ABSTRACT
DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.
Subject(s)
Nervous System Diseases/metabolism , Psychotic Disorders/metabolism , Receptors, Dopamine D1/metabolism , Animals , Antipsychotic Agents/therapeutic use , Blinking/drug effects , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine Agents/therapeutic use , Isoquinolines/therapeutic use , Levodopa/therapeutic use , Macaca mulatta , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nervous System Diseases/drug therapy , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Psychotic Disorders/drug therapy , Receptors, Dopamine D1/genetics , Reserpine/therapeutic use , Sleep/drug effects , Wakefulness/drug effectsABSTRACT
Based on its proposed ability to block the effect of selective serotonin reuptake inhibitors (SSRIs) on the firing rate of serotonergic neurons, the 5-HT1A partial agonist/beta-adrenergic antagonist pindolol has been examined in clinical trials for its ability to enhance the efficacy of SSRIs. However, varying results have been obtained in these clinical trials. To explore this issue, we examined the effects of pindolol alone and in combination with fluoxetine on the electrophysiological activity of serotonergic neurons in the dorsal raphe nucleus of anesthetized rats. Administration of pindolol (1, 5, and 20 mg/kg, s.c.) alone decreased the number of spontaneously active serotonergic neurons. Administration of fluoxetine (10 mg/kg, i.p.) alone also decreased the number of spontaneously active serotonergic neurons. However, when administered following fluoxetine, pindolol significantly attenuated, but did not block completely, the inhibitory effects of fluoxetine on the number of spontaneously active serotonergic neurons. These results indicate that pindolol can attenuate the effects of fluoxetine on the firing of serotonergic neurons. These results may help explain the varying efficacy of pindolol in clinical trials with SSRIs.