Natural Reinforcers Research Articles

Neuroanatomical specificity of conditioned responses to cocaine versus food in mice

Neural circuits implicated in drug conditioning, craving and relapse overlap extensively with those involved in natural reward and reinforcement. To determine whether specificity could be detected in conditioned brain responses to drugs versus food, male outbred HSD:ICR mice were conditioned to a common environment using either 20 mg/kg cocaine (ip) or a familiar food (under food restriction). The mice were then re-exposed to the same environment without the reinforcer and patterns of brain activation were compared using immunohistochemical detection of Fos. Conditioned place preference tests were conducted first to establish relative potency of each reward and facilitate analysis of correlations between Fos and motivation. Place preference was stronger for cocaine than food. Food- but not cocaine-paired cues increased Fos in the paraventricular hypothalamic nucleus whereas the opposite occurred for prefrontal, cingulate and piriform cortices. Individual differences in cocaine place preference were negatively correlated with Fos in the prefrontal cortex. One difference between drugs and natural reinforcers may be lack of feedback from the periphery for drugs which may circumvent control from the hypothalamus in the development of reinforcement circuits.

Effects of GABAB receptor agents on cocaine priming, discrete contextual cue and food induced relapses

In the present study we investigated the effects of the GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phosphinic acid (SKF 97541), and the allosteric positive modulator 3,5-bis(1,1-dimethylethyl)-4-hydroxy-beta,beta-dimethylbenzenepropanol (CGP 7930) on cocaine seeking behavior. The effects of the above drugs on the reinstatement of responding induced by natural reinforcer (food) were also studied. Male Wistar rats were trained to self-administer either cocaine (0.5 mg/kg/infusion) or food (sweet milk) and responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine, i.p.), a discrete contextual cue, or a contingent presentation of food. SCH 50911 (3-10 mg/kg) dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned cue reinstatement. At the same time, it failed to alter reinstatement of food-seeking behavior. Baclofen (1.25-5 mg/kg) and SKF 97541 (0.03-0.3 mg/kg) attenuated cocaine- or food-seeking behavior; the effect of the drug appeared more effective for cocaine-seeking than food-seeking. CGP 7930 (10-30 mg/kg) reduced cocaine seeking without affecting food-induced reinstatement on reward seeking. Our results indicate that tonic activation of GABA(B) receptors is required for cocaine seeking behavior in rats. Moreover, the GABA(B) receptor antagonist SCH 50911 was effective in reducing relapse to cocaine at doses that failed to alter reinstatement of food-seeking behavior (present study), basal locomotor activity, cocaine and food self-administration (Filip et al., submitted for publication), suggesting its selective effects on motivated drug-seeking behavior. The potent inhibitory responses on cocaine seeking behavior were also seen following the GABA(B) receptor agonists or the allosteric positive modulator, however, doses of baclofen and SKF 97541 that inhibited cocaine-seeking were only threefold lower of those that inhibited food-seeking. In addition, the direct GABA(B) receptor agonists and the allosteric positive modulator cause decreases in cocaine or food self-administration (Filip et al., submitted for publication), indicating their nonspecific effects on relapse to drug-seeking and drug-taking behavior. In conclusion, the GABA(B) receptor antagonist SCH 50911 seems to be viable treatment for reducing cocaine craving and preventing relapse, while the GABA(B) receptor allosteric positive modulator CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as the direct rewarding properties of cocaine.

Rapid induction of Pavlovian approach to an ethanol-paired visual cue in mice

Although many studies have shown Pavlovian conditioned approach to cues paired with natural reinforcers, it has been quite difficult to induce such behavior with drug reinforcers. This experiment tested a novel Pavlovian procedure for inducing approach to a conditioned stimulus (CS) paired with ethanol. Mice (NZB/B1NJ, DBA/2J) received intraperitoneal injections of ethanol (2 g/kg) immediately before 10-min exposure to a rectangular chamber that contained a distinctive visual cue (star) at one end (Paired group, CS+ trials). On alternate days, saline injection preceded apparatus exposure with no distinctive cues (CS- trials). Unpaired control mice received ethanol in the home cage 60-75 min after each CS+ trial. NZB/B1NJ Paired group mice spent increasing amounts of time (>85% of the session) in proximity to the star, whereas Unpaired group mice did not. DBA/2J Paired group mice spent slightly more time on the star side than Unpaired group mice but did not show an acquisition curve. Postconditioning tests showed a strong preference for the star side in Paired groups from both strains after saline injection. However, only NZB/B1NJ mice showed a preference after ethanol. This study provides the first unambiguous demonstration of Pavlovian conditioned approach to an ethanol-paired visual stimulus in the absence of any contingency between the animal's behavior and drug exposure. This effect, which is remarkable both in terms of its magnitude and the rapidity with which it was produced (within 2-3 trials), may be related to the cue-associated craving that accompanies alcohol and drug addiction.

Parent implemented joint attention intervention for preschoolers with autism.

Introduction The absence of joint attention is one of the earliest symptoms of autism, reflecting the hallmark social disturbance that characterizes the disorder (Mundy & Crowson, 1997). Joint attention, first seen in infants between 9 and 12 months of age, involves two people sharing attentional focus on interesting objects and events (Bakeman & Adamson, 1984). Early joint attention behaviors involve children's use of eye gaze and conventional gestures. For example, a child might initiate joint attention, directing his mother's attention to a toy on the floor, by looking from the toy to his mother and back to the toy (i.e., gaze alternating) while simultaneously pointing at the toy. Alternatively, a mother might direct her child's attention by pointing and looking at an object while commenting on the object (e.g., What a fun toy!) to which the child responds by looking from the object to his mother and back to the object (i.e., gaze alternating). These joint attention interactions are considered uniquely social in that they result in an interaction between adult and child about the object/event. Joint attention is also related to social and language skill development, playing a significant role in typical development (Mundy & Gomes, 1998; Mundy, Sigman, & Kasari, 1990; Travis, Sigman, & Ruskin, 2001). Deficits in joint attention are evident in children with autism from very early in development (Baron-Cohen, Allen, & Gillberg, 1992; Charman et al., 1998; Osterling & Dawson, 1994). Infant screening and diagnostic instruments for autism, such as the Checklist for Autism in Toddlers (CHAT) (Baron-Cohen et al., 1992) and the Autism Diagnostic Observation Schedule (ADOS) (Lord, Rutter, DiLavore, & Risi, 1999), include assessment of deficits in joint attention as a marker for autism. In comparison to children with mental retardation or specific language delay (matched for developmental level), preschool children with autism show significant deficits in both responding to others' joint attention directives and initiating joint attention (Charman et al., 1998; Mundy, Sigman, Ungerer, & Sherman, 1986; Sigman, Mundy, Sherman, & Ungerer, 1986; Stone, Ousley, Yoder, Hogan, & Hepburn, 1997). This impairment in joint attention discriminates 80% to 90% of children with autism from those with other developmental disabilities (Lewy & Dawson, 1992; Mundy et al., 1986). Because of the social nature of joint attention, its absence reflects the core social disturbance that characterizes autism (Mundy & Crowson, 1997). Joint attention is also related to two of the areas, social and communication development (Mundy & Gomes, 1998; Mundy et al., 1990; Travis et al., 2001), that are significantly impaired in individuals with autism (American Psychiatric Association, 2000). Thus, the development of effective intervention procedures to address joint attention deficits in young children with autism is of utmost importance. A handful of studies have examined intervention procedures to address joint attention deficits in children with autism with at least some improvement in targeted joint attention skills (e.g., Hwang & Hughes, 2000; Kasari, Freeman, & Paparella, 2001, 2006). Using a behaviorally based intervention, Whalen and Schreibman (2003) examined pivotal response training strategies (Koegel, Koegel, Harrower, & Carter, 1999; Pierce & Schreibman, 1995) with an emphasis on the use of child preferred materials, interspersing difficult tasks among easier ones, and using natural reinforcers as consequences for appropriate behavior to teach joint attention skills to 5 participants with autism (all 4 years of age). All participants acquired responding to others' joint attention directives and 4 of the participants acquired skills to initiate joint attention. More recently, we (Jones, Carr, & Feeley, 2006) also examined the use of a behavioral intervention consisting of discrete trial instruction and pivotal response training strategies to teach five 2-3 year old children with autism to both respond to others' joint attention directives and initiate joint attention. …

Cocaine during adolescence enhances dopamine in response to a natural reinforcer

The use of cocaine during adolescent development could alter the normal growth of brain regions affected by cocaine, specifically the reward system, and impact the adult mesolimbic system. However, there is scant literature aimed at determining whether animals are more vulnerable to the adverse effects of drugs during adolescence. The present study investigated whether cocaine pretreatment in either adolescence or adulthood altered the dopaminergic response to a naturally reinforcing substance in adulthood. To evaluate the responsivity of the mesolimbic system after repeated cocaine, sucrose was offered during the dialysis procedure and dialysates were collected. Regardless of age all saline pretreated rats had significant increases in sucrose-induced extracellular dopamine (DA) levels in the nucleus accumbens septi (NAcc) as compared to baseline levels. Rats pretreated with cocaine as adults also had significant increases in DA levels after sucrose. Interestingly, sucrose intake significantly enhanced DA levels in cocaine pretreated adolescent rats as compared to all other conditions. The results from the present study show that in rats pretreated with cocaine during adolescence there is an enhanced response of the dopaminergic system in animals exposed to a naturally reinforcing substance. Therefore, cocaine exposure during adolescence results in long-term functional changes in the mesolimbic pathway. Future studies need to ascertain the underlying mechanisms and their potential role in cocaine addiction.

Selective dopaminergic lesions of the ventral tegmental area impair preference for sucrose but not for male sexual pheromones in female mice

The role of the meso-accumbens dopaminergic pathway in reward-related behaviours is the subject of intense investigation. In this regard, here we analyse the effects of specific lesions of dopaminergic cells of the ventral tegmental area (VTA) of female mice on two goal-directed behaviours, namely sucrose preference (intake of sucrose solution vs. water) and preference for male sexual pheromones (exploration of male-soiled vs. clean bedding). The results indicate that partial lesions of the VTA that impair neither locomotion nor general exploratory behaviour reduce the preference for sucrose (over a 48-h period) but do not alter the innate attraction that females display for male sexual pheromones (in 5-min tests). This differential effect of the lesions can be interpreted as demonstrating the existence of separate neural mechanisms and circuits for signalling the reward of different natural reinforcers (e.g. sweet taste of sucrose and sexual pheromones). Alternatively, VTA lesions may result in an impaired attribution of incentive salience (which depends on the dopaminergic tegmento-striatal system) of sucrose-predicting cues, thus leading to a long-term decrease in sucrose consumption. By contrast, the same lesions do not affect the unconditioned attraction to male-derived pheromones, which may depend on amygdalo-striatal pathways.

The effects of smoking and abstinence on experience of happiness and sadness in response to positively valenced, negatively valenced, and neutral film clips

Incentive motivation theories of addiction suggest that behavioural concomitants of compromised mesocorticolimbic reward activity during abstinence might include decreased affective reactions to natural reinforcers. This study tested implications for hedonic reactions in abstinent smokers. It was hypothesised that positively valenced (pleasurable) film clips would elicit lower ratings of happiness in abstinent than satiated smokers. Twenty-nine smokers, randomly assigned to either an ‘abstinent’ or a ‘satiated’ condition, and 15 non-smokers took part in a single session in which they rated (i) signs and symptoms of nicotine withdrawal and (ii) affective responses to positively valenced, negatively valenced, and neutral film clips. Compared with satiated smokers, abstinent smokers rated positive clips as eliciting significantly lower levels of happiness, and this was independent of self-reported nicotine withdrawal symptoms; the scores of non-smokers fell between those of abstinent and satiated smokers, more closely approximating those of the latter. By contrast, sadness ratings in response to negative clips were not affected by smoking status, indicating that the effect on happiness was not simply due to general emotional blunting. These results suggest that, for regular smokers, stimuli that are motivationally salient for the general population may elicit reduced positive affective responses during periods of abstinence.

The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats

It has been reported that N-methyl-D-aspartate (NMDA) receptor is implicated in drug addiction and antagonists of the NMDA receptor complex can inhibit the development and expression of conditioned place preference (CPP) induced by several addictive drugs, implying that this class of compounds might be considered as candidate for the treatment of substance abuse. To explore this possibility, it is important to evaluate whether the inhibitory effect of NMDA receptor antagonists would be confined to behaviors produced by drugs of abuse only, but not by natural reinforcers. According to the quantitative changes of NMDA receptor subunits, including NR1, NR2A, and NR2B, induced by diverse types of reinforcers, we chose NR2B subunit as the target of research. Experimental results showed that (1) an augmented expression of NR2B subunit was revealed by Western blotting in the nucleus accumbens (NAc) and the hippocampus in rats with CPP induced by morphine, but not by natural rewards such as food, novel environment and social interaction. (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction. Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse.

Aripiprazole Therapy for Nicotine Dependence

Aripiprazole Therapy for Nicotine Dependence

Differential involvement of the prelimbic cortex and striatum in conditioned heroin and sucrose seeking following long‐term extinction

Relapse to drug taking is triggered by stimuli previously associated with consumption of drugs of misuse (cues) and involves brain systems controlling motivated behaviour towards natural reinforcers. In this study, we aimed to identify and compare neuronal pathways in corticostriatal systems that control conditioned heroin or natural reward (sucrose) seeking. To that end, rats were trained to self-administer heroin or sucrose in association with an identical compound cue. After more than 3 weeks of abstinence during extinction training, cue exposure robustly reinstated heroin and sucrose seeking, but induced distinct and even opposing changes in the expression of the neuronal activation marker zif268 in the prelimbic cortex and striatal complex, respectively. Because in the prelimbic area zif268 expression was enhanced during cue-induced heroin seeking but unaffected during sucrose seeking, a pharmacological intervention was aimed at this prefrontal region. Injection of a GABA agonist mixture within the prelimbic area enhanced conditioned heroin seeking, but had no effect on conditioned sucrose seeking. Our findings suggest a differential role of the prelimbic area and the striatum in the persistence of heroin vs. sucrose seeking following long-term extinction.

Opposite effects of MK-801 on the expression of food and morphine-induced conditioned place preference in rats

Behavioural studies have provided strong evidence for common substrates in the rewards of natural and addictive substances, but it is still unclear whether there is a common glutamatergic NMDA receptor mechanism involved in the processing of reward for both. The present study was designed to investigate the effects of MK-801 (0.1mg/kg) on the expression of place preference conditioned with food and morphine (5.0mg/kg) in rats. The data indicates that MK-801 potentiates the expression of food-induced conditioned place preference (CPP) but retards that of morphine CPP. It also demonstrates that the opposite effects of MK-801 on food and morphine CPP expression were caused neither by hyperactivity nor by the impairment of memory retrieval. These results suggest that MK-801 enhances food craving and inhibits morphine craving in rats, and that the roles of glutamatergic NMDA receptor mechanisms in the reward processing of natural reinforcers and addictive drugs may be dissociable.

Human dopamine response to drugs and natural rewards

The anhedonia hypothesis of drug addiction posits that drugs of abuse target the same neural systems as natural rewards such as food and sex. The most likely candidate brain region is the mesolimbic dopamine system. In animals, dopamine is released in the ventral striatum, or nucleus accumbens, in response to food, sexual mates, and to almost all drugs of abuse. There are several predictions one can make from the anhedonia hypothesis: (1) dopamine release in response to reinforcers will correlate with the degree of pleasure experienced; (2) natural reinforcers and drugs of abuse will release dopamine in the same brain areas; (3) aversive stimuli will not release dopamine. These predictions can be tested with PET experiments in human subjects. The method we use consists in comparing the binding potential of the D2 ligand [11C]raclopride in baseline and activation conditions. Studies in humans: Oral amphetamine and alcohol caused dopamine release in the ventral striatum in humans. The effect was greater in individuals with the novelty-seeking personality, a risk factor for addiction. The effect did not correlate with pleasure. However, while alcohol and amphetamine caused dopamine release in the ventral striatum, two natural rewards (money and food) targeted the main body and dorsal portion of the striatum. Thus there may be a dissociation between natural and drug rewards with respect to dopamine transmission. Another possibility is that conditioned rewarding stimuli target different brain regions than novel ones. We provided evidence for this second explanation by measuring dopamine release in response to smoking cigarettes in habitual smokers. Cigarette smoking caused dopamine release in the dorsal striatum. Finally, human and animal data suggest that hyper-responsiveness of the dopamine system may be a risk factor for addiction. How does dopamine hyper-responsiveness develop? We investigated this issue using two paradigms. We showed that poor parental bonding early in life was associated with a greater dopamine response to mental stress in adulthood. We also demonstrated sensitization in human subjects: we showed that repeated doses of oral amphetamine caused an enhanced response to subsequent amphetamine. This effect persisted after one year (See Figure 1).

The dopamine D 3 receptor and drug dependence: Effects on reward or beyond?

Abused drugs (alcohol, heroin, cocaine, tetrahydrocannabinol and nicotine) elicit a variety of chronically relapsing disorders by interacting with brain reward systems. All of these drugs increase dopamine levels in the shell of nucleus accumbens, a structure that has been involved in their hedonic and reinforcing properties. Dopamine D 3 receptors (DRD3) are predominantly expressed in the nucleus accumbens, but also in the ventral tegmental area and in the amygdala, brain structures implicated in drug dependence. Moreover, converging pharmacological, human post-mortem and genetic studies have suggested the involvement of the DRD3 in drug dependence. Based on early studies using non-selective DRD3 ligands, the DRD3 was proposed as having a direct role in the rewarding effects of psychostimulants. However, recent studies using highly selective DRD3 ligands and the DRD3-deficient mice have revealed that the DRD3 is not implicated in the direct reinforcing effects of drugs of abuse. In contrast, the DRD3 appears to be implicated in the motivation to self-administer drugs under schedules where the response requirements are high. This is consistent with a behavioral economic analysis, with the effects of DRD3 ligands revealed only in situations with high prices for drug. Drug-self administration and relapse are strongly controlled by environmental stimuli. The DRD3 strongly modulates the influence of these environmental stimuli on drug-seeking behavior. DRD3 blockade disrupts the reactivity to drug-associated stimuli in various paradigms, such as second-order schedules of drug-self administration, conditioned place preference and Pavlovian conditioning procedures. In several paradigms, the involvement of the DRD3 has been confirmed by using DRD3-deficient mice. On the contrary, reactivity to stimuli associated with natural reinforcers, such as food, appears unaffected by modulation of the DRD3. All these findings suggest that DRD3 ligands may represent a useful strategy for decreasing relapse in abstinent drug-abusers.

The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewards

A challenge in treating drug addicts is preventing their pathological motivation for the drug without impairing their general affective state toward natural reinforcers. Here we have shown that discrete lesions of the subthalamic nucleus greatly decreased the motivation of rats for cocaine while increasing it for food reward. The subthalamic nucleus, a key structure controlling basal ganglia outputs, is therefore able to oppositely modulate the effect of 'natural' rewards and drugs of abuse on behavior. Modulating the activity of the subthalamic nucleus might prove to be a new target for the treatment of cocaine addiction.

Suppression of conditioned nicotine and sucrose seeking by the cannabinoid-1 receptor antagonist SR141716A

The present study shows that the selective cannabinoid CB1 receptor antagonist SR141716A attenuated responding for both nicotine- and sucrose-associated stimuli in a long-term extinction-reinstatement model. The results suggest that endocannabinoids play a general role in modulating cue reactivity or conditioned reinforcement following prolonged abstinence of both drug and natural reinforcers. In line with previous preclinical and recent clinical observations, our results provide a strong rationale for the use of CB1 antagonists in the treatment of addictive behaviors.

Preference for cocaine- versus pup-associated cues differentially activates neurons expressing either Fos or cocaine- and amphetamine-regulated transcript in lactating, maternal rodents

We studied the neuronal basis of the motivational response to two powerful but radically different rewards—cocaine and maternal nurturing of pups in the postpartum rat (dam) which is in a unique motivational state. We used a place preference method designed to offer a choice between cues associated with a natural reinforcer (pups) and those associated with a pharmacologic reinforcer (cocaine). Using c-Fos or cocaine- and amphetamine-regulated transcript (CART) immunocytochemistry, we identified the neuronal groups that are activated when the dams expressed a preference for either cues-associated with pups or cues-associated with cocaine. Dams that preferred the cocaine-associated cues had more c-Fos positive neurons in medial prefrontal cortex, nucleus accumbens, and basolateral nucleus of amygdala than pup-associated cue preferring dams or control. Except for the accumbens, there was activation of neurons in these same regions with the pup-associated cue preference. In the nucleus accumbens only CART-immunoreactive (not c-Fos) neurons were activated with pup-cue preference. Notably, the medial preoptic area was the single area where greater activation of neurons was seen with a preference for pup-associated versus cocaine-associated cues. These responses were identified in the absence of the stimuli (cocaine or pups) and are proposed to be, in part, activation of these neurons related to motivational processing. Neither the distribution of neurons responding to pup-associated cue preference nor the demonstration that CART-expressing neurons are responsive to reward-associated cue preference has been previously reported. We hypothesize that the expression of preference for cocaine versus pup-associated cues is made possible by the concerted activity of these regionally distributed networks of neurons that are in part specific to the preference response.

Nucleus accumbens dopamine receptors in the consolidation of spatial memory.

Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular events related to neural plasticity. Therefore, in this study we wished to investigate the role of the two classes of dopamine receptors within the nucleus accumbens on the consolidation of spatial information. On day 1, CD1 male mice were placed in an open field containing five different objects and, immediately after three sessions of habituation, the animals were focally injected within the nucleus accumbens with either the D1 antagonist SCH 23390 (12.5, 25 or 50 ng/side), or the D2 antagonist sulpiride (25, 50, 75 or 100 ng/side). Twenty-four hours later the ability of mice to discriminate an object displacement was assessed. Both the D1 and the D2 antagonists impaired the ability of mice to detect the spatial change. If the highest doses of the two antagonists were injected 2 h after the end of the last of the habituation sessions, no effect was observed in the reactivity to spatial change examined 24 h later. These data demonstrate that activation of both D1 and D2 receptors within the accumbens is necessary in the early stages of the consolidation of spatial information. The data are discussed in terms of involvement of nucleus accumbens dopamine in information processing in the absence of explicit reinforcers.

Decreased plasma membrane targeting of NMDA-NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self-administering morphine.

Opioid abuse is associated with repeated administration and escalation of dose that can result in profound adaptations in homeostatic processes. Potential cellular mechanisms and neural sites mediating opiate-dependent adaptations may involve NMDA-dependent synaptic plasticity within brain areas participating in behaviors related to consumption of natural reinforcers, as well as affective-autonomic integration, notably the medial nucleus tractus solitarius (mNTS). NMDA-dependent synaptic plasticity may be mediated by changes in the intracellular and surface targeting of NMDA receptors, particularly in postsynaptic sites including spines or small distal dendrites. High-resolution immunogold electron microscopic immunocytochemistry combined with morphometry were used to measure changes in targeting of the NMDA-NR1 (NR1) receptor subunit between intracellular and plasmalemmal sites in dendrites of neurons of the intermediate mNTS of rats self-administering escalating doses of morphine (EMSA). In control and EMSA rats, the density of plasmalemmal and cytosolic gold particles was inversely related to profile size. Collapsed across all NR1-labeled dendrites, rats self-administering morphine had a lower number of plasmalemmal gold particles per unit surface area (7.1 +/- 0.8 vs. 14.4 +/- 1 per 100 microm), but had a higher number of intracellular gold particles per unit cross-sectional area (169 +/- 6.1 vs. 148 +/- 5.1 per 100 microm2) compared to saline self-administering rats. Morphometric analysis showed that the decrease in plasma membrane labeling of NR1 was most robust in small dendritic profiles (<1 microm), where there was a reciprocal increase in the density of intracellular particles. These results indicate that the plasmalemmal distribution of the essential NR1 subunits in distal sites may prominently contribute to NMDA receptor-dependent modulation of neural circuitry regulating homeostatic processes, and targeting of these proteins can be prominently affected by morphine self-administration.

Volkow May Have Uncovered Answer to Addiction Riddle

Volkow May Have Uncovered Answer to Addiction Riddle

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications.

The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.