Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT1A receptor knockout mice: Implications for schizophrenia
Highlights
► Enhanced amphetamine locomotor hyperactivity in 5-HT1A receptor knockout (KO) mice. ► Markedly reduced effect of the hallucinogen 5-MeO-DMT in 5-HT1A receptor KO mice. ► No KO effect on MK-801 locomotor hyperactivity or apomorphine PPI disruption. ► No major changes in the density of dopamine transporters, D1 or D2 receptors. ► Important role of 5-HT1A receptors in hallucinations and dopaminergic activity.
Introduction
There is extensive evidence for a role of dopaminergic and serotonergic mechanisms in the symptoms of schizophrenia. Most of this knowledge is based on the receptor binding profile and pharmacological mechanism of action of antipsychotic drugs (Millan, 2000, Roth et al., 2004, Seeman, 1987). Recent imaging studies have confirmed the importance of dopamine receptor occupancy for the clinical effects of these drugs and also suggest differences in dopamine release levels in some brain regions between patients with schizophrenia and controls (Laruelle et al., 1999, Stone et al., 2009). While different levels of in vivo dopamine receptor binding are a common feature of all antipsychotic drugs, additional mechanisms may contribute to their effects. Thus, many studies have suggested that combined effects at dopaminergic and serotonergic receptors in the brain may be responsible for some of the differences between various antipsychotics in terms of clinical efficacy and side-effect profile (Meltzer and Huang, 2008, Wood and Wren, 2008, Yadav et al., 2011). In this context, the serotonin-1A (5-HT1A) receptor has received increasing interest (Millan, 2000) as its activation modulates dopaminergic activity and may enhance cognition in schizophrenia (Meltzer and Sumiyoshi, 2008, Sumiyoshi et al., 2008, Sumiyoshi et al., 2001). For example, micro-dialysis studies have shown that administration of the prototypical 5-HT1A receptor agonist, 8-hydroxy-2-(dipropylamino)tetralin (8–OH–DPAT) inhibits dopamine release in the frontal cortex (Kuroki et al., 1996) and nucleus accumbens (Ichikawa and Meltzer, 2000) of rats. However, despite such evidence, the mechanism by which the 5-HT1A receptor is involved in schizophrenia remains unclear.
Therefore, in the present study, we assessed behaviour of 5-HT1A receptor knockout mice in behavioural models of aspects of schizophrenia. These mice have been available for many years but most of the psychopharmacological research with these animals has been directed towards the role of 5-HT1A receptors in anxiety and depression (Parks et al., 1998, Ramboz et al., 1998, Toth, 2003). We used psychotropic drug-induced locomotor hyperactivity as a model of psychosis, with amphetamine-induced increases in dopamine release mimicking subcortical hyperdopaminergia, and administration of N-methyl-d-aspartate (NMDA) receptor blockers, such as MK-801 or phencyclidine, used to model hypoglutamatergia (Geyer and Moghaddam, 2002, van den Buuse, 2010). We also tested the effect on locomotor activity of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), an indoleamine hallucinogen with non-selective serotonin receptor agonist properties (Halberstadt et al., 2008). So far, locomotor hyperactivity studies showed that the effect of MK-801 was not substantially different between 5-HT1A receptor knockout mice and wildtype controls (Castañé et al., 2008, Scorza et al., 2010). The effect of amphetamine or 5-MeO-DMT have not been tested in these animals so far.
Following the results on amphetamine-induced locomotor hyperactivity and the effects of 5-MeO-DMT, we then used another behavioural model with relevance to schizophrenia, prepulse inhibition of acoustic startle (PPI). PPI has been widely used as a model of sensory gating, which is deficient in schizophrenia and some other psychiatric illnesses (Braff et al., 1995). This disruption can be modeled in mice by treatment with psychotropic and dopaminergic drugs, including the dopamine receptor agonist, apomorphine (Geyer et al., 2001, van den Buuse, 2010). There are few previous studies in 5-HT1A receptor knockout mice on non-serotonergic regulation of PPI (Dulawa et al., 2000).
Finally we performed receptor binding autoradiography for dopamine D1 and D2 receptors and dopamine transporters (DAT). This was to ascertain whether the knockout mice used here with their constitutive deletion of the 5-HT1A receptor could have developed compensatory mechanisms in central neurotransmitter activity, notably dopamine.
Section snippets
Animals
The 5-HT1A receptor knockout mice and their wildtype littermate controls were derived from two breeding colonies at the Mental Health Research Institute (MHRI), Melbourne, Australia, and the University of California at San Diego (UCSD), CA, respectively. Breeders on a pure 129Sv background were originally obtained from Dr. Rene Hen, Columbia University, New York, NY (Dulawa et al., 2000). These mice were back-crossed for at least ten generations on a C57Bl/6 background and used to establish a
Amphetamine-induced locomotor hyperactivity
In the first cohort of mice, 5-HT1A knockout mice tended to be slightly less active during the pre-injection habituation period than WT controls (main effect of Genotype: F(1,36) = 4.8, P < 0.05) but there was no difference between male and female mice (Table 1). Treatment with 1 mg/kg of amphetamine-induced minor hyperlocomotion (main effect of Drug: F(1,38) = 5.8, P < 0.05) which was not different between 5-HT1A knockout mice and WT controls or between male and female mice (Table 1).
Discussion
The main findings of this study were that compared to WT littermate controls, 5-HT1A receptor knockout mice showed (1) significantly increased locomotor hyperactivity to treatment with amphetamine but not MK-801; (2) marked attenuation of the effect of the hallucinogen, 5-MeO-DMT; (3) no changes in PPI or its disruption after treatment with apomorphine; (4) subtle changes in DAT, dopamine D2 and D1 receptor binding.
Few previous studies have used 5-HT1A receptor mice in behavioural models with
Acknowledgements
The authors are grateful to Perrin Kwek and Angela Hurley for technical assistance with aspects of the project. M. van den Buuse is a Senior Research Fellow of the National Health and Medical Research Council of Australia (NHMRC). These studies were supported by the Percy Baxter Charitable Trust and Operational Infrastructure Support (OIS) from the Victorian State Government. The generation of the mice was supported by National Institute for Drug Abuse grant R01 002925-27.
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