Mechanism of action of antipsychotic drugs : focus on the nucleus accumbens and the prefronta cortex : an experimental study

Antipsychotic drugs have been classified as typical or atypical. To achieve an effective antipsychotic effect with typical antipsychotic drugs, e.g. haloperidol, a dopamine D2 receptor blockade of about 70% seems necessary. On the other hand, the prototype for atypical antipsychotic drugs clozapine is clinically effective already at about 45% D2 receptor occupancy. Clozapine possesses affinity for a large number of receptors and an important question is to what extent these other receptor affinities may contribute to its therapeutic action. Atypical antipsychotic drugs have been claimed to exert an advantageous effect on negative symptoms as well as cognitive deficits in schizophrenia. These symptoms/deficits are thought to be largely related to dysfunctions in the prefrontal cortex, and both preclinical and clinical studies indicate deficits in prefrontal dopamine functioning, which in turn may be linked to a glutamatergic dysfunction in the prefrontal cortex.

By using in vivo voltammetry in anaesthetized rats we have examined to what extent different types of antipsychotic drugs modulate dopamine release in two subdivisions of the nucleus accumbens, the core and the shell, regions that are associated with motor control and limbic functions, respectively. Haloperidol and drugs that yield a high D2 receptor occupancy induced a higher dopamine release in the core than in the shell. In contrast, atypical antipsychotic drugs, given in doses that generate high 5HT2- but low D2, receptor occupancy, caused a higher dopamine output in the shell than in the core. Both selective 5-HT2A- and alpha1 adrenoceptor antagonists caused a significantly increased dopamine output exclusively in the shell region. In addition, even very low doses of haloperidol which generate very low D, receptor occupancies still induced the highest dopamine output in the core. These results show that typical and atypical antipsychotic drugs exert differential effects on dopaminergic function in the two subdivisions of the nucleus accumbens. Whereas the typical profile largely seems to be related to the D2 receptor blockade, the atypical profile may also involve actions at other receptors, such as 5-HT2A- and a, receptor blockade.

Clozapine is a potent alpha2 adrenoceptor antagonist and adjunctive treatment with idazoxan, an (12 adrenoceptor antagonist, enhances the effect of typical antipsychotic drugs in treatment-resistant schizophrenia. The effects of clozapine, idazoxan, the D2/3 receptor antagonist raclopride and the combination of idazoxan and raclopride were examined on i) glutamatergic neurotransmission in the medial prefrontal cortex, using electrophysiological intracellular recording in pyramidal cells in vitro, and ii) impaired cognitive performance induced by the selective Nmethyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test in rats. Whereas neither idazoxan nor raclopride had any effect when given alone, the combination exerted the same facilitation of glutamatergic transmission as clozapine, an effect found to be mediated by D, receptor activation. In similarity with clozapine, the combination of alpha2- and D2/3 receptor blockage completely reversed the impaired cognitive function. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D2-, alpha2Aand alpha2C receptors. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha2 adrenoceptor antagonistic properties.

Schizophrenic patients are mostly heavy smokers. Nicotine has been shown to improve both cognitive dysfunction and negative symptoms in schizophrenia, and it has been suggested that the intense tobacco consumption may represent a form of self-medication with nicotine. We examined whether nicotine, when given alone or in combination with raclopride or L-745,870, a D4 antagonist, might facilitate glutamatergic neurotransmission in the medial prefrontal cortex, using intracellular recording in pyramidal cells in vitro. Neither nicotine, nor raclopride or L-745,870 showed any effect. However, combining nicotine with raclopride or L-745,870 facilitated glutamatergic transmission, supporting a cognitive-enhancing effect of nicotine in schizophrenic patients.

List of scientific papers

I. Marcus MM, Nomikos GG, Svensson TH (1996). "Differential actions of typical and atypical antipsychotic drugs on dopamine release in the core and shell of the nucleus accumbens." Eur Neuropsychopharmacol 6(1): 29-38
https://pubmed.ncbi.nlm.nih.gov/8866935

II. Marcus MM, Nomikos GG, Svensson TH (2000). "Effects of atypical antipsychotic drugs on dopamine output in the shell and core of the nucleus accumbens: role of 5-HT(2A) and alpha(1)-adrenoceptor antagonism." Eur Neuropsychopharmacol 10(4): 245-53
https://pubmed.ncbi.nlm.nih.gov/10871706

III. Marcus MM, Malmerfelt A, Nyberg S, Svensson TH (2002). "Biochemical effects in brain of low doses of haloperidol are qualitatively similar to those of high doses." Eur Neuropsychopharmacol 12(5): 379-86
https://pubmed.ncbi.nlm.nih.gov/12208555

IV. Marcus MM, Jardemark KE, Wadenberg ML, Langlois X, Hertel P, Svensson TH (2005). "Combined alpha2- and D2/3 receptor blockage enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat." International Journal of Neuropsychopharmacology Apr 28: 1-13 [Epub ahead of print]
https://pubmed.ncbi.nlm.nih.gov/15857571

V. Jardemark K, Marcus MM, Konradsson A, Svensson TH (2004). "The combination of nicotine with the D2 antagonist raclopride or the weak D4 antagonist L-745,870 generates a clozapine-like facilitation of NMDA receptor-mediated neurotransmission in pyramidal cells of the rat medial prefrontal cortex." Int J Neuropsychopharmacol Oct 7: 1-6 [Epub ahead of print]
https://pubmed.ncbi.nlm.nih.gov/15469665