Classical as well as novel antipsychotic drugs increase self-stimulation threshold in the rat — Similar mechanism of action?

Abstract

Antipsychotic drugs given acutely increase the threshold for intracranial self-stimulation elicited from the ventral tegmental area. As all the antipsychotic drugs share the dopamine D₂-receptor antagonism it is reasonable to believe that this is the cause for suppression of intracranial self-stimulation behaviour. The objective of this investigation was to examine the effect of classical (haloperidol) as well as novel antipsychotic drugs (clozapine, olanzapine and sertindole) on intracranial self-stimulation behaviour. Furthermore, the effects of different specific receptor antagonists on intracranial self-stimulation behaviour were examined. Our results showed that both the classical (haloperidol) and the three novel antipsychotic drugs increase the threshold for intracranial self-stimulation. The results obtained with the receptor specific antagonists showed that dopamine D₂, α₁-adrenoceptor and serotonin 5-HT_2A receptor antagonisms inhibit intracranial self-stimulation behaviour and that muscarinic receptor antagonism is without effect. Even though all the tested antipsychotic drugs inhibited intracranial self-stimulation behaviour, there seems to be a difference in their ratio between doses that inhibits intracranial self-stimulation behaviour and those that produce antipsychotic effect in a preclinical model (amphetamine hyperactivity). Sertindole was the only antipsychotic drug able to produce antipsychotic effect without significant inhibition of intracranial self-stimulation behaviour at a narrow dose interval. The remaining antipsychotic drugs all inhibited intracranial self-stimulation behaviour at equal or lower doses than those producing antipsychotic effect.

Introduction

Antipsychotic effect is believed to be achieved by inhibition of dopaminergic transmission in the mesolimbic pathway; for review see (Deutch et al., 1991, Kinon and Lieberman, 1996, Arnt, 1996). This inhibition can be achieved by direct blockade of dopamine D₂ receptors, as with the classical antipsychotic drugs. The inhibition of dopaminergic transmission in the mesolimbic pathway can also be achieved by modulating dopamine-interacting neurotransmitter systems. The novel antipsychotic drugs (e.g. clozapine, olanzapine and sertindole) inhibit dopaminergic transmission through both direct dopamine D₂ receptor antagonism and the modulation caused by e.g. serotonin 5-HT_2A receptor blockade, as well as through other neurotransmitter systems.

As the mesolimbic pathway also play a major role in reward processes and/or motivation (Fibiger et al., 1987, Wise, 1978, Phillips, 1984, Wise, 1982), the aforementioned blockade could lead to anhedonia. In fact, patients on antipsychotic medication commonly describe antipsychotic induced dysphoria (Lader, 1993, Lewander, 1994, Harrow et al., 1994). It has been shown that the patients' quality of life is severely influenced by the subjective experience of a drug treatment (Naber, 1995), and that the subjective experience predicts medication compliance (Naber, 1995, Van-Putten et al., 1981). Even though these subjectively experienced side effects have been shown to be more distressing than other side effects (Buis, 1992), they have received relatively little attention by the scientific community.

Clinical studies propose that patients on novel antipsychotic drugs might have a lower prevalence of antipsychotic induced dysphoria than patients on classical antipsychotic drugs (Voruganti et al., 2000). This finding is corroborated by the emotional awakening seen in many patients when changing treatment from classical to a novel antipsychotic drug (Lindström, 1994).

In the present study we have examined if this is mirrored in the threshold value of intracranial self-stimulation delivered to the ventral tegmental area of rats. Earlier studies used response rate measures to represent the rewarding effect of stimuli. However, response rate measures confounded reward and motor processes and so-called rate-free measures such as reinforcement threshold have been proposed to be valid methods of measuring anhedonic response to drug treatment (Miliaressis et al., 1986). In the present study a rate-frequency curve-shift method was applied to determine the rewarding properties of the self-stimulation. The properties of the rate-frequency function, in particular with regard to separating intracranial self-stimulation reward effects from operant motor/performance capacity, have been extensively validated and investigated (Kling-Petersen and Svensson, 1993, Hunt and Atrens, 1992, Miliaressis et al., 1986). As a supplement, we include the locomotor activity test to assess non-specific motor effects.

That classical antipsychotic drugs inhibit intracranial self-stimulation behaviour has been shown extensively in the literature (Nakajima and Patterson, 1997, Schaefer and Michael, 1980, Baldo et al., 1999). In addition, some of the novel antipsychotic drugs have shown to inhibit intracranial self-stimulation behaviour (Greenshaw, 1993, Szewczak et al., 1995, Frank et al., 1995). In the present study, we examined a classical (haloperidol) and three novel (clozapine, olanzapine and sertindole) antipsychotic drugs in the intracranial self-stimulation model. Furthermore, in order to elucidate the effect of the different receptor profiles of the antipsychotic drugs we explore the effect of serotonin 5-HT_2A, adrenergic α₁ and muscarinic receptor antagonists on intracranial self-stimulation behaviour.