Possible Mechanism for Perception of Auditory-Verbal Hallucinations in Schizophrenia and Approaches to Their Weakening

We put forward a hypothesis that the processing and perception of auditory-verbal hallucinations in schizophrenia — internally generated speech, occurs in the same neural circuits as speech from external sources. These topographically organized cortico—basal ganglia—thalamocortical neural circuits include auditory, language, and frontal neocortical areas. It follows from our proposed mechanism for sound processing, that the increased action on dopamine D2 receptors on striatal neurons, which is considered the cause of hallucinations, should lead to a determined reorganization of activity in these neural circuits. As a result of this reorganization, the inhibition of neurons in the thalamic nuclei, including the internal geniculate body, should decrease synergistically through the direct and indirect pathways in the basal ganglia, and the excitation of connected with them cortical neurons, in the activity of which speech is represented, should increase. From this mechanism it follows that in order to weaken the perception of auditory-verbal hallucinations, it is necessary to increase the inhibition of thalamic neurons. Taking into account the known data on the distribution of receptors of different types on neurons in the striatum, thalamus and neocortex, as well as the previously formulated unified modification rules for the effectiveness of synaptic transmission in different structures, we proposed that agonists of adenosine A1 and muscarinic M4 receptors located on striatonigral spiny cells, giving rise to a direct disinhibitory pathway through the basal ganglia as well as antagonists of delta-opioid and cannabinoid CB1 receptors, located on striatopallidal spiny cells, giving rise to an indirect inhibitory pathway through the basal ganglia may be useful to weaken the perception of hallucinations. In addition, activation of A1 receptors can directly weaken the activity of neurons in the thalamus and neocortex due to the induction of long-term depression in the efficiency of their excitation. Inactivation of cannabinoid CB1 receptors on the projection GABAergic cells of the reticular thalamic nucleus may enhance their inhibitory effect on neurons of different thalamic nuclei. Since the proposed substances only indirectly affect the dopaminergic system, their use should not cause such pronounced side effects as D2 receptor antagonists, antipsychotics that are widely used to suppress auditory-verbal hallucinations.