The amygdala-ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine.

Background And Purpose: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]-ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine.

Prevention of relapse to methamphetamine self-administration by environmental enrichment: involvement of glucocorticoid receptors.

Rationale: In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE's actions on the stress system.

Objectives: This study investigated whether exposure to EE during abstinence reduces methamphetamine seeking after extended self-administration. In addition, we investigated whether these effects are associated with alterations in the levels of glucocorticoid receptors (GR) in the brain and whether administration of GR antagonists blocks methamphetamine relapse.

Protracted Abstinence From Extended Cocaine Self-Administration Is Associated With Hypodopaminergic Activity in the VTA but Not in the SNc.

The chronic relapsing nature of cocaine addiction suggests that chronic cocaine exposure produces persistent neuroadaptations that may be temporally and regionally dynamic in brain areas such as the dopaminergic (DA) system. We have previously shown altered metabolism of DA-target structures, the ventral and dorsal striatum, between early and late abstinence. However, specific changes within the midbrain DA system were not investigated.

Dopamine and addiction: what have we learned from 40 years of research.

Among the neurotransmitters involved in addiction, dopamine (DA) is clearly the best known. The critical role of DA in addiction is supported by converging evidence that has been accumulated in the last 40 years. In the present review, first we describe the dopaminergic system in terms of connectivity, functioning and involvement in reward processes.

Dopamine System Dysregulation in Major Depressive Disorders.

Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, including the ventral subiculum of the hippocampus and the basolateral amygdala. Whereas basic and clinical studies demonstrate deficits of the dopaminergic system in depression, the origin of these deficits likely lies in dysregulation of its regulatory afferent circuits.

Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration.

The chronic and relapsing nature of addiction suggests that drugs produce persistent adaptations in the brain that make individuals with drug addiction particularly sensitive to drug-related cues and stress and incapable of controlling drug-seeking and drug-taking behavior. In animal models, several long-lasting neuroadaptations have been described. However, few studies have used brain-imaging techniques to provide a complete picture of brain functioning in the course of withdrawal from cocaine.

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine.

Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats.

Regulation of dopamine system responsivity and its adaptive and pathological response to stress.

Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood.

Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity.

Background: One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients.

Role of the prefrontal cortex in altered hippocampal-accumbens synaptic plasticity in a developmental animal model of schizophrenia.

Schizophrenia is characterized by alterations in cortico-limbic processes believed to involve modifications in activity within the prefrontal cortex (PFC) and the hippocampus. The nucleus accumbens (NAc) integrates information from these 2 brain regions and is involved in cognitive and psychomotor functions that are disrupted in schizophrenia, indicating an important role for this structure in the pathophysiology of this disorder. In this study, we used in vivo electrophysiological recordings from the NAc and the PFC of adult rats and the MAM developmental disruption rodent model of schizophrenia to explore the influence of the medial PFC on the hippocampal-accumbens pathway.

Disruption of prefrontal cortical-hippocampal balance in a developmental model of schizophrenia: reversal by sulpiride.

The nucleus accumbens (NAc) receives converging inputs from the medial prefrontal cortex (mPFC) and the hippocampus which have competitive interactions in the NAc to influence motivational drive. We have previously shown altered synaptic plasticity in the hippocampal-NAc pathway in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in rodents that is dependent on cortical inputs. Thus, because mPFC-hippocampal balance is known to be partially altered in this model, we investigated potential pathological changes in the hippocampal influence over cortex-driven NAc spike activity.

Reorganization of striatal inhibitory microcircuits leads to pathological synchrony in the Basal Ganglia.

Neural synchronization plays an important role in information flow in the nervous system under healthy and pathological conditions. In this issue of Neuron, Gittis et al. show that reorganization of striatal microcircuits promotes synchronous activity and may underlie the pathological network oscillations at the root of motor symptoms described in Parkinson's disease.

Hippocampus, amygdala, and stress: interacting systems that affect susceptibility to addiction.

Stress is one of the major factors in drug abuse, particularly in relapse and drug-seeking behavior. However, the mechanisms underlying the interactions between stress and drug abuse are unclear. For many years, studies have focused on the role of the dopaminergic reward system in drug abuse.

Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment.

Chronic levodopa treatment for Parkinson's disease often results in the development of abnormal involuntary movement, known as L-dopa-induced dyskinesia (LIDs). Studies suggest that LIDs may be associated with aberrant corticostriatal plasticity. Using in vivo extracellular recordings from identified Type I and Type II medium spiny striatal neurons, chronic L-dopa treatment was found to produce abnormal corticostriatal information processing.

Involvement of Basal Ganglia network in motor disabilities induced by typical antipsychotics.

Background: Clinical treatments with typical antipsychotic drugs (APDs) are accompanied by extrapyramidal motor side-effects (EPS) such as hypokinesia and catalepsy. As little is known about electrophysiological substrates of such motor disturbances, we investigated the effects of a typical APD, alpha-flupentixol, on the motor behavior and the neuronal activity of the whole basal ganglia nuclei in the rat.

Methods And Findings: The motor behavior was examined by the open field actimeter and the neuronal activity of basal ganglia nuclei was investigated using extracellular single unit recordings on urethane anesthetized rats.

Summary of the 1st Schizophrenia International Research Society Conference oral sessions, Venice, Italy, June 21-25, 2008: the rapporteur reports.

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. A wide range of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversies about early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology and neurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiology and for use as targets in drug studies.

Critical role of the prefrontal cortex in the regulation of hippocampus-accumbens information flow.

The nucleus accumbens (NAc) is an integral part of limbic circuits proposed to play a central role in the pathophysiology of schizophrenia, and is positioned to integrate information from limbic and cortical regions, including the medial prefrontal cortex (mPFC) and the hippocampus. The ventral subiculum (vSub) of the hippocampus, in particular, is proposed to gate information flow within the NAc, a factor that is disrupted in models of schizophrenia. Using in vivo extracellular recordings in anesthetized rats, we examined the response of NAc neurons to vSub stimulation and how this is modulated by the mPFC.

Noradrenergic modulation of subthalamic nucleus activity: behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats.

The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine (6-OHDA)-lesioned rats.