Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART I

R Miller

doi:10.2174/157015909790031229

Abstract

Many issues remain unresolved about antipsychotic drugs. Their therapeutic potency scales with affinity for dopamine D2 receptors, but there are indications that they act indirectly, with dopamine D1 receptors (and others) as possible ultimate targets. Classical neuroleptic drugs disinhibit striatal cholinergic interneurones and increase acetyl choline release. Their effects may then depend on stimulation of muscarinic receptors on principle striatal neurones (M4 receptors, with reduction of cAMP formation, for therapeutic effects; M1 receptors for motor side effects). Many psychotic patients do not benefit from neuroleptic drugs, or develop resistance to them during prolonged treatment, but respond well to clozapine. For patients who do respond, there is a wide (>ten-fold) range in optimal doses. Refractoriness or low sensitivity to antipsychotic effects (and other pathologies) could then arise from low density of cholinergic interneurones. Clozapine probably owes its special actions to direct stimulation of M4 receptors, a mechanism available when indirect action is lost.

Highlights

The first antipsychotic drug - chlorpromazine - was discovered serendipitously in the early 1950s
For much of this historical development, common understanding has been based on a number of implicit assumptions: (i) A single receptor type - the D2 receptor - is responsible for both the antipsychotic main effect, and the motor side effects; (ii) Antipsychotic action is relatively rapid, once the receptors are blocked, and as with most drugs, the bigger the dose, the bigger, and more rapid the effects, for both the therapeutic and the adverse side effects. (iii) Failure of therapeutic response may be because the dose is not enough
The focus here is on pharmacological receptor types and related functions involved in actions of various classes of antipsychotic drugs

Summary

INTRODUCTION

The first antipsychotic drug - chlorpromazine - was discovered serendipitously in the early 1950s. By the early 1980s it was known that there is more than one type of dopamine receptor, and today these are divided into two classes - the D1-class receptor (D1 and D5), and the D2-class (D2, and its variants, plus D3 and D4) For much of this historical development, common understanding has been based on a number of implicit assumptions: (i) A single receptor type - the D2 receptor - is responsible for both the antipsychotic main effect, and the motor side effects; (ii) Antipsychotic action is relatively rapid, once the receptors are blocked, and as with most drugs, the bigger the dose, the bigger, and more rapid the effects, for both the therapeutic and the adverse side effects. The focus here is on pharmacological receptor types and related functions involved in actions of various classes of antipsychotic drugs

PSYCHOSIS AS AN EXAGGERATION OF THE REINFORCEMENT FUNCTION OF DOPAMINE

THEORY

CHOLINERGIC INTERNEURONES AS “NEURODYNAMIC STABILIZERS”

Findings

ACTIONS OF CLOZAPINE