Bryon Adinoff

Neurobiologic Processes in Drug Reward and Addiction

&NA; Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These “hard‐wired” changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

Suppression of the HPA Axis Stress-Response: Implications for Relapse

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the placebo group, but not the medication groups [corrected] Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects. Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcohol-dependent subjects, and disinhibition of the axis with medication may have therapeutic potential.

The Role of Acetylcholine in Cocaine Addiction

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Drug abuse and bipolar disorder: comorbidity or misdiagnosis?

Bipolar disorder is a common, severe and cyclic psychiatric illness. A strong association between alcohol dependence and bipolar disorder has been reported in numerous studies. The abuse of other drugs including cocaine, amphetamines, opiates, cannabis, and prescription medications in bipolar patients is also an important public health concern and has been less extensively investigated. This review examines the abuse of drugs other than alcohol or nicotine in people with bipolar disorder. The high rates of milder affective symptoms but not mania observed in patients in drug abuse treatment settings suggests the symptoms may in many cases be associated with the drug use. However, such patients presenting in psychiatric settings might be suffering from cyclothymic and related attenuated bipolar disorders (type II). Substance abuse may be associated with medication non-compliance, more mixed or dysphoric mania and possibly an earlier onset of affective symptoms and more hospitalizations. The pharmacotherapy of patients with bipolar disorder and drug abuse is examined, including evidence on the use of mood stabilizers, neuroleptics and the newer atypical antipsychotics in this population.

Increased Salivary cortisol concentrations during Chronic alcohol intoxication in a naturalistic clinical sample of men

BACKGROUND Cortisol, the primary glucocorticoid in humans, is intimately involved in the regulation of such varied and critical biological processes as emotion, cognition, reward, immune functioning, and energy utilization. A persistent increase in cortisol concentration as a result of chronic intoxication could therefore result in alcohol-related disorders such as sleep disruption, cognitive deficits, diabetes, and mood disturbances. Although moderate levels of acute alcohol ingestion are reported to produce an increase in cortisol levels, it is uncertain whether cortisol remains persistently increased during long-term chronic intoxication. METHODS Salivary cortisol and breath alcohol concentrations (BAC) were obtained on 73 subjects with primary alcohol dependence on initial presentation for treatment and 22 alcohol-dependent subjects participating in a residential treatment program. RESULTS Both intoxicated alcohol-dependent subjects (n = 38) and nonintoxicated subjects in acute alcohol withdrawal (n = 30) demonstrated significantly increased salivary cortisol concentrations compared with abstinent subjects (n = 27; p < 0.001). Nonintoxicated subjects in acute withdrawal demonstrated significantly increased salivary cortisol concentrations compared with highly intoxicated subjects (BAC >100 mg/dl) but were similar to subjects with lower levels of intoxication (BAC, 10-100 mg/dl). CONCLUSIONS Chronic alcohol-dependent subjects experience continuously increased concentrations of cortisol during both intoxication and withdrawal. Increased levels of cortisol during chronic intoxication seem to progressively increase with the onset of withdrawal. This suggests a daily cycle of hypercortisolemia during the active drinking phase, with further increases on the cessation of drinking and the emergence of withdrawal symptoms. Persistently increased levels of cortisol may extract a costly allostatic load, resulting in significant central nervous system and peripheral organ morbidity.

Comprehensive review of the psychiatric uses of valproate

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as treatment for psychiatric conditions, including bipolar, depressive, anxiety, and psychotic disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation associated with dementia; and borderline personality disorder. Valproate shows the most promising efficacy in treating mood and anxiety disorders, with possible efficacy in the treatment of agitation and impulsive aggression, and less convincing therapeutic response in treating psychosis and alcohol withdrawal or dependence. The authors conclude with a brief summary of its mechanism of action and therapeutic spectrum.

Alcoholic organic brain disease: Nosology and pathophysiologic mechanisms

Study of alcoholic chronic organic brain syndrome may have applicability to the large population of alcoholics with less severe cerebral dysfunction. Brain impairment in alcoholics may be conceptualized as two clinically and neuropathologically distinguishable organic brain syndromes: alcohol amnestic disorder or Korsakoffs psychosis (KP) and alcoholic dementia. Alcoholic organic brain disease may result from two interacting pathophysiological processes: nutritional (thiamine) deficiency and ethanol neurotoxicity. Subcortical periventricular lesions associated with KP result primarily from thiamine deficiency, whereas ethanol neurotoxicity and various secondary effects of alcoholism may contribute to the cortical neuropathological changes associated with alcoholic dementia. These two patterns of brain damage may be differentiable in individual alcoholics using cognitive tests and other measures of CNS function and, therefore, allow selection of a treatment strategy based on pathophysiological considerations. Studies in animals and humans suggest that a genetic predisposition to thiamine deficiency may contribute to alcoholism-associated dysfunction of brain and other organ systems and possibly have a causative role in the development of alcoholism.

Acute Ethanol Poisoning and the Ethanol Withdrawal Syndrome

SummaryEthanol, a highly lipid-soluble compound, appears to exert its effects through interactions with the cell membrane. Cell membrane alterations indirectly affect the functioning of membrane-associated proteins, which function as channels, carriers, enzymes and receptors. For example, studies suggest that ethanol exerts an effect upon the γ-aminobutvric acid (GABA)-benzodiazepine-chloride ionophore receptor complex, thereby accounting for the biochemical and clinical similarities between ethanol, benzodiazepines and barbiturates.The patient with acute ethanol poisoning may present with symptoms ranging from slurred speech, ataxia and incoordination to coma, potentially resulting in respiratory depression and death. At blood alcohol concentrations of greater than 250 mg% (250 mg% = 250 mg/dl = 2.5 g/L = 0.250%), the patient is usually at risk of coma. Children and alcohol-naive adults may experience severe toxicity at blood alcohol concentrations less than WO mg%, whereas alcoholics may demonstrate significant impairment only at concentrations greater than 300 mg%. Upon presentation of a patient suspected of acute ethanol poisoning, cardiovascular and respiratory stabilisation should be assured. Thiamine (vitamin B1) and then dextrose should be administered, and the blood alcohol concentration measured. Subsequent to stabilisation, alternative aetiologies for the signs and symptoms observed should be considered. There are presently no agents available for clinical use that will reverse the acute effects of ethanol. Treatment consists of supportive care and close observation until the blood alcohol concentration decreases to a non-toxic level. In the non-dependent adult, ethanol is metabolised at the rate of approximately 15 mg%/ hour. Haemodialysis may be considered in cases of a severely ill child or comatose adult. Follow-up may include referral for counselling for alcohol abuse, suicide attempts, or parental neglect (in children).The ethanol withdrawal syndrome may be observed in the ethanol-dependent patient within 8 hours of the last drink, with blood alcohol concentrations in excess of 200 mg%. Symptoms consist of tremor, nausea and vomiting, increased blood pressure and heart rate, paroxysmal sweats, depression, and anxiety. Alterations in the GABA-benzodiazepine-chloride receptor complex, noradrenergic overactivity, and hypothalamic-pituitary-adrenal axis stimulation are suggested explanations for withdrawal symptomatology. The initial evaluation of ethanol withdrawal requires taking a history of ethanol intake, assessment of severity of past withdrawal episodes and other drug intake, and a physical examination to evaluate potential coexisting illnesses.As most patients in ethanol withdrawal do not require pharmacotherapy, a clinical evaluation, including measurement of the blood alcohol concentration and objective rating (i.e. CIWA-A scale) of withdrawal severity is indicated upon admission. Mild withdrawal symptoms may be treated with supportive care only (comfort, fluids, thiamine, multivi-tamins). Moderate withdrawal (tremors, agitation, diaphoresis) is generally well controlled with pharmacotherapy (oral diazepam 10mg every 6 hours according to circumstances). A loading dose of diazepam (10 mg orally every hour) until symptoms subside, then every 6 hours when necessary is recommended for severe ethanol withdrawal (marked autonomic hyperactivity, severe distress, prodromal symptoms of delirium tremens). Other benzodiazepines or carbamazepine are also effective in the treatment of ethanol withdrawal.Other complications of the ethanol withdrawal syndrome should be treated as follows. Elevated blood pressure not responding to benzodiazepines, clonidine 0.2mg every hour, then every 6 hours when necessary; arrhythmias, potassium and magnesium replacement, or more aggressive treatment as indicated; seizures, if history of withdrawal seizures, treat prophylactically. Following grand mal seizures, treat with benzodiazepines or carbamazepine. Other types of seizures require neurological evaluation for alternative aetiologies. Delirium tremens, exclude complicating illnesses; administer diazepam Wmg intravenously every 30 to 60 minutes for sedation, haloperidol 5mg intramuscularly every 6 hours for severe agitation, propranolol 1 mg intravenously every 5 minutes (up to 5mg) for sympathetic hyperactivity. Fluid/electrolyte imbalance should be corrected as needed.All patients in ethanol withdrawal, if physically able, should partake in an alcohol treatment programme. Following resolution of the withdrawal syndrome, further inpatient or outpatient therapy, including Alcoholics Anonymous (AA), is required to maintain sobriety.

Dose-related effects of ethanol on visual sustained attention and event-related potentials

The effects of acute ethanol intoxication on visual sustained attention were investigated in male social drinkers. Four doses ranging from 0 (placebo) to 1.05 g/kg lean body weight, with periodic maintenance dosing of 0.12 g/kg, were given in separate sessions. The task required subjects to monitor a series of blurred digits presented singly at a rate of one per sec and to respond to occasional (p = 0.25) target digits with a speeded button press. Detection performance deteriorated as a function of both dose and time on task. In addition, the factors of dose and time on task interacted to produce a more rapid performance decrement under the higher doses. Early event-related potential (ERP) components (N1 and P2) were not greatly affected, suggesting that the performance decrement reflects central rather than peripheral factors. Later components related to cognitive appraisal processes (N2, P3), in contrast, varied in both amplitude and latency. Ethanol yielded dose-related delays in N2 and P3 latencies, which paralleled reaction time increases. The amplitude of N2 also decreased over time on task, and P3 amplitude decreased both as a function of dose and time on task. ERP and performance data were interpreted as demonstrating an adverse effect of ethanol on central processing capacity.

Tanning as a Behavioral Addiction

Background: Persistent tanning despite potentially fatal consequences suggests a compulsive behavior similar to other addictive disorders. Objectives: To review the literature supporting tanning addiction from an epidemiological, behavioral, and neurobiological perspective. Methods: A comprehensive review of the medical literature was conducted to assess the health consequences of tanning, behaviors and other psychiatric disorders associated with tanning, and central rewarding effects of ultraviolet light. Results: Many frequent tanners endorse signs and symptoms adapted from Diagnostic and Statistical Manual-IV (DSM IV) substance abuse or dependence criteria. Recent studies suggest biochemical mechanisms may reinforce ultraviolet light seeking behavior. Conclusions and Scientific Significance: Frequent and persistent tanning may reveal itself to be a dermatologic-psychiatric disorder with carcinogenic sequelae. Multidisciplinary studies are required to determine the validity of an addiction diagnosis and to explore pharmacologic and cognitive therapeutic options for affected persons.