Effects of lamotrigine on PCP-evoked elevations in monoamine levels in the medial prefrontal cortex of freely moving rats.
Lamotrigine is suggested to have potential as an add-on treatment for patients with schizophrenia. Supporting evidence comes from the efficacy of the drug in models of psychotic-like behaviour induced by N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP). These drugs enhance levels of the monoamines in the cortex, which may contribute to their psychotomimetic effects. The ability of lamotrigine to prevent these neurochemical changes has not been examined. We studied PCP-evoked overflow of noradrenaline, dopamine and serotonin in the medial prefrontal cortex of awake rats using microdialysis. Rats were administered lamotrigine or vehicle, followed by PCP. Locomotor activity was also recorded before and after drug treatment. Lamotrigine did not have an influence on basal levels of the monoamines, but significantly reduced PCP-evoked overflow of dopamine and serotonin; PCP-evoked overflow of noradrenaline was also reduced by lamotrigine, but not to a significant degree. In contrast, PCP-induced hyperactivity was unaffected by lamotrigine. It is concluded that lamotrigine can modify PCP-evoked monoamine overflow in the cortex, consistent with an ability to prevent the psychotomimetic effects of NMDA receptor antagonists in rodents and humans. The dissociation between monoamine overflow and locomotor activity suggests the involvement of different brain circuits; relevance to the treatment of schizophrenia is also discussed.
Mood and Anxiety DPU, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy. Davide.Quarta@aptuit.com
Davide
D
Quarta
Charles H
CH
Large
D000818:Animals; D015306:Biogenic Monoamines / Q000032:analysis*; D004298:Dopamine / Q000032:analysis; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D000077213:Lamotrigine; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000032:analysis; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis; D014227:Triazines / Q000494:pharmacology*
D015306:Biogenic Monoamines; D018691:Excitatory Amino Acid Antagonists; D014227:Triazines; D012701:Serotonin; D010622:Phencyclidine; D000077213:Lamotrigine; D004298:Dopamine; D009638:Norepinephrine