The effects of chronic lithium treatment on methylphenidate-, D1 dopamine receptor agonist (A-77636)-, and tactile stimulation-induced increases in frontal cortical acetylcholine release were studied in the rat using in vivo brain microdialysis. Cortical acetylcholine release in control rats was maximally stimulated by methylphenidate (1.25 and 2.5 mg/kg) to 173% and 212% above baseline, respectively. The effect of methylphenidate (2.5 mg/kg) was blocked by pretreatment with the dopamine D1 receptor antagonist SCH 23390 (0.3 mg/kg). Chronic treatment with lithium chloride (3-4 weeks) produced plasma lithium concentrations of 0.45 +/- 0.02 meq/l. Chronic lithium significantly reduced increases in cortical acetylcholine release produced by methylphenidate. Stimulation of dopamine D1 receptors with the full D1 receptor agonist A-77636 (0.73 mg/kg) increased cortical acetylcholine release. Chronic lithium significantly reduced this effect of A-77636. In contrast, lithium failed to influence the increases of cortical acetylcholine release produced by tactile stimulation. These results suggest that while lithium does not influence normal, arousal-related increase in cortical acetylcholine release, this ion selectively attenuates dopamine mediated increases and/or abnormally large increases, which in the present circumstances were pharmacologically induced. The relevance of these findings to the antimanic actions of lithium is discussed.
"Given the procognitive efficacy of MPH and A-412997 in the rat NOR and the involvement of the hippocampus in the NOR task (Wood et al., 1993; Clark et al., 2000) we sought to further understand the neurochemical alterations in the hippocampus as well as the medial prefrontal cortex, two brain regions associated with cognitive function, and exhibiting high expression of the D 4 receptor, after administration of procognitive doses of the two compounds to conscious, freely moving rats. When tested at 0.32 mg/kg s.c., the dose revealing the efficacy in the rat NOR task, MPH, significantly increased extracellular levels of dopamine, noradrenaline and acetylcholine in the medial prefrontal cortex, consistent with its known mechanism of action, that is, inhibition of DAT and the noradrenaline transporter (Acquas and Fibiger, 1996; Berridge et al., 2006) and previous findings showing elevated levels of extracellular acetylcholine with a noradrenaline transporter inhibitor atomoxetine (Tzavara et al., 2006). Similarly, at procognitive doses, A-412997 (0.32 and 1 mg/kg i.p.) significantly increased extracellular dopamine and acetylcholine within this region but had no effect on extracellular levels of noradrenaline. "
[Show abstract][Hide abstract] ABSTRACT: Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.
"Specifically, activation of D 1 receptors appears to exert a stimulatory effect on the release of ACh (Damsma et al., 1990, 1991). In addition , blockade of D 1 receptors with SCH 23390 has been shown to attenuate the increase in cortical ACh release produced by amphetamine (Day and Fibiger, 1992), cocaine (Imperato et al., 1993), and methylphenidate (Acquas and Fibiger, 1996). In the present report, administration of SCH 23390 significantly diminished the MDMA-induced release of ACh in the PFC. "
[Show abstract][Hide abstract] ABSTRACT: 3,4-Methylenedioxymethamphetamine (MDMA), an amphetamine analog, has been shown recently to increase the release of acetylcholine (ACh) in the prefrontal cortex (PFC). The present study further characterizes the stimulatory effect of MDMA on cortical ACh release and examines the role of serotonin (5-HT) and dopamine (DA) receptors in this response. The extracellular concentration of ACh was increased dose-dependently and similarly by the (+) and (-) enantiomers of MDMA (5 and 20 mg/kg, i.p.). The systemic administration of the 5-HT(4) antagonist SDZ 205,557 (1 mg/kg, i.p.), but not the 5-HT(2A/2B/2C) antagonist LY-53,857 (3 mg/kg, i.p.), significantly decreased cortical ACh release induced by MDMA. The MDMA-induced increase in the extracellular concentration of ACh also was significantly blunted in rats treated with the D(1) receptor antagonist SCH 23390 (0.5 mg/kg, i.p.). The extent to which the coadministration of SDZ 205,557 and SCH 23390 suppressed the MDMA-induced release of ACh in the PFC was no greater than that produced by either antagonist alone. These results suggest that the 5-HT(4) and D(1) receptor subtypes contribute to the mechanism by which MDMA increases ACh release in the PFC.
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