Gérard Emilien

Dopamine receptors—physiological understanding to therapeutic intervention potential

There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their intracellular signal transduction systems by G-proteins. The implications of DA receptors in neuropsychiatry and cardiovascular and renal diseases are discussed. Neuropsychiatry indications include Parkinsons disease, schizophrenia, migraine, drug dependence, mania and depression, and Gilles de la Tourette syndrome. The underlying dysfunction of dopaminergic systems and the potential benefits of dopaminergic therapy in these different indications are critically examined. With respect to the pharmacological treatment of Parkinsons disease, a range of DA agonists are in various stages of preclinical and clinical development. D2-receptor agonist activity is predominant in most effective antiparkinsonian DA agonists. However, in practice, it is difficult to treat patients for several years with DA agonists alone; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the efficacy of DA partial agonists await confirmation, and recent clinical investigations also suggest the potential of D1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evidence suggests that DA is involved in this disorder. Most prodromal and accompanying symptoms may be related to dopaminergic activation. Several drugs acting on DA receptors are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration, when compared with normal controls. In cardiology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopaminergic effects on renal function, which are suggested to be beneficial, and for its alpha- and beta-adrenergic-mediated responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.

Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists

Abstractβ-Adrenoceptors are members of a large family of hormone and neurotransmitter receptors that initiate their biological function by coupling to GTP-binding regulatory proteins. β-Adrenoceptors can be subdivided into two main subgroups, designated β1 and β2. Atypical β-adrenoceptors or β3-adrenoceptors, which are present on adipocytes, have been demonstrated pharmacologically. Their function in adipose tissue is currently being investigated.β2-Adrenoceptor agonists have played a key role in the treatment of asthma for some 30 years, being used for the relief and prophylaxis of symptoms. There is, however, no evidence that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators.In neuropsychiatry, β-adrenoceptor antagonists have been used for the treatment of acute stress reactions and generalised anxiety, essential tremor and prophylaxis of migraine. In general, they are effective in anxiety disorders if the somatic symptoms are not extreme. For prophylactic treatment of migraine, β-adrenoceptor antagonists such as propranolol, metoprolol, nadolol and atenolol are the drugs of first choice.In cardiology, β-adrenoceptor antagonists are an important class for the treatment of high blood pressure, arrhythmias and angina pectoris, and for prevention of myocardial infarction. With chronic treatment, they reduce mortality in hypertension and prolong survival in patients with coronary heart disease.

Dopamine receptors and schizophrenia: contribution of molecular genetics and clinical neuropsychology.

Family, twin and adoption studies suggest that genetic factors play an important role in the aetiology of schizophrenia. The mode of inheritance, however, is complex and non-Mendelian. Although the aetiology of schizophrenia is unknown, it has been hypothesized that the necessary conditions for developing the disease are environmental stress and a vulnerability to psychosis. The implication of dopamine receptors to schizophrenia has been greatly studied. Several linkage and association studies have been performed in an attempt to establish the involvement of dopamine receptors in schizophrenia. However, although no conclusive evidence of linkage or association to any gene has been established, some results, suggestive of linkage for chromosomes 6, 22 and 13, await confirmation from other studies. Concerning association studies, it is also of interest that some studies support an association between schizophrenia and homozygosity at D(3). More work in larger samples is required before conclusive linkage hypothesis or association to a dopamine receptor may be established. Schizophrenic patients have been shown to have significant deficits in a wide range of cognitive processes, including memory, attention, reasoning ability and language. Since cognitive deficits are significant symptoms of schizophrenia which require effective treatment, their assessment in schizophrenic patients and during clinical trials of new potential antipsychotics is highlighted. Cognitive impairment in schizophrenia impedes psychosocial performance and is therefore an especially relevant target variable in the development of new therapeutic approaches. It is most prominent in tasks involving attention, memory and executive functions which are thought to reflect involvement of prefrontal and left-temporal brain areas. Semantic networks in schizophrenic patients with a younger age of onset are observed to be more disorganized and differ significantly to those of control subjects. The need to use broader approaches such as neuropsychological-related measures to identify pertinent phenotypes in non-affected subjects carrying vulnerability genes is also emphasized. Since dopamine receptors are the primary targets in the treatment of schizophrenia, improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. In the development of novel antipsychotics, D(3) and D(4) receptors have received much attention and this is partly related to the fact that these receptors have a high abundance in brain areas associated with cognitive and emotional functions, such as parts of the limbic system and cortex. Recent studies suggest that atypical neuroleptics may significantly improve the cognitive deficits observed in schizophrenic patients and that atypical neuroleptics such as risperidone appear to improve memory and alertness suggesting that further clinical studies are needed to determine the precise influence of antipsychotics on the cognitive system of schizophrenic patients. Such studies could lead to useful insights as to the potential advantages of the newer antipsychotics which appear to have a sparing or beneficial effect on various components of cognitive function. However, the observation that cortical D(2) receptors are important sites of action for antipsychotics, that the cerebral cortex may harbour the common sites of actions of antipsychotics and that the balancing of the opposing actions of D(1) and D(2) receptor regulation may be an appropriate drug treatment suggests that the adjustment of D(1) receptor levels in the cortex may become an important goal of future antipsychotic generation. Such antipsychotics will be able to treat the positive, negative and cognitive deficits of schizophrenia.

The dose-response relationship in Phase I clinical trials and beyond: use, meaning, and assessment

Knowledge of the relationships among dose, drug concentration in blood, and clinical response is important for the safe and effective use of drugs in individual patients. Recently, pharmacokinetic-pharmacodynamic modeling has been taking an increasingly important place in clinical pharmacology because of its role in the determination of the optimal dosage of a new drug. Its primary objective is also to identify the characterization and prediction of the time course of drug effects under physiological and pathological conditions. Dose-response studies are useful in Phase I for assessing drug tolerance and safety, and invaluable in Phase II for characterizing drug efficacy. Apart from the confirmation of efficacy, the acquired information may help to investigate the shape and location of the dose-response curve, the choice of an appropriate therapeutic starting dose, the identification of optimal strategies for individual dose adjustments, and the determination of a maximal dose beyond which additional benefit is unlikely to be obtained. Recent development of pharmacodynamic models such as the mechanism-based indirect effect model may permit the identification of the physiological component of drug action that is affected by disease, other medications, gender, and other variables. Assessment of dose response should be an integral component of drug development, with studies designed to assess dose response an inherent part of establishing the safety and efficacy of the drug. Drug development can be enhanced with a good understanding of dose-response characteristics and ultimately the benefit/risk ratio of a drug.

Circadian system and sleep anomaly in depression

Abnormalities of circadian rhythms in depressed patients have been noted, including decreased amplitude, distorted waveform, day-to-day instability, and unusual 48 hour periods. Consistent electroencephalographic sleep recording in these patients show a shortened rapid eye movement latency and slow-wave sleep (stages 3 and 4), resulting in an increase in rapid eye movement sleep. This phenomenon appears to be a dependable, measurable marker for diagnosing primary depression. Total sleep deprivation appears to significantly improve mood in a high percentage of depressed patients. Current pharmacological research suggests that drug treatment such as lithium would not affect the intra sleep cycles of the REM stage-but would shift the phase backward and lithium would also shift the phase of circadian rhythm of the daytime sleepiness backward. This paper highlights some of the new approaches for investigating the molecular substrate for the control of circadian rhythmicity and sleep in man and critically examines the hypothesis of the alteration of this mechanism in psychopathology, particularly depression. What is known of the endogenous clock mechanism is discussed with known molecular circadian mechanisms with a view towards understanding how circadian information is transmitted to the rest of the central nervous system and how it is affected in depression.

Pharmacological treatment of neuropsychiatric symptoms

Behavioral and psychological symptoms of dementia cause premature institutionalization and significant loss of quality of life for the patient and his/her family and caregivers. An imbalance of different neurotransmitters (ACh, dopamine, noradrenaline, serotonin) has been proposed as the neurochemical correlate of these neuropsychiatric symptoms. The significant decrease in cholinergic activity may result in a relative increase in monoaminergic activities, leading to hypomanic or manic symptoms and behavior including delusions, hallucinations and physical aggression (Folstein, 1997). Conversely, AChE inhibitors have shown to be able to reduce neuropsychiatric severity (see Table 13.1).

Assessment of memory

Carrying out the neuropsychological assessment at an early stage of dementia has the goal of revealing memory disorders, which are not always associated with memory complaints. It also characterizes the memory disorder in the context of cognitive neuropsychology, thus permitting other cognitive functions to be integrated with the memory disorder into a broader syndrome.

Obsessive-compulsive disorder

OCD is characterised by recurrent, unpleasant thoughts which enter consciousness against the will of the individual, termed obsessions, and repetitive, unwanted behaviours, which may be ritualistic, termed compulsions, that lead to severe impairment in daily functioning. One of the most common compulsions is cleaning. Some individuals concerned about contamination will spend hours showering or bathing, others will wash their hands almost constantly, and some will spend hours and hours of each day cleaning their home. In addition to cleaning there are a number of other compulsions including checking (e.g., individuals may check hundreds of times if all doors at home are locked), repeating (e.g., some people may wish to ease anxiety by repeating a name or phrase over and over), slowness (being overly meticulous and tidy and spending hours organising and arranging objects and possessions) and fear of contamination (e.g., a person may devote hours of the day to washing their hands and avoids any social contact with others due to the fear of contamination).

Cognitive impairment in Alzheimer disease

The most important cognitive deficit of AD is the progressive loss of memory that is manifested according to the traditional classification in both STM and LTM tasks (see Tables 8.1, 8.2 and 8.3). The earliest and most prominent symptom in AD is a profound impairment in the ability to acquire and remember new information whether tested by recall or recognition (Grady et al., 1988; Welsh et al., 1991). Many patients have purely episodic memory impairment for a number of years (Perry & Hodges, 2000; Perry et al., 2000). Semantic memory, the database of conceptual knowledge that gives meaning to sensory experience, is eventually affected in AD, but early in the disease patients show mild and variable impairment of semantic memory. Written language deficits are frequently noted and occur at early beginning of the disease (Eustache & Lambert, 1996). They initially take the form of a lexical agraphia: the characteristic symptom is the production of errors so called “de regulation” (of regulation) occurring during the writing of words with irregular orthography (e.g. femme > fame). On the contrary, deficits of phonological type often appear with the progression of the dementia.

Promises of animal models of Alzheimer disease

The hypothesis that a cholinergic deficit might be responsible for memory impairment was based on studies showing learning and memory deficits in animals and humans whose cholinergic system was blocked by atropine or scopolamine (Drachman, 1977). Confirmation was sought by animal investigations in which the forebrain cholinergic nuclei were destroyed, initially by electrolytic lesions, then by excitotoxins and finally by the selective immunotoxins 192 IgG-saporin (Wenk et al., 1994). Intracerebroventricular (i.c.v.) injection of 192 Ig-G-saporin brings about a widespread degeneration of cholinergic neurons including the nucleus basalis of Meynert and the septum (Lin et al., 1999). The reversion of the learning and memory deficits induced by nucleus basalis of Meynert lesions has become a classical preclinical test for the screening of drugs aimed to correct the cholinergic hypo-function in AD (see Pepeu, 2000).