Common Neurobiological Substrate Research Articles

Defensive burying in rodents: ethology, neurobiology and psychopharmacology

Defensive burying refers to the typical rodent behavior of displacing bedding material with vigorous treading-like movements of their forepaws and shoveling movements of their heads directed towards a variety of noxious stimuli that pose a near and immediate threat, such as a wall-mounted electrified shock-prod. Since its introduction 25 years ago by Pinel and Treit [J. Comp. Physiol. Psychol. 92 (1978) 708], defensive (shock-prod) burying has been the focus of a considerable amount of research effort delineating the methodology/ethology, psychopharmacology and neurobiology of this robust and species-specific active avoidance or coping response. The present review gives a summary of this research with special reference to the behavioral (face and construct) and pharmacological (predictive) validity of the shock-prod burying test as an animal model for human anxiety. Emphasis is also placed on some recent modifications of the paradigm that may increase its utility and reliability as to individual differences in expressed emotional coping responses and sensitivity to pharmacological treatments. Overall, the behavioral and physiological responses displayed in the shock-prod paradigm are expressions of normal and functionally adaptive coping patterns and the extremes of either active (i.e., burying) or passive (i.e., freezing) forms of responding in this test cannot simply be regarded as inappropriate, maladaptive or pathological. For this reason, the shock-prod paradigm is not an animal model for anxiety disorder or for any other psychiatric disease, but instead possesses a high degree of face and construct validity for normal and functionally adaptive human fear and anxious apprehension. However, the apparent good pharmacological validation (predictive validity) of this test reinforces the view that normal and pathological anxiety involves, at least partly, common neurobiological substrates. Therefore, this paradigm is not only suitable for screening potential anxiolytic properties of new drugs, but seems to be especially valuable for unraveling the neural circuitry and neurochemical mechanisms underlying the generation of active and passive coping responses as different expressions of anxiety.

The neurobiology of addiction.

Drug addiction includes complex neurobiological and behavioural processes. Acute reinforcing effects of drugs of abuse are responsible for the initiation of drug addiction, whereas the negative consequences of drug abstinence have a crucial motivational significance for relapse and maintenance of the addictive process. The mesocorticolimbic system represents a common neuronal substrate for the reinforcing properties of drugs of abuse. Both dopamine and opioid transmission play a crucial role in this reward pathway. Common neuronal changes have also been reported during the abstinence to different drugs of abuse that could underlie the negative motivational effects of withdrawal. These changes include decreased dopaminergic activity in the mesolimbic system and a recruitment of the brain stress pathways. All drugs of abuse interact with these brain circuits by acting on different molecular and neurochemical mechanisms. The existence of bidirectional interactions between different drugs of abuse, such as opioids and cannabinoids, provides further findings to support this common neurobiological substrate for drug addictive processes.

Risperidone Treatment of Schizophrenia: Improvement in Psychopathology and Neuropsychological Tests

The aim of the study was to assess the effects of short-term risperidone treatment on schizophrenic symptoms and on neuropsychological frontal tests, and to find an association between the improvements in these two kinds of domains. Twenty-two schizophrenic patients treated with risperidone (2–6 mg/day) for 4 weeks were studied. Treatment with risperidone resulted in a significant decrease in the intensity of schizophrenic symptoms and in an improvement in all neuropsychological tests applied. A robust correlation was obtained between the amelioration of negative symptoms and improvements in many neuropsychological tests, specifically with amelioration in the Wisconsin Card Sorting Test (WCST), perseverative errors. Some correlation was also found with the improvement of positive symptoms, specifically with amelioration in the WCST, completed categories. The results may suggest a common neurobiological substrate of negative and cognitive symptoms, reflected in prefrontal cortex pathology and in therapeutic response to atypical antipsychotics.

Neuroadaptations to chronic exposure to drugs of abuse: relevance to depressive symptomatology seen across psychiatric diagnostic categories.

Depressive symptomatology is expressed across a wide spectrum of psychiatric disorders including major depression and schizophrenia. Further, depressive symptomatology is also observed in individuals undergoing withdrawal from chronic exposure to various drugs of abuse including cocaine, amphetamine and nicotine. The negative affective state associated with drug withdrawal is phenomenonologically similar to that observed in depressed and schizophrenia patients suggesting that common underlying pathophysiological deficits may be involved in the depressive symptomatology seen across these different psychiatric disorders. The aim of the present review is to examine clinical and preclinical evidence in support of a common neurobiological substrate mediating the negative affect associated with different psychiatric illnesses. First, clinical and epidemiological data are presented demonstrating the high comorbidity between nicotine and psychostimulant dependence, and depression or schizophrenia. It is hypothesized that drug-use may represent an attempt to self-medicate an underlying negative affective state present in depressed and schizophrenia patients. Second, preclinical findings are presented that demonstrate common neurochemical deficits in drug withdrawal and depression. Taken together, these clinical and preclinical data support the hypothesis that common neurobiological substrates may mediate the depressive state observed across psychiatric diagnostic categories. Therefore, it is proposed that the study of drug-induced depressions in laboratory animals may have heuristic value in identifying the mechanisms underlying the depressive symptomatology associated not only with drug withdrawal but also major depression and schizophrenia.

Eating behavior in anorexia nervosa--an excess of both orexigenic and anorexigenic signalling?

Anorexia nervosa (AN) is a disorder characterized by abnormal eating behavior, weight regulation, and disturbances in attitudes and perceptions toward body weight and shape. Although progress has been made in the treatment of AN, a substantial portion of patients have a limited response to treatment. Multiple endocrine and metabolic changes occur after prolonged starvation, conserving energy and protein. A number of the endocrine findings in patients with AN may be secondary to adaptive mechanisms. However, AN differs from simple starvation in that excess of both feeding-stimulatory (orexigenic) and feeding-inhibitory (anorexigenic) signalling is characteristic, producing the "mixed" signal about satiety and desire to feed. This leads to a failure of the adaptive feeding response that is initiated by a decrease in leptin, an adiposity signal from fat tissue, and the resultant increase and decrease of orexigenic and anorexigenic signalling, respectively. The hypothesis of unbalanced shift of feeding-regulatory circuitry places anorexigenic corticotropin-releasing factor and orexigenic neuropeptide Y in the final common neurobiological substrate for AN. Therapeutic intervention using such receptor antagonists may lead to more successful and targeted psychopharmacological treatment.

Suicidal behavior in patients with schizophrenia is related to COMT polymorphism.

A common functional polymorphism that results in a three- to four-fold difference in catechol-O-methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra-ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other-directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self- and other-directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients.

Psychobiological risk factors for vulnerability to psychostimulants in human adolescents and animal models

Adolescence is associated with an increased risk of developing drug abuse/dependence. During this ontogenetic phase, brain and hormonal systems are still undergoing crucial maturational rearrangements, which take place together with significant modifications in psychosocial development. However, the neurohormonal and behavioral facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants such as MDMA (“Ecstasy”) and amphetamine (AMPH). Novelty-seeking, a temperamental/behavioral trait that is typical of this age period, might substantially contribute to both psychological and psychobiological vulnerability. In humans, an elevated score of novelty-sensation seeking and a derangement of monoaminergic function were both associated with late adolescence MDMA users compared to controls. In animal models of periadolescence, the search for novel stimuli and sensations actually shares a common neurobiological substrate (the reward-related brain mesolimbic pathways) with psychostimulants. The present review summarises recent work in mice, which indicates that periadolescent subjects are characterized by an unbalanced and “extremes-oriented” behavior and by elevated novelty-seeking compared to adults. Repeated and intermittent administration of cocaine or AMPH was associated with the development of a prominent locomotor sensitization in periadolescents, which failed to exhibit the marked sensitization of the stereotyped behavioral syndrome—possibly associated with poor welfare—that was typical of adults. A unique profile of integrated behavioral and physiological hyporesponsivity to both forced novelty and acute AMPH administration during periadolescence was also found. As a whole, these results, together with previous work on this topic, suggest that periadolescents may be more “protected” from AMPH-related aversive properties, and perhaps more vulnerable to the experience of internal states of reward, than older animals. Thus, the present animal model of adolescence seems to represent a reliable and useful method for the investigation of vulnerability to a variety of habit-forming agents or emotional experiences whose positive reinforcing properties may rely on common neurobiological substrates. A deeper understanding of psychostimulant effects during adolescence on the complex interaction between genetic, neurobiologic, psychosocial, and environmental factors will lead to earlier and more effective prevention and treatment.

Pharmacologic treatments effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical implications.

To review the efficacy of anxiolytics (alprazolam and azapirones) in major depressive disorder (MDD) and that of antidepressants in generalized anxiety disorder (GAD), thereby exploring the possible theoretical and clinical implications of this efficacy. A Medline literature search was performed for the period January 1980 to September 1997 of randomized, double-blind comparison studies between anxiolytics and antidepressants in the acute treatment of adult patients with either MDD or GAD. Alprazolam, at doses double those generally recommended for anxiety disorders, appears to be as effective as tricyclic antidepressants (TCAs) in the acute treatment of mild to moderate MDD. Alprazolam was also found to have a more rapid onset of action than to TCAs, particularly for the improvement of anxiety, somatization, and insomnia. Two azapirones (buspirone and gepirone) also have demonstrated a modest acute antidepressant effect in preliminary studies, albeit only in a depressed outpatient sample with considerable anxiety at baseline. Finally, various antidepressant drugs (imipramine, trazodone, paroxetine) were shown to have, at the least, comparable efficacy to benzodiazepines (BZDs) in the acute treatment of GAD. The nonspecificity of treatment response suggests that GAD and MDD are 1) different expressions of a similar disorder with a common neurobiological substrate, 2) discrete diagnostic entities that respond to independent pharmacological effects of the same drugs, or 3) a combination of the two (heterogeneity hypothesis). The most relevant clinical finding is the efficacy of antidepressants in the acute treatment of GAD.

Schizophrenia and nicotine use: report of a pilot smoking cessation program and review of neurobiological and clinical issues.

Nicotine use is a major public health problem that increases medical morbidity and mortality. Nicotine's action and the pathobiology of schizophrenic disorders have common neurobiological substrates. Tobacco smoking alters medication blood levels and effectiveness, modifies psychiatric symptoms, and is a clue for other substance abuse. This article presents an evaluation of a smoking cessation program for 24 smokers with schizophrenia. Fifty percent completed the program, 40 percent decreased use by 50 percent, and 13 percent remained abstinent (carbon monoxide verified) for 6 months. Nicotine replacement, motivational enhancement therapy, and relapse prevention behavioral therapy were important components of treatment. Pharmacotherapy strategies of a higher-dose nicotine patch, combining nicotine gum and a patch, and augmentation medication to nicotine replacement should be evaluated in future studies in this population.

Lesions of the lateral parabrachial nucleus block the aversive motivational effects of both morphine and morphine withdrawal but spare morphine's discriminative properties.

This study examined if the aversive properties of morphine, the aversive properties of morphine withdrawal, and the discriminative properties of morphine are mediated by common neurobiological substrates. Lesions of the lateral parabrachial nucleus, which blocked the aversive properties of morphine in the conditioned taste aversion paradigm, also blocked the acquisition of conditioned place aversions to environments paired with the aversive properties of morphine withdrawal in morphine-dependent rats. When morphine and saline were used as cues in a discrimination task, however, both sham-operated and lesioned rats were able to solve the task.