Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine

Three weeks following intermittent amphetamine exposure (2.5 mg/kg/day for 5 days), rats showed an enhanced locomotor response to an amphetamine challenge. Mifepristone (20 mg/kg) given 45 min prior to the challenge completely prevented the expression of amphetamine hyperresponsiveness. The glucocorticoid antagonist did not affect the locomotor response to amphetamine in drug-naive rats. These data demonstrate for the first time that glucocorticoid receptor antagonist treatment may prevent long-term hyperreactivity to drugs of abuse in individuals with a drug history.     

Strain-dependent behavioural sensitization to amphetamine: role of environmental influences

Repeated daily pairings of 1mg/kg of amphetamine and test environment induced a large, significant increase of locomotion in mice of the C57BL/6 strain, while a slight, non-significant increase was observed in mice of the DBA/2 strain. Neither C57BL/6 nor DBA/2 mice showed behavioral sensitization to amphetamine in the test cages when the drug was repeatedly administered in their home cage. Moreover, C57BL/6 but not DBA/2 mice showed conditioned hyperactivity. Subsequently six daily pairings of saline and test cage produced a slight, non-significant reduction of the hyperactive response shown by C57BL/6 mice, accompanied by a further increase in the behavioural effect of amphetamine. Finally, a similar, significant context-independent sensitization (unpaired vs control) was observed in mice of the two strains subjected to pairings of saline with the test cage; while context-dependent sensitization (paired vs unpaired) was observed only in C57BL/6 mice. Naive DBA/2 were less susceptible than C57BL/6 mice to the behavioural effect of high doses of amphetamine. However, effects of the low dose of amphetamine used in this experiment did not show strain differences in naive mice. These results show that C57BL/6 are more susceptible than DBA/2 mice to context-dependent behavioural sensitization to amphetamine. Moreover, they suggest that neither conditioned hyperactivity nor context-independent sensitization account for strain differences in environment-specific behavioural sensitization.     

Neurocognitive and neuroimaging evidence of behavioural dysregulation in human drug addiction: implications for diagnosis, treatment and prevention

Neuropsychological and neuroimaging studies have generated a wealth of data demonstrating structural and functional brain changes, as well as cognitive deficits in drug addicted populations. Despite this, it is often difficult to make generalisations or conclusive statements about the neuropsychological and neurobiological correlates of chronic drug use given variations in the nature or extent of deficits observed within or across different classes of drugs. In this review, we focus specifically on the evidence for impairments in prefrontally-mediated cognitive functions that underlie behavioural regulation, namely decision making and inhibitory control. We argue that impairments in these specific domains, which are often compounded by an earlier initiation of drug use, polydrug abuse, comorbid psychiatric conditions, previous head injury, and acute withdrawal effects can serve to increase the risk for making decisions that are impulsive, focussed on short-terms gains and lack inhibitory control. We further argue that these impairments of prefrontal functioning may underpin the compulsive and 'loss-of-control' pattern of drug-seeking and drug-taking that is characteristic of drug addiction. Finally, we consider the implications of these findings for diagnosis, treatment and prevention, suggesting that a comprehensive understanding of the nature and extent of these cognitive deficits should form a core part of the conceptualization and focus of effective treatment.     

Response sensitization and depression following long-term amphetamine treatment in a self-stimulation paradigm

The effects of long-term amphetamine treatment were evaluated on responding supported by self-stimulation of the substantia nigra. Rats repeatedly treated with d-amphetamine, and tested with a low dose of the drug that ordinarily has no behavioral effect, showed higher response rates than animals repeatedly treated with saline and tested with the same dose of amphetamine. In contrast, a depression in responding was observed among animals that received long-term amphetamine administration and were tested with saline. The effects of long-term amphetamine treatment on self-stimulation could not be explained by the intrusion of drug-induced competitive behaviors such as locomotor activity and stereotypy. The results were attributed to changes in dopamine neurotransmission following prolonged exposure to amphetamine and were also discussed in terms of an animal model for amphetamine psychosis and postamphetamine depression in man.     

Assessment of spirituality and its relevance to addiction treatment

The prominence of Twelve-Step programs has led to increased attention on the putative role of spirituality in recovery from addictive disorders. We developed a 6-item Spirituality Self-Rating Scale designed to reflect a global measure of spiritual orientation to life, and we demonstrated here its internal consistency reliability in substance abusers on treatment and in nonsubstance abusers. This scale and the measures related to recovery from addiction and treatment response were applied in three diverse treatment settings: a general hospital inpatient psychiatry service, a residential therapeutic community, and methadone maintenance programs. Findings on these patient groups were compared to responses given by undergraduate college students, medical students, addiction faculty, and chaplaincy trainees. These suggest that, for certain patients, spiritual orientation is an important aspect of their recovery. Furthermore, the relevance of this issue may be underestimated in the way treatment is framed in a range of clinical facilities.     

Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders

There is extensive comorbidity between depression and anxiety disorders. Dimensional psychiatric and psychometric approaches have suggested that dysregulation of a limited number of behavioural dimensions that cut across diagnostic categories can account for both the shared and unique symptoms of depression and anxiety disorders. Such an approach recognizes that anxiety, the emotional response to stress, is a key element of depression as well as the defining feature of anxiety disorders, and many antidepressants appear to be effective in the treatment of anxiety disorders as well as depression. Therefore, the pharmacological actions of these drugs must account for their efficacy in both. Brain noradrenergic and serotonergic systems, and perhaps to a more limited extent the dopaminergic system, regulate or modulate many of the same behavioural dimensions (e.g. negative or positive affect) that are affected in depression and anxiety disorders, and that are ameliorated by drug treatment. Whereas much recent research has focused on the regulatory effects of antidepressants on synaptic function and cellular proteins, less emphasis has been placed on monoaminergic regulation at a more global systemic level, or how such systemic alterations in monoaminergic function might alleviate the behavioural, cognitive, emotional and physiological manifestations of depression and anxiety disorders. In this review, we discuss how chronic antidepressant treatment might regulate the tonic activity and/or phasic reactivity of brain monoaminergic systems to account for their ability to effectively modify the behavioural dimensions underlying improvement in both depression and anxiety disorders.     

Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED₅₀ values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D₂ antagonist), 0.023 mg/kg for SCH 23390 (dopamine D₁ antagonist), 6.42 mg/kg for clozapine (dopamine D₄ antagonist). This supports the involvement of D₁ and D₂ receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D₁ and D₂, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization.     

Applying laboratory research: drug anticipation and the treatment of drug addiction

Basic research concerning drug tolerance and withdrawal may inform clinical practice, and vice versa. Three areas that integrate the work of the laboratory and the clinic are discussed: (a) drug overdose, (b) cue exposure treatment of addiction, and (c) pharmacological treatment of withdrawal symptoms. The areas are related in that they indicate the contribution of drug-paired cues to the effects of addictive drugs and the role of Pavlovian conditioning of drug effects in drug tolerance and withdrawal symptoms.     

Obsessive-compulsive disorder, impulse control disorders and drug addiction: common features and potential treatments

The basic concepts underlying compulsive, impulsive and addictive behaviours overlap, which may help explain why laymen use these expressions interchangeably. Although there has been a large research effort to better characterize and disentangle these behaviours, clinicians and scientists are still unable to clearly differentiate them. Accordingly, obsessive-compulsive disorder (OCD), impulse control disorders (ICD) and substance-related disorders (SUD) overlap on different levels, including phenomenology, co-morbidity, neurocircuitry, neurocognition, neurochemistry and family history. In this review we summarize these issues with particular emphasis on the role of the opioid system in the pathophysiology and treatment of OCD, ICD and SUD. We postulate that with progression and chronicity of OCD, the proportion of the OCD-related behaviours (e.g. checking, washing, ordering and hoarding, among others) that are driven by impulsive 'rash' processes increase as involvement of more ventral striatal circuits becomes prominent. In contrast, as SUD and ICD progress, the proportion of the SUD- and ICD-related behaviours that are driven by compulsive 'habitual' processes increase as involvement of more dorsal striatal circuits become prominent. We are not arguing that, with time, ICD becomes OCD or vice versa. Instead, we are proposing that these disorders may acquire qualities of the other with time. In other words, while patients with ICD/SUD may develop 'compulsive impulsions', patients with OCD may exhibit 'impulsive compulsions'. There are many potential implications of our model. Theoretically, OCD patients exhibiting impulsive or addictive features could be managed with drugs that address the quality of the underlying drives and the involvement of neural systems. For example, agents for the reduction or prevention of relapse of addiction (e.g. heavy drinking), which modulate the cortico-mesolimbic dopamine system through the opioid (e.g. buprenorphine and naltrexone), glutamate (e.g. topiramate), serotonin (e.g. ondansetron) or γ-aminobutyric acid (e.g. baclofen and topiramate) systems, may prove to show some benefit in certain forms of OCD. Based on the available evidence, we suggest that the treatment of patients with these disorders must account for alterations in the underlying motivations and neurobiology of the condition. We provide an initial guide to the specific treatments that future clinical trials might consider in patients with OCD. For example, it might be wise to test naltrexone in patients with co-morbid SUD and ICD, topiramate in patients with co-morbid ICD and eating disorders, and baclofen in patients with co-morbid Tourette's syndrome. These trials could also include scales aimed at assessing underlying impulsivity (e.g. Barratt Impulsiveness Scale) to check whether this construct might predict response to drugs acting on the reward system.     

The role of the endogenous cannabinoid system in drug addiction

This review aims to present the more recent knowledge on the role of the endocannabinoid system in drug addiction. For a long time, dopamine has been consistently associated with the reinforcing effects of most drugs of abuse but, recently, pharmacological evidence points to the possibility that pharmacological management of the endocannabinoid system might not only block the direct reinforcing effect of cannabis, opioids, nicotine and ethanol, but also prevent the relapse to various drugs of abuse including opioids, cocaine, nicotine, alcohol and amphetamine. Preclinical and clinical studies suggest that the manipulation of the endocannabinoid system through the CB(1) receptor antagonist SR-141716A (rimonabant) might constitute a new therapeutical strategy for treating addiction across different classes of abused drugs.     

A therapeutic workplace for the long-term treatment of drug addiction and unemployment: Eight-year outcomes of a social business intervention

This study evaluated the long-term effects of a therapeutic workplace social business on drug abstinence and employment. Pregnant and postpartum women (N = 40) enrolled in methadone treatment were randomly assigned to a therapeutic workplace or usual care control group. Therapeutic workplace participants could work weekdays in training and then as employees of a social business, but were required to provide drug-free urine samples to work and maintain maximum pay. Three-year outcomes were reported previously. This paper reports 4- to 8-year outcomes. During year 4 when the business was open, therapeutic workplace participants provided significantly more cocaine- and opiate-negative urine samples than controls; reported more days employed, higher employment income, and less money spent on drugs. During the 3 years after the business closed, therapeutic workplace participants only reported higher income than controls. A therapeutic workplace social business can maintain long-term abstinence and employment, but additional intervention may be required to sustain effects.     

Drug addiction among young people: a study of typology and its relevance to treatment programmes

On the basis of clinical observation, the authors have classified drug addiction into four types: traumatic, actual, transitional and sociopathic. Such classification helps in epidemiological research to understand better the distribution of people addicted to a given drug. Each type of addiction differs in respect of onset, evolution, prognosis and certain other characteristics relevant to the treatment of drug-addicted persons. Thus, the classification helps in making an appropriate selection of a treatment method and in the evaluation of a treatment programme. It has been observed that (a) traumatic and actual types of addiction have a much more favourable prognosis; (b) individual psychotherapy and support in a medical setting is effective for the traumatic type of addiction; (c) treatment in a family setting appears to be suitable for actual and transitional types of addiction; and (d) the therapeutic community may prove to be effective in the treatment of persons affected by socio-pathic type of addiction.     

The effects of methamphetamine self-administration on behavioural sensitization in the olfactory bulbectomy rat model of depression

Depression is frequently comorbid with a drug addiction and may seriously complicate its treatment. Currently, there is no routinely used animal model to investigate this comorbidity. In this study the effect of repeated administration of methamphetamine on i.v. drug self-administration in an olfactory bulbectomy model of depression in rats was investigated in order to propose and validate a rat model of comorbid depression and addiction. Male Wistar rats were either olfactory-bulbectomized (OBX) or sham-operated. They subsequently underwent a methamphetamine sensitization regime, which consisted of daily i.p. injections of methamphetamine for a 14-d period; controls received Sal injections at the same frequency. The i.v. self-administration of methamphetamine (0.08 mg/kg in one infusion) paradigm on a fixed ratio schedule of reinforcement was performed using operant chambers. A significant decrease of the drug intake was recorded in sham-operated animals pretreated with methamphetamine when compared to the unpretreated group. This was not apparent in the OBX groups. Both groups of OBX animals exhibited a higher intake of methamphetamine compared to the corresponding sham-operated groups, thus confirming the hypothesis of higher drug intake in depressive conditions in this rodent model. The procedure of behavioural sensitization to methamphetamine decreased the number of self-administered drug doses per session in the sham-operated rats. It is hypothesized that this phenomenon resulted from increasing efficacy of the drug after behavioural sensitization caused by repeated methamphetamine intermittent administration.     

Neurometabolic and behavioural effects of haloperidol in relation to drug levels in serum and brain

Summary A method has been developed for the quantitative determination of haloperidol in brain and other tissues. Such determinations have been made after acute and chronic administration of haloperidol to Sprague-Dawley rats. Different regions of the brain including the striatum, the limbic forebrain and the cerebellum have been analyzed separately. The haloperidol effects on Dopa formation have been studied in the same tissue samples. The stimulation of prolactin secretion via blockade of hypothalamic dopaminergic mechanisms and behavioural effects of the drug have been evaluated in parallel experiments.The elimination of haloperidol from brain tissue is a multiphasic process. The fourth phase of elimination is the slowest with a half life of 4 days. No strict correlation was found between serum and brain concentrations of haloperidol. Both after acute and chronic administration there exists apparently a saturating dose above which the brain concentration of the drug increases very little. The dose seems to coincide with that beyond which little increase in Dopa formation is observed. A pharmacokinetic analysis suggests an element of saturable binding or transfer of haloperidol to brain tissue. This mechanism is not preferentially localized to areas of brain rich in dopaminergic synapses. A good correlation was found between the haloperidol concentration in the brain on the one hand and its effects on behaviour, on serum prolactin values and on Dopa formation on the other.