OBJECTIVE: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. METHOD: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. RESULTS: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to tr...

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Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.

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Animal models of neuropsychiatric disorders

This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.

Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation

https://zenodo.org/record/1259773/files/article.pdf

Brain dopamine and obesity.

Rats exposed chronically (5–9 weeks) to a variety of mild unpredictable stressors showed a reduced consumption of and preference for saccharin or sucrose solutions. Preference deficits took at least 2 weeks to develop and were maintained for more than 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 1 week of treatment with the tricyclic antidepressant DMI but returned to normal after 2–4 weeks of DMI treatment. DMI did not alter sucrose preference in unstressed animals. No significant changes were seen in saline preference either during stress or following drug treatment. DMI reduced blood corticosterone and glucose levels, but stress did not significantly alter either measure. The results are discussed in terms of an animal model of endogenous depression.

Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant.

The chronic mild stress (CMS) model of depression has high validity but has in the past been criticized for being difficult to replicate. However, a large number of recent publications have confirmed

Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS

Eighteen animal, models of depression are reviewed in relation to three sets of validating criteria. Of the 18 models, five could only be assessed for predictive, validity, seven could be assessed for predictive and face validity, and six could potentially have predictive, face and construct validity. Some traditional models (reserpine reversal, amphetamine potentiation) are rejected as invalid; the models with the highest overall validity are the intracranial self-stimulation, chronic stress and learned helplessness models in rats, and the primate separation model.

Paul Willner

Papers

Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation

Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant.

Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS

The validity of animal models of depression.

Chronic mild stress-induced anhedonia : a realistic animal model of depression