Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events

While it has previously been assumed that mesolimbic dopamine neurons carry a reward signal, recent data from single-unit, microdialysis and voltammetry studies suggest that these neurons respond to a large category of salient and arousing events, including appetitive, aversive, high intensity, and novel stimuli. Elevations in dopamine release within mesolimbic, mesocortical and nigrostriatal target sites coincide with arousal, and the increase in dopamine activity within target sites modulates a number of behavioral functions. However, because dopamine neurons respond to a category of salient events that extend beyond that of reward stimuli, dopamine levels are not likely to code for the reward value of encountered events.The paper (i) examines evidence showing that dopamine neurons respond to salient and arousing change in environmental conditions, regardless of the motivational valence of that change, and (ii) asks how this might shape our thinking about the role of dopamine systems in goal-directed behavior.     

Alpha7 nicotinic cholinergic neuromodulation may reconcile multiple neurotransmitter hypotheses of schizophrenia

The long prevailing hypothesis of schizophrenia pathogenesis implicates dopaminergic systems in the mesolimbic pathways as responsible for the positive symptoms of schizophrenia (hallucinations and delusions) and those in the mesocortical pathway as contributing to the negative symptoms (e.g., social disconnection, flattened affect and anhedonia). Several challenges to the dopamine hypothesis and the proposal of an alternative hypothesis implicating glutamate have provided additional support for the development of non-dopaminergic drugs for the management of schizophrenia symptomatology. Furthermore, preclinical and clinical evidence of alpha7 neuronal nicotinic acetylcholine receptor-mediated benefits in the triad of positive symptoms, negative symptoms and cognitive dysfunction in schizophrenia, as well as the genetic linkage of this receptor to the disease, have added another level of complexity. Thus schizophrenia is increasingly believed to involve multi-neurotransmitter deficits, all of which may contribute to altered dopaminergic tone in the mesolimbic, mesocortical and other areas of the brain. In this paper we provide a model that reconciles the dopamine, glutamate and alpha7 cholinergic etiopathogenesis and is consistent with the clinical benefit derived from therapies targeted to these individual pathways.     

The weaver mutant mouse: a model to study the ontogeny of dopamine transmission systems and their role in drug addiction

Dopaminergic neurons and their projection-systems are important in some fundamental human activities like locomotion, feeding and sex, essential for survival and procreation, and are relevant to pathologies like Parkinson's disease and drug abuse. Three main dopaminergic projection-systems, namely the nigrostriatal, mesocortical and mesolimbic pathways are the major targets of the neuropharmacological actions of psychomotor stimulants such as cocaine and amphetamine. Studies on knockout mice for dopamine or its receptors provide substantial information but fail to reveal the role of individual dopaminergic projection-systems. Mutant animals with defects specific to one or more projection-systems might be useful for studying the role of individual dopaminergic projection-systems. We propose the weaver mutant mouse, with a defective nigrostriatal dopaminergic projection-system and dopamine depletion in the dorsal striatum but with intact mesocorticolimbic projection-systems, as a suitable model to study the role of individual dopaminergic systems in diverse biological processes including Parkinson's disease and drug abuse.     

Risk factors for neuroleptic malignant syndrome.

Neuroleptic malignant syndrome, a rare and potentially fatal complication of antipsychotic drugs, is poorly understood. Equally poorly understood are the risk factors of neuroleptic malignant syndrome. Long-term and parenteral treatment with high doses of neuroleptic drugs are implicated as risk factors for the syndrome. Recently, attention has been drawn to the frequency of neuroleptic malignant syndrome in patients treated with a combination of haloperidol and lithium. This article reports a case in which the patient's risk factors for neuroleptic malignant syndrome included not only haloperidol and lithium but also a predisposition to substances of abuse.     

Association analysis of the proneurotensin gene and bipolar disorder

Neurotensin (NT) localizes within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems, and it is now clear that NT can selectively modulate dopaminergic neurotransmission. It has therefore been proposed that altered NT function might contribute to the pathogenesis of neuropsychiatric disorders in which disordered dopaminergic neurotransmission is suspected. We have previously screened the gene encoding NT in a sample of schizophrenic and bipolar subjects, and identified three sequence variants. These have now been tested for association with bipolar disorder using a case-control sample of unrelated bipolar subjects and matched controls. No evidence for association was found, and our data therefore suggest that sequence variation in this gene does not make an important contribution to susceptibility to bipolar disorder.     

Methamphetamine acts on subpopulations of neurons regulating sexual behavior in male rats

Methamphetamine (Meth) is a highly addictive stimulant. Meth abuse is commonly associated with the practice of sexual risk behavior and increased prevalence of Human Immunodeficiency Virus and Meth users report heightened sexual desire, arousal, and sexual pleasure. The biological basis for this drug–sex nexus is unknown. The current study demonstrates that Meth administration in male rats activates neurons in brain regions of the mesolimbic system that are involved in the regulation of sexual behavior. Specifically, Meth and mating co-activate cells in the nucleus accumbens core and shell, basolateral amygdala, and anterior cingulate cortex. These findings illustrate that in contrast to current belief drugs of abuse can activate the same cells as a natural reinforcer, that is sexual behavior, and in turn may influence compulsive seeking of this natural reward.     

Dopamine,addiction and reward

The role of dopamine was inferred in reward processes from early studies showing that psychomotor stimulants such as cocaine and amphetamine could facilitate intracranial self-stimulation. Subsequent studies showed that dopamine-receptor antagonists could attenuate brain stimulation reward and completely block the reinforcing effects of cocaine and amphetamine as measured by direct intravenous self-administration of these drugs. A specific dopaminergic substrate for both the facilitation of brain stimulation reward and the self-administration of psychomotor stimulants appears to be the region of the nucleus accumbens in the forebrain. This structure receives significant limbic afferents and has significant projections to the extrapyramidal motor system. Chronic administration of cocaine and amphetamine seem to have the opposite effects to acute injections and during withdrawal lead to increases in brain stimulation reward thresholds and decreases in dopamine release in the nucleus accumbens. This same nucleus accumbens dopamine projection seems to be critical for the motor activation associated with the anticipation of both drug and non-drug rewards. These results suggest that drugs that activate the mesolimbic dopamine system have such powerful reinforcing effects because they facilitate the attentional-motor systems critical for approach behaviour and the behavioural activation associated with incentive-motivation.     

Involvement of the brain histaminergic system in addiction and addiction-related behaviors: A comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is involved in many physiological and behavioral functions such as arousal, feeding behavior and learning. Although conflicting data have been published, several studies have also demonstrated a role of histamine in the psychomotor and rewarding effects of addictive drugs. Pharmacological and brain lesion experiments initially led to the proposition that the histaminergic system exerts an inhibitory influence on drug reward processes, opposed to that of the dopaminergic system. The purpose of this review is to summarize the relevant literature on this topic and to discuss whether the inhibitory function of histamine on drug reward is supported by current evidence from published results. Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors. Finally, the hypothesis that the histaminergic system plays an inhibitory role on drug reward appears to be essentially supported by place conditioning studies that focused on morphine reward. The present review suggests that the development of drugs capable of activating the histaminergic system may offer promising therapeutic tools for the treatment of opioid dependence.     

Is dopamine required for natural reward?

Reward is fundamental to the organization of behavior, and the neurotransmitter dopamine (DA) is widely recognized to be critical to the neurobiology of reward, learning and addiction. Virtually all drugs of abuse, including heroin and other opiates, alcohol, cocaine, amphetamine and nicotine activate dopaminergic systems. So called "natural" rewards such as food, positive social interactions and even humor, likewise activate DA neurons and are powerful aids to attention and learning. Sweet solutions are a well-characterized natural reward. When a source of sugar is encountered, animals will consume substantial amounts, return to it preferentially, and will work to obtain access. Dopamine systems are activated in animals drinking sugar solutions, and lesions of dopaminergic neurons or pharmacological blockade of DA receptors seem to reduce the reward value of both sweet tastes and drugs of abuse. However, we have recently demonstrated that genetically modified mice that cannot make DA (DD mice) manifest normal sucrose preference. During preference tests, mutant mice initiated licking less frequently than did normal mice, but the rate of licking by DD mice for sweets was actually higher than that of normal mice, indicating that their motor ability to lick is intact. We conclude that DA is not required for the hedonic response to sweets nor for their discrimination. This brief and slightly humorous review discusses these findings in the context of current and historical answers to the question, "What is the role of DA in reward?"     

Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system

The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABA(B) receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC(50)) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABA(B) receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse gamma-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABA(B) receptor agonists exert parallel cellular and behavioral effects due to the cell-specific expression of GIRK subunits.     

Susceptibility of ascending dopamine projections to 6-hydroxydopamine in rats: effect of hypothermia

The aims of this study were to determine (1) whether mesolimbic and nigrostriatal DA cell bodies degenerate to different extents after 6-hydroxydopamine (6-OHDA) is administered into their respective terminal fields and (2) whether hypothermia, associated with sodium pentobarbital anesthesia, protects DA neurons from the toxic effects of 6-OHDA. To address these questions, 6-OHDA or vehicle was infused into either the ventral or dorsal striatum or into the medial forebrain bundle, under conditions of brain normothermia or hypothermia. Two weeks post-surgery, tyrosine hydroxylase-positive cell bodies were counted in the ventral tegmental area (VTA) and substantia nigra. In addition, autoradiographic labeling of tyrosine hydroxylase protein and dopamine transporter was quantified in dopamine terminal fields and cell body areas. Overall, DA cell bodies in the VTA were substantially less susceptible than those in the substantia nigra to depletion of dopaminergic markers. Hypothermia provided two types of neuroprotection. The first occurred when 6-OHDA was administered into the dorsal striatum, and was associated with a 30-50% increase in residual dopaminergic markers in the lateral portion of the VTA. The second neuroprotective effect of hypothermia occurred when 6-OHDA was given into the medial forebrain bundle. This was associated with a 200-300% increase in residual dopaminergic markers in the mesolimbic and nigrostriatal terminal fields; no significant protection occurred in the cell body regions.Collectively, these findings show that (1) the dopaminergic somata in the substantia nigra are more susceptible than those in the VTA to 6-OHDA-induced denervation, and (2) hypothermia can provide anatomically selective neuroprotection within the substantia nigra-VTA cell population. The continued survival of mesolimbic dopamine cell bodies after a 6-OHDA lesion may have functional implications relating to drugs of abuse, as somatodendritic release of dopamine in the VTA has been shown to play a role in the effectiveness of cocaine reward.     

The mesocortical dopamine projection to anterior cingulate cortex plays no role in guiding effort-related decisions

Both mesolimbic dopamine (DA) and the anterior cingulate cortex (ACC) have been implicated in enabling animals to expend effort to obtain greater reward. To investigate the role of the DA pathway to ACC in working for reward, the authors tested rats on a cost-benefit T-maze paradigm in which they could either climb a barrier to obtain large reward in 1 arm (high reward [HR]) or select the low-effort alternative containing less reward (low reward [LR]). Surprisingly, ACC DA depletions had no effect on choice performance. Manipulations of barrier and reward sizes demonstrated that lesioned rats were as sensitive to the costs and benefits of the alternatives as controls. These results imply that the DA projection to ACC is not involved in guiding effort-related decisions.     

Phenotypic and genotypic characterization of the Indiana University rat lines selectively bred for high and low alcohol preference

The Indiana lines of selected rats, the HAD and LAD replicates and the P and NP lines, were bred for high and low alcohol preference. The P and HAD lines have met criteria for an animal model of alcoholism in that they voluntarily consume sufficient ethanol to achieve significant blood alcohol concentrations, and their alcohol-seeking behavior is reinforced by the pharmacological effects of ethanol rather than its taste, caloric content, or other properties. These lines have been characterized extensively for associated behavioral and physiological phenotypes. The P and HAD rats show an enhanced responsiveness to the stimulatory effects of ethanol and reduced sensitivity to the aversive sedative effects of ethanol. Consistent findings with the selected lines include differences in the mesolimbic dopamine reward system, as well as differences in serotonin, GABA, endogenous opioid, and neuropeptide Y systems. Genetic mapping studies have identified quantitative trait loci influencing alcohol preference on chromosomes 3, 4, and 8 in the inbred P/NP rats and on chromosomes 5, 10, 12, and 16 in the noninbred HAD1/LAD1 rats. The elucidation of the genotypes and phenotypes that result in excessive alcohol intake may lead to a better understanding of alcohol abuse and alcoholism and could guide strategies for potential treatment and prevention.     

Early relapse in alcohol dependence may result from late withdrawal symptoms

Alcohol dependence has two distinct clinical features: (1) Physiological Dependence (PD), which characterizes the pharmacological tolerance that alcohol progressively induces in the brain and (2) Alcohol Addiction (AA), which is the behavioral conditioning of alcohol drinking resulting from the chronic activation of the reward system.PD results from a progressive imbalance between excitatory and inhibitory neurotransmission systems and leads to the occurrence of Alcohol Withdrawal Syndrome (AWS), which is prevented by benzodiazepines in cases of alcohol cessation. AA is considered to persist much longer and results from a disruption of the dopaminergic mesolimbic pathway, which is treated by anticraving drugs. Relapse in alcohol dependence is usually considered to be the result of AA.However, 50% of the relapses in alcohol occur within the first month after alcohol cessation. During this period, it has been shown that many patients experience anxious symptoms that have been neurobiologically related to withdrawal symptoms and PD. Thus, we hypothesize that early relapses are more the consequence of late symptoms of PD than AA. From this standpoint, we propose that prolonged treatment with benzodiazepines may reduce the first-month relapse rate.     

Running is rewarding and antidepressive

Natural behaviors such as eating, drinking, reproduction and exercise activate brain reward pathways and consequently the individual engages in these behaviors to receive the reward. However, drugs of abuse are even more potent in activating the reward pathways. Rewarding behaviors and addictive drugs also affect other parts of the brain not directly involved in the mediation of reward. For instance, running increases neurogenesis in hippocampus and is beneficial as an antidepressant in a genetic animal model of depression and in depressed humans. Here we discuss and compare neurochemical and functional changes in the brain after addictive drugs and exercise with a focus on brain reward pathways and hippocampus.     

Chronic food restriction: enhancing effects on drug reward and striatal cell signaling

Chronic food restriction (FR) increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, which shares comorbidity with drug abuse, in clinical populations. Behavioral, biochemical and molecular studies conducted in this laboratory to elucidate the functional and mechanistic bases of these phenomena are briefly reviewed. Results obtained to date indicate that FR increases the reward magnitude and locomotor-activating effects of abused drugs, and direct dopamine (DA) receptor agonists, as a result of neuroadaptations rather than changes in drug disposition. Changes in striatal DA dynamics, and postsynaptic cell signaling and gene expression in response to D-1 DA receptor stimulation have been observed. Of particular interest is an upregulation of NMDA receptor-dependent MAP kinase and CaM Kinase II signaling, CREB phosphorylation, and immediate-early and neuropeptide gene expression in nucleus accumbens (NAc) which may facilitate reward-related learning, but also play a role in the genesis of maladaptive goal-directed behaviors. Covariation of altered drug reward sensitivity with body weight loss and recovery suggests a triggering role for one of the endocrine adiposity hormones. However, neither acute nor chronic central infusions of leptin or the melanocortin 3/4 receptor agonist, MTII, have attenuated d-amphetamine reward or locomotor activation in FR rats. Interestingly, chronic intracerebroventricular leptin infusion in ad libitum fed (AL) rats produced a sustained decrease in food intake and body weight that was accompanied by a reversible potentiation of rewarding and locomotor-activating effects of d-amphetamine. This raises the interesting possibility that rapid progressive weight loss is sufficient to increase behavioral sensitivity to drugs of abuse. Whether weight loss produced by leptin infusion produces the same neuroadaptations as experimenter-imposed FR, and whether any of the observed neuroadaptations are necessary for expression of increased behavioral responsiveness to acute drug challenge remain to be investigated.     

NIH symposium series: ingestive mechanisms in obesity, substance abuse and mental disorders

This report summarizes the background and specific objectives for a symposium on the neurobiology of nonhomeostatic eating and drug abuse that was held at the 2004 Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB). The symposium was the first of a series funded by a conference grant from four institutes of the National Institutes of Health. The encompassing goal of the series is to analyze the roles for the biological mechanisms of ingestion in obesity, eating disorders and other theoretically related areas including addiction, depression and schizophrenia. The symptoms and treatments of these diverse pathologies routinely involve aberrations in the mechanisms regulating eating and body weight. The presentations and discussion from this symposium (1) identified changes in neurotransmitter dynamics and gene expression in brain "reward circuits" accompanying learning of behaviors to obtain palatable foods or drugs of abuse; (2) analyzed behavioral findings in animals and humans, and neuroimaging data in humans, supporting treatment with GABA(B) agonists to reduce craving for drugs of abuse and possibly for highly rewarding foods; and (3) used neuroimaging data in humans to establish novel serotonergic targets for normalizing reward processes and impulse control in anorexia nervosa and bulimia. Overall, the symposium clearly revealed our rapidly broadening understanding of the alterations in the brain at the molecular, cellular and systems levels that are associated with craving and nonhomeostatic consumption of food and drugs of abuse. This knowledge gained largely in animal models translates to novel and better strategies for treating human patients.     

Beta-endorphin and drug-induced reward and reinforcement

Although drugs of abuse have different acute mechanisms of action, their brain pathways of reward exhibit common functional effects upon both acute and chronic administration. Long known for its analgesic effect, the opioid beta-endorphin is now shown to induce euphoria, and to have rewarding and reinforcing properties. In this review, we will summarize the present neurobiological and behavioral evidences that support involvement of beta-endorphin in drug-induced reward and reinforcement. Currently, evidence supports a prominent role for beta-endorphin in the reward pathways of cocaine and alcohol. The existing information indicating the importance of beta-endorphin neurotransmission in mediating the reward pathways of nicotine and THC, is thus far circumstantial. The studies described herein employed diverse techniques, such as biochemical measurements of beta-endorphin in various brain sites and plasma, and behavioral measurements, conducted following elimination (via administration of anti-beta-endorphin antibodies or using mutant mice) or augmentation (by intracerebral administration) of beta-endorphin. We suggest that the reward pathways for different addictive drugs converge to a common pathway in which beta-endorphin is a modulating element. beta-Endorphin is involved also with distress. However, reviewing the data collected so far implies a discrete role, beyond that of a stress response, for beta-endorphin in mediating the substance of abuse reward pathway. This may occur via interacting with the mesolimbic dopaminergic system and also by its interesting effects on learning and memory. The functional meaning of beta-endorphin in the process of drug-seeking behavior is discussed.     

Cell-type specific increases in female hamster nucleus accumbens spine density following female sexual experience

Female sexual behavior is an established model of a naturally motivated behavior which is regulated by activity within the mesolimbic dopamine system. Repeated activation of the mesolimbic circuit by female sexual behavior elevates dopamine release and produces persistent postsynaptic alterations to dopamine D1 receptor signaling within the nucleus accumbens. Here we demonstrate that sexual experience in female Syrian hamsters significantly increases spine density and alters morphology selectively in D1 receptor-expressing medium spiny neurons within the nucleus accumbens core, with no corresponding change in dopamine receptor binding or protein expression. Our findings demonstrate that previous life experience with a naturally motivated behavior has the capacity to induce persistent structural alterations to the mesolimbic circuit that can increase reproductive success and are analogous to the persistent structural changes following repeated exposure to many drugs of abuse.     

Myocardial signs of cardiotoxicity

The myocardium have been get from 70 died patients suffered from schizophrenia and treated by neuroleptic drugs. The cardiotoxic effect of neuroleptic drugs was characterized as adaptive, degenerative, and fibrous changes in the miocardium. In the extracellular matrix of the myocardium the processes of microcirculation and the collagenogenesis were damaged. As a result of the using neuroleptic drugs a compensatory hypertrophy of cardiomyocytes was transformed into their degeneration and atrophy that could be reason of a heart failure.