Antipsychotics often lose efficacy in patients despite chronic continuous treatment. Why this occurs is not known. It is known, however, that withdrawal from chronic antipsychotic treatment induces behavioral dopaminergic supersensitivity in animals. How this emerging supersensitivity might interact with ongoing treatment has never been assessed. Therefore, we asked whether dopamine supersensitivity could overcome the behavioral and neurochemical effects of antipsychotics while they are still in use. Using two models of antipsychoticlike effects in rats, we show that during ongoing treatment with clinically relevant doses, haloperidol and olanzapine progressively lose their efficacy in suppressing amphetamine-induced locomotion and conditioned avoidance responding. Treatment failure occurred despite high levels of dopamine D 2 receptor occupancy by the antipsychotic and was at least temporarily reversible by an additional increase in antipsychotic dose. To explore potential mechanisms, we studied presynaptic and postsynaptic elements of the dopamine system and observed that antipsychotic failure was accompanied by opposing changes across the synapse: tolerance to the ability of haloperidol to increase basal dopamine and dopamine turnover on one side, and 20 -40% increases in D 2 receptor number and 100 -160% increases in the proportion of D 2 receptors in the high-affinity state for dopamine (D 2 High ) on the other. Thus, the loss of antipsychotic efficacy is linked to an increase in D 2 receptor number and sensitivity. These results are the first to demonstrate that "breakthrough" supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy. These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics.

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D₂-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D₂ receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D₂ receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.

How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, 'spiking' brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder.

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The potential for addiction is thought to be greatest when drugs of abuse reach the brain rapidly, because this produces intense subjective pleasurable effects. However, the ability of drugs to induce forms of cellular plasticity related to behavioral sensitization may also contribute to addiction. Therefore, we studied the influence of rate of intravenous cocaine delivery on its ability to induce psychomotor sensitization. In one experiment, rotational behavior in rats with a unilateral 6-hydroxydopamine lesion was used as an index of psychomotor activation, and in a second experiment, locomotor activity in neurologically intact rats was used. Rapid (5-16 sec) intravenous infusions of cocaine induced robust psychomotor sensitization at all doses tested (0.5-2.0 mg/kg). Treatments given over 25 sec failed to induce sensitization at all doses tested. Treatments given over 50 or 100 sec induced sensitization only at the highest dose tested. Thus, the rate of intravenous cocaine delivery has profound effects on the ability of cocaine to induce psychomotor sensitization. This suggests that the temporal dynamics of drug delivery to the brain is a critical factor in the ability of cocaine to induce forms of neuronal plasticity that may contribute to addiction.