Effect of apomorphine on cognitive performance and sensorimotor gating in humans

Department of Psychiatry, Radboud Medical Centre Nijmegen, 6500 HB Nijmegen, The Netherlands.
Psychopharmacology (Impact Factor: 3.88). 10/2009; 207(4):559-69. DOI: 10.1007/s00213-009-1686-1
Source: PubMed


Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level.
Fifteen healthy male volunteers received apomorphine sublingually (2 mg), subcutaneously (0.005 mg/kg), and placebo in a balanced, double-blind, cross-over design. Outcome measures were plasma GH levels, performance on an AX continuous performance test, and prepulse inhibition of the acoustic startle. The relation between central outcome measures and apomorphine levels observed in plasma and calculated in the brain was modeled using a two-compartmental pharmacokinetic-pharmacodynamic analysis.
After administration of apomorphine, plasma GH increased and performance on the AX continuous performance test deteriorated, particularly in participants with low baseline performance. Apomorphine disrupted prepulse inhibition (PPI) on high-intensity (85 dB) prepulse trials and improved PPI on low intensity (75 dB) prepulse trials, particularly in participants with low baseline PPI. High cognitive performance at baseline was associated with reduced baseline sensorimotor gating. Neurophysiological measures correlated best with calculated brain apomorphine levels after subcutaneous administration.
The apomorphine challenge test appears a useful tool to assess dopamine receptor functioning at the forebrain level. Modulation of the effect of apomorphine by baseline performance levels may be explained by an inverted U-shape relation between prefrontal dopamine functioning and cognitive performance, and mesolimbic dopamine functioning and sensorimotor gating. Future apomorphine challenge tests preferentially use multiple outcome measures, after subcutaneous administration of apomorphine.

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Available from: Arnt F A Schellekens
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    • "Some of these studies specifically investigate the dopaminergic system in the prefrontal cortex (PFC) (Zavitsanou et al., 1999) or in the striatum (Swerdlow et al., 2007), showing that the DA system in both the PFC and the striatum might be involved in PPI modulation. Similarly, in healthy humans, there is support for modulation of PPI by substances influencing DA metabolism or transmission , or DA receptor agonists/antagonists, but results have been inconclusive (Bitsios et al., 2005; Giakoumaki et al., 2008; Roussos et al., 2009b; Schellekens et al., 2010; Swerdlow et al., 2002; Swerdlow et al., 2003). "
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    • "Nevertheless, 11 participants reported nausea and somnolence after administration of apomorphine. Consistent with existing work employing this combination of drugs [52], [55], these side effects were short-lived, generally lasting no more than 15 minutes, and participants reported being alert and task-ready after this interval. "
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    • "Apomorphine is a nonselective dopamine agonist, although it exhibits a very high affinity for the D2 receptor family, and particularly the D4 receptor (Millan et al. 2002). At low doses (i.e., ~0.004 mg/kg), apomorphine reduces the dopamine release within the striatum via the inhibitory D2 receptors located presynaptically (i.e., on the nigrostriatal terminals) (Montoya et al. 2008; Schellekens et al. 2010). In contrast, at the higher (10-fold) doses used for PD treatment (i.e., ~0.04 mg/kg), apomorphine mainly stimulates the postsynaptic D2 receptors expressed by striatal neurons (Bowron 2004; LeWitt 2004). "
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