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Despite the availability of several antidepressants, the treatment of major depression is far from being satisfactory. With conventional antidepressants, more than 30 to 45% of the patient will not respond or present only partial remission. In the prospect of a better treatment of depression, research tends to develop original molecules, more effective, with a faster onset of action and a better tolerability. The new targets of antidepressive pharmacotherapy are beyond the membrane receptor. The future in the treatment of depression requires a better understanding of cellular and molecular mechanisms involved in the pathophysiology of depression and biochemical mechanisms explaining the antidepressive effect. In this context, the glutamatergic system plays a role in the pathophysiology of depression. Agents modulating glutamatergic activity could act as antidepressants.

In the brain of vertebrates, glutamate receptor ion channels (iGluR) mediate fast neurotransmission at excitatory synapses. They exist as distinct subfamilies (AMPA, Kainate and NMDA) differing in their functional properties. Yet, all iGluR are tetramers sharing a common molecular architecture, and a common scheme applies for the general mechanisms of their activation, which are discussed in this review. The dissection of the molecular mechanisms responsible for the operation of iGluR explain how they match their physiological requirements and paves the way to new strategies for pharmacological regulations of these receptors. This could prove useful for the discovery of drugs of therapeutic interest, such as cognitive enhancers, pain killers or anti-psychotics.

Repeated cocaine administration induces numerous neuroadaptations. Cocaine controls many neurotransmitter systems, including glutamate, GABA, dopamine, serotonin, and noradrenalin. Cocaine exposure modifies neuron morphology. Peptide systems such as the orexins probably play a key role in cocaine's long-term effects. The opioid system may be involved in cocaine's long-term effects. The complexity and the multiplicity of the neuroadaptations observed with cocaine may explain the current absence of effective pharmacotherapy.

Current treatments for Alzheimer's disease aim to compensate for biochemical deficits in the brain. They are purely symptomatic and restore the central cholinergic deficit. Acetylcholinesterase inhibitors have modest but significant efficacy on cognitive disorders, activities of daily living, and the global clinical impression. Glutaminergic receptor antagonists are used for more advanced forms. Future treatments may be curative, acting specifically on the amyloid cascade. Secretase inhibitors and immunotherapy are in the pipeline. Trials will begin within a few months and will open up new perspectives.

Involuntary movements, or dyskinesias, represent a debilitating complication of levodopa therapy for Parkinson's disease. Dyskinesia is, ultimately, experienced by the vast majority of the patients. Despite the importance of this problem, little was known about the cause of dyskinesia, a situation that has dramatically evolved in the last few years. The present review presents: 1) the current understanding of dyskinesia pathophysiology and 2) the therapeutic modalities, mainly non-dopaminergic, available or in development. We here show that the questions raised by the dyskinesia may have a clinically-driven pharmacological answer: the symptomatic treatment of dyskinesia, the prevention of the priming and the de-priming of the neural networks.

Glutamatergic hypothesis stemmed from the observation of phencyclidine-induced psychosis. Phencyclidine is able to induce in healthy subjects negative and positive schizophrenic-like symptoms, as well as thought disorganization. Phencyclidine acts as an antagonist of NMDA receptor, one of the glutamatergic receptors. Experimental studies in animals have demonstrated that compartmental effect of phencyclidine is due to its action at striatal level, allowing the disinhibition of down-stream structures. The organization of the two striato-thalamocortical loops, which exert, respectively, a positive and negative retro-control on cortical activity, may explain how a glutamatergic deficiency induces both positive and negative symptoms. Positive symptoms could also be due to a secondary hyperdopaminergia, since a part of striatum, the striosomes, connected with limbic system, control the activity of dopaminergic neurons. This model validates the hypothesis that a single anomaly can lead to the different symptomatic dimensions of schizophrenia and supports the implication of basal ganglia in the expression of mental disease.

Atypical neuroleptics can be defined as dopamine (DA) receptor blockers which differ from typical neuroleptics in that they have a markedly lower or absent propensity for the induction of parkinsonian side effects of tardive dyskinesias. Some of them, but not all, are also more effective in treating schizophrenic patients, i.e. those with negative symptoms or who resist to classical treatments. There may be four classes of potential atypical neuroleptics: 1) Antipsychotics such as sulpiride and remoxipride that block a subgroup of D2 receptors; 2) D1 antagonists that may prove to be a valuable new type of antipsychotic drug; 3) Partial D2 agonists and 4) Antipsychotics such as clozapine and risperidone which block DA as well as other receptors and which appear to have the most pronounced antipsychotic effect. The differences between typical and atypical neuroleptics may first relate to regional specificity in site of actions. Animal studies suggest that atypical neuroleptics may act preferentially on mesolimbic and mesocortical as opposed to striatal DA systems. Most studies which have attempted to define the biological mechanisms which subserve the differences between atypical and typical neuroleptic drugs have focused on receptor binding profile of these drugs. Relatively higher affinity for the serotonin (5HT2) receptor than for the D2 receptor may be important to the action of clozapine-like compounds. However, many other systems might be involved and it seems likely that the atypical neuroleptic profile could be achieved in more than one way.(ABSTRACT TRUNCATED AT 250 WORDS)