO 20 s to obtain six food pellets). Rather, when the basal level of responding was sufficiently high, footshock stress induced a significant suppression of the instrumental performance. These data are discussed in light of several behavioral mechanisms which may explain the specificity of stress in reinstating drug-seeking behavior and not food-seeking behavior.     

N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens

Systemic nicotine enhances burst firing of dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens, mainly via stimulation of nicotinic acetylcholine receptors in the ventral tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excitatory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral tegmental area for the effects of nicotine on dopamine release in the nucleus accumbens using microdialysis, with one probe implanted in the ventral tegmental area for drug application and another in the ipsilateral nucleus accumbens for measuring dopamine, in awake rats. Systemic nicotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the ventral tegmental area increased dopamine output in the nucleus accumbens. Intrategmental infusion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumbal dopamine release; these effects were antagonized by concomitant infusion of a selective antagonist at N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively. Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegmental area did not affect basal dopamine levels, whereas infusion of 2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, starting 40 min before nicotine injection dose-dependently attenuated the nicotine-induced increase in accumbal dopamine release. Concurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucleus accumbens. These results indicate that the stimulatory action of nicotine on the mesolimbic dopamine system is to a considerable extent mediated via stimulation of N-methyl-D-aspartate receptors within the ventral tegmental area.     

Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat

Afferents from the basolateral amygdala and dopamine projections from the ventral tegmental area to the nucleus accumbens have both been implicated in reward-related processes. The present study used in vivo chronoamperometry with stearate-graphite paste electrodes in urethane-anaesthetized rats to determine how basolateral amygdala efferents to the nucleus accumbens synaptically regulate dopamine efflux. Repetitive-pulse (20 Hz for 10 s) electrical stimulation of the basolateral amygdala evoked a complex pattern of changes in monitored dopamine oxidation currents in the nucleus accumbens related to dopamine efflux. These changes were characterized by an initial increase that was time-locked to stimulation, a secondary decrease below baseline, followed by a prolonged increase in the dopamine signal above baseline. The effects of burst-patterned stimulation (100 Hz, 5 pulses/burst, 1-s interburst interval, 40 s) of the basolateral amygdala on the basal accumbens dopamine signal were similar to those evoked by 20 Hz stimulation, with the lack of a secondary suppressive component. Infusions of the ionotropic glutamate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid (APV) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the nucleus accumbens dose-dependently blocked or attenuated the initial and prolonged increases in the dopamine signal following 20 Hz or burst-patterned basolateral amygdala stimulation. Infusions of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine selectively blocked the intermediate suppressive effect of 20 Hz basolateral amygdala stimulation on dopamine oxidation currents. Blockade of glutamate receptors or inhibition of dopamine neuronal activity via infusions of either APV + DNQX, lidocaine or gamma-hydroxybutyric acid, respectively, into the ventral tegmental area did not effect the pattern of changes in the accumbens dopamine signal evoked by basolateral amygdala stimulation. These data suggest that the glutamatergic basolateral amygdala inputs to nucleus accumbens dopamine terminals synaptically facilitate or depress dopamine efflux, and these effects are independent of dopamine neuronal firing activity. Moreover, these results imply that changes in nucleus accumbens dopamine levels following presentation of reward-related stimuli may be mediated, in part, by the basolateral amygdala.     

Electron microscopic tomography of rat-liver mitochondria and their interaction with the endoplasmic reticulum

The distributed neural networks involved in the intravenous self-administration of nicotine and cocaine, and in a model of relapse of nicotine-taking after abstinence, were compared in Wistar rats. Post-mortem brain maps of c-fos-related antigens expression showed specific activation in prefrontal cortex, anterior cingulate and nucleus accumbens for both drugs, but of the anterior cingulate cortex only during relapse, suggesting that a subset of the neural network involved in drug self-administration is activated during relapse.     

Increase in dopamine release from the nucleus accumbens in response to feeding: a model to study interactions between drugs and naturally activated dopaminergic neurons in the rat brain

The aim of the present study was to investigate the interactions between the in vivo release of dopamine and certain drugs, during conditions of increased dopaminergic activity. Dopaminergic neurons in the nucleus accumbens were activated by feeding hungry rats. 48-96 h after implantation of a microdialysis probe 30 min food ingestion by hungry rats induced an immediate eating response that was accompanied with a reproducible and long-lasting increase in extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC). The effect of various drugs (infused into the nucleus accumbens via the microdialysis probe), on the extracellular levels of dopamine and DOPAC were recorded, and the effect of eating was determined. Infusion of 5 mumol/l nomifensine and 3.4 mmol/l calcium increased dopamine release respectively 5.4 and 2-fold but did not modify the eating related increase in dopamine and DOPAC release. Infusion (1 mumol/l) as well as intraperitoneal administration (20 mg/kg) of sulpiride induced an increase in basal dopamine release to 220 and 195% of controls, respectively. Both routes of sulpiride pretreatment enhanced the eating related increase in extracellular dopamine and DOPAC. The results of the sulpiride experiments indicate that a behaviorally induced stimulation of dopamine release is modified by autoinhibition.     

A comparison between systolic aortic root pressure and finger blood pressure

Isolation of the rat pup from the nest and dam for one hour per day from PN 2-9 is a useful paradigm for producing stress in the neonate. These previously isolated rats respond to an amphetamine challenge with alterations in activity at the juvenile stage or as adults. Furthermore, when dopamine release is measured in the nucleus accumbens, juveniles release 3 times more dopamine after amphetamine than do controls. This study describes changes in behavior and brain dopamine systems at PN 10. Experiment 1 determined an appropriate amphetamine dose that could be used for behavioral activation at PN 10. Experiment 2 produced significant evidence of enhanced behavioral activation after the isolation paradigm and indicated that brain regions innervated by the mesolimbic dopamine system, septum, and hypothalamus display increased dopamine turnover and that the nigrostriatal pathway is less active. Likewise, in Experiment 3, in vivo microdialysis of the nucleus accumbens indicated that previously isolated pups respond to an amphetamine challenge with a several-fold increase in dopamine release over a 4-hour session.     

Repeated isolation stress in the neonatal rat: Relation to brain dopamine systems in the 10-day-old rat.

Isolation of the rat pup from the nest and dam for one hour per day from PN 2–9 is a useful paradigm for producing stress in the neonate. These previously isolated rats respond to an amphetamine challenge with alterations in activity at the juvenile stage or as adults. Furthermore, when dopamine release is measured in the nucleus accumbens, juveniles release 3 times more dopamine after amphetamine than do controls. This study describes changes in behavior and brain dopamine systems at PN 10. Experiment 1 determined an appropriate amphetamine dose that could be used for behavioral activation at PN 10. Experiment 2 produced significant evidence of enhanced behavioral activation after the isolation paradigm and indicated that brain regions innervated by the mesolimbic dopamine system, septum, and hypothalamus display increased dopamine turnover and that the nigrostriatal pathway is less active. Likewise, in Experiment 3, in vivo microdialysis of the nucleus accumbens indicated that previously isolated pups respond to an amphetamine challenge with a several-fold increase in dopamine release over a 4-hour session. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural substrates of latent inhibition: The switching model.

Latent inhibition (LI) refers to decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. This robust phenomenon has been shown in classical and instrumental conditioning procedures and in many mammalian species, including humans. Development of LI reflects decreased associability of, or attention to, stimuli that predict no significant outcome. The fact that LI reflects attentional processes has become important to neuroscientists who see LI as a convenient tool for measuring the effects of drug treatments and lesions on attention. Data on brain systems studied for their involvement in LI are surveyed. These are presented in sections on noradrenergic, cholinergic, dopaminergic, serotonergic, and septo-hippocampal manipulations. It is concluded that the neural substrates of LI include the mesolimbic dopaminergic system (MDS), the mesolimbic serotonergic system (MSS), and the hippocampus. The preexposed stimulus loses its capacity to affect behavior in conditioning, even though it predicts reinforcement, because the hippocampus inhibits the switching mechanism of the nucleus accumbens via the subiculum-accumbens pathway. This hippocampal action is modulated by the MSS via its interactions with the hippocampal system or MDS, or both. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanisms behind drug dependence

The neurobiological mechanisms involved in the development and maintenance of drug dependency are reviewed and discussed. Whereas physical dependency is related to abstinence symptoms with a noradrenergic hyperactivity in locus ceruleus, motivational dependency is related to euphoria, which correlates with dopaminergic activity in the mesolimbic pathway, especially in nucleus accumbens. Despite the fact that many addictive drugs are chemically unrelated, they increase the extracellular levels of dopamine in nucleus accumbens. This has been observed with cocaine, amphetamine, ecstacy, nicotine, opiates, ethanol, and cannabinoids. On the other hand, substances like LSD do not appear to influence the dopamine level in the mesolimbic pathway. Increasing knowledge about how drug abuse modulates signal pathways in discrete parts of the brain gives a new insight into the development and maintenance of drug dependency.     

Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability.

Conditioned stimuli (CSs) can control behavior either by activating responses when presented noncontingently or through their ability to maintain responding when presented contingently, that is, as conditioned reinforcers. In the present study, the extent to which drug-seeking behavior could be subject to these different types of stimulus control was studied by presenting to rats CSs that were either paired with each drug infusion or presented as discriminative stimuli (DSs) signaling the availability of drug. It was found that stimuli paired with either cocaine or heroin infusions increased drug seeking when presented contingent on responding, but not when presented noncontingently. By contrast, DSs that signaled cocaine availability increased drug seeking when presented either noncontingently or contingently. These results suggest that drug-seeking behavior can be influenced differentially by CSs and that conditioned reinforcers are especially important for maintaining prolonged sequences of drug-seeking behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli

Brain microdialysis was used to study changes in dopamine in the nucleus accumbens and the dorsal striatum during associative learning between two neutral stimuli, flashing light and tone, presented on a paired schedule during stage 1 of a sensory preconditioning paradigm. The tone was subsequently paired with mild footshock using standard aversive conditioning procedures and the formation of a conditioned association between the flashing light and the tone in stage 1 was assessed by measuring the ability of the flashing light to elicit the same conditioned response as the tone when presented at test. The first experiment used behavioural monitoring only, to establish stimulus parameters for subsequent microdialysis experiments. Animals receiving paired presentation of the light and tone in stage 1 showed a conditioned suppression of licking to the light as well as to the tone, indicating that associative learning between the flashing light and the tone had occurred during stage 1, whilst in a separate group of animals given the same stimuli over the same time period but on an explicitly non-paired schedule, the conditioned emotional response was seen to the tone, but not to the light, showing that no association had been formed between the two stimuli during stage 1. In dialysis experiments using the same procedure, we measured a two-fold rise in dopamine in the nucleus accumbens during paired presentation of flashing light and tone, but not during non-paired presentation of the two stimuli. On subsequent test presentation of the two stimuli, we saw increases in accumbal dopamine on presentation of the tone in both groups, reflecting the formation of an association with the footshock in both. However the flashing light elicited an increase in dopamine only in the group which had received paired presentation at stage 1. Thus accumbal dopamine release at test is correlated to the ability of the stimulus to evoke a conditioned response measured behaviourally. Hypotheses of the behavioural function of the mesolimbic dopamine system centre on its role in mediating the effects of biological reinforcers, both rewarding and aversive, conditioned and unconditioned. The present results, showing increases in extracellular dopamine in the nucleus accumbens when an association is formed between two stimuli of which neither is a biological reinforcer nor, prior to formation of the association, affects dopamine levels, suggest a role for accumbal dopamine in the modulation of associative learning in general, not only that involving reinforcement.     

Role of the nucleus accumbens and the striatum in the production of turning behaviour in intact rats

Recent knowledge of the mechanisms underlying turning or circling behaviour in intact rats is reviewed. Most interest has been directed towards the striatum because of the classical hypothesis that turning behaviour results from lateral differences in the activity of the bilateral nigrostriatal pathway. However, the assumption that asymmetrical activation of the striatum is a necessary condition for dopamine-dependent turning behaviour has been questioned by several studies showing that unilateral injection of amphetamine or dopamine receptor agonists into the nucleus accumbens, a target of the mesolimbic dopaminergic system, also produces reliable circling away from the side of injection. Apart from discussing differences in stepping patterns of turning and discussing the role of the dopamine D1/D2 receptor interaction, the present survey focuses attention upon the two-component hypothesis, especially in relation to our recent studies in which activities of dopamine D1 and D2 receptors in the striatum and the nucleus accumbens have been manipulated separately in intact rats. It is hypothesized that turning behaviour is produced by asymmetry within nucleus accumbens circuits which involve neuronal connections from the nucleus accumbens to the A9 cell area, which in turn projects to the ventrolateral striatum that determines the direction of turning.     

Role of (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors in amelioration of conditioned fear stress in rats: association with mesolimbic dopaminergic systems

Rats exhibited a marked suppression of motility when they were re-placed in the same environment as that in which they had previously received an electric footshock. We examined the behavioral and neurochemical effects of (+)-N-allylnormetazocine hydrochloride ((+)-SKF-10,047) and (+)-pentazocine, putative sigma 1 receptor ligands, on this psychological-stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently attenuated the conditioned fear stress, whereas (+)-pentazocine failed to do so even at a higher dose (32 mg/kg). In rats showing the conditioned fear stress, dopamine turnover (i.e., the ratio of dopamine metabolites/dopamine contents) was decreased in the nucleus accumbens and was increased in the medial prefrontal cortex, but remained unchanged in the striatum. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently reversed the decreased dopamine turnover in the nucleus accumbens without changing the increased dopamine turnover in the medial prefrontal cortex. (+)-Pentazocine (32 mg/kg) did not affect the stress-induced changes in dopamine turnover in these brain regions. Thus, the decreased dopamine turnover in the nucleus accumbens appears to be involved in the conditioned fear stress. These results suggest that (+)-SKF-10,047 ameliorates the conditioned fear stress by reversing the psychological stress-induced dysfunction in the mesolimbic dopaminergic systems, and that the (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors may play in important role in this stress response.     

Stress, habits, and drug addiction: A psychoneuroendocrinological perspective.

It is well known that stress is a significant risk factor for the development of drug addiction and addiction relapse. Remarkably, the cognitive processes involved in the effects of stress on addictive behavior remain poorly understood. Here it is proposed that stress-induced changes in the neural circuits controlling instrumental action provide a potential mechanism by which stress affects the development of addiction and relapse vulnerability. Instrumental action can be controlled by two anatomically distinct systems: a goal-directed system that involves learning of action-outcome associations, and a habit system that learns stimulus–response associations. The transition from initial voluntary drug use to subsequent involuntary, compulsive drug use represents a switch from goal-directed to habitual control of action. Recent evidence indicates that this switch from goal-directed to habit action can be prompted by stress and stress hormones. We argue (i) that acute stressors reinstate habitual responding to drug-related cues and thus trigger relapse to addictive behavior, and (ii) that prolonged or repeated stress may accelerate the transition from voluntary to involuntary drug use and thus promote the development of addiction. The suggested mechanism encompasses cognitive processes that may contribute to the effects of stress on addictive behavior and could have important implications for the treatment of addiction and the prevention of relapse. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior

cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc) has been implicated in cocaine addiction because (1) cocaine reinforcement is mediated by dopamine receptors that modulate cAMP formation, and (2) repeated exposure to cocaine upregulates the cAMP system in NAc neurons. This study tested PKA involvement in cocaine self-administration and relapse of cocaine-seeking behavior by infusing cAMP analogs that activate or inhibit PKA into the NAc of rats. Bilateral intra-NAc infusions of the PKA inhibitor Rp-cAMPS reduced baseline cocaine self-administration, shifted the dose-response curve for cocaine self-administration to the left, and induced relapse of cocaine-seeking behavior after extinction from cocaine self-administration, consistent with an enhancement of cocaine effects in each paradigm. In contrast, pretreatment with intra-NAc infusions of a PKA activator, Sp-cAMPS or dibutyryl cAMP, increased baseline cocaine self-administration during the second hour of testing and shifted the dose-response curve to the right, consistent with an antagonist-like action. After extinction from cocaine self-administration, similar infusions of Sp-cAMPS induced generalized responding at both drug-paired and inactive levers. As an index of PKA activity in vivo, NAc infusions of Rp-cAMPS reduced basal levels of dopamine-regulated phosphoprotein-32 phosphorylation and blocked amphetamine-induced increases in cAMP response element-binding protein (CREB) phosphorylation. Conversely, NAc infusions of Sp-cAMPS increased phosphorylation of CREB. Together, these results suggest that sustained upregulation of the cAMP system in the NAc after repeated cocaine exposure could underlie tolerance to cocaine reinforcement, whereas acute inhibition of this system may contribute to drug craving and relapse in addicted subjects.     

Sensitization and conditioning of feeding following multiple morphine microinjections into the nucleus accumbens

The effects of repeated morphine infusions (10 micrograms/0.5 microliter) into the nucleus accumbens on feeding were studied in sated rats. As shown previously, intra-accumbens morphine infusions induced a large increase in food intake. After undergoing repeated morphine treatment, animals consumed significant quantities of food in response to a saline or sham injection, compared to their pre-morphine baseline. This conditioned feeding was present up to 18 days after the final drug infusion. Additionally, repeated morphine administration caused a progressive sensitization of feeding; the final morphine infusion elicited nearly double the amount of food intake as the first. Multiple saline infusions had no behavioral effects. Repeated stimulation of opiate receptors may enhance associative mechanisms such that previously neutral environmental stimuli acquire the ability to elicit feeding. Abnormal activation of this system may be a possible neural substrate for compulsive feeding and bulimia.     

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.     

The tonic/phasic model of dopamine system regulation: its relevance for understanding how stimulant abuse can alter basal ganglia function

The changes in dopamine system regulation occurring during stimulant administration are examined in relation to a new model of dopamine system function. This model is based on the presence of a tonic low level of extracellular dopamine that is released by the presynaptic action of corticostriatal afferents. In contrast, spike-dependent dopamine release results in a phasic, high concentration of dopamine in the synaptic cleft that is rapidly inactivated by reuptake. Tonic dopamine has the ability to down-modulate spike-dependent phasic dopamine release via stimulation of the very sensitive dopamine autoreceptors present on dopamine terminals. Stimulants are known to elicit locomotion and stimulate reward sites by releasing dopamine from terminals in the nucleus accumbens, which is followed by a rebound depression. It is proposed that the initial activating action of stimulants is caused by increasing the release of dopamine into the synaptic cleft to activate the phasic dopamine response. However, by interfering with dopamine uptake, stimulants also allow dopamine to escape the synaptic cleft, thereby depressing subsequent spike-dependent phasic dopamine release by increasing the tonic stimulation of the autoreceptor. In contrast, repeated stimulant administration is proposed to cause long-term sensitization by pharmacological disruption of a cascade of homeostatic compensatory processes. Upon drug withdrawal, the fast compensatory systems that were blocked by stimulants rapidly restore homeostasis to the system at a new steady-state level of interaction. As a consequence, the slowly changing but potentially more destabilizing compensatory responses are prevented from returning to their baseline conditions. This results in a permanent change in the responsivity of the system. Homeostatic systems are geared to compensate for unidimensional alterations in a system, and are capable of restoring function even after massive brain lesions or the continuous presence of stimulant drugs. However, the system did not evolve to deal effectively with repetitive introduction and withdrawal of drugs that disrupt dopamine system regulation. As a consequence, repeated insults to a biological system by application and withdrawal of drugs that interfere with its homeostatic regulation may be capable of inducing non-reversible changes in its response to exogenous and endogenous stimuli.     

Professor Matthew Stewart: asbestosis research 1929-1934

The chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without changing dopamine transporter binding. In order to examine more closely the dopaminergic contribution to this effect, the selective dopamine uptake inhibitor GBR 12,909 (30 mg/kg/day), cocaine (50 mg/kg/day), or vehicle, were continuously infused via osmotic minipump, and their effects on the dopamine transporter examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and removed after seven days. [3H]WIN 35,428 binding and [3H]dopamine uptake were measured in caudate putamen and nucleus accumbens at varying intervals after pump removal. The Bmax for [3H]WIN 35,428 binding was decreased by approximately 75% in the caudate putamen and by 40% in the nucleus accumbens of GBR 12,909-treated rats both 1 and 4 days after pump removal, and was still significantly decreased after 10 days, but had returned to normal by 20 days post-treatment. In contrast, cocaine did not significantly alter [3H]WIN 35,428 binding. GBR 12,909 produced both tolerance to the inhibition of [3H]dopamine uptake by cocaine, and a decrease in total uptake of dopamine, in the caudate putamen, with no change in the nucleus accumbens. The persistent reduction of [3H]WIN 35,428 binding following continuous GBR 12,909 does not appear to result from residual drug binding. These findings suggest that GBR 12,909 and cocaine may bind to and regulate the dopamine transporter in different ways.