Dopamine vs Noradrenaline: Inverted-U Effects and ADHD Theories

School of Psychiatry, University of New South Wales,, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Australian and New Zealand Journal of Psychiatry (Impact Factor: 3.41). 03/2009; 43(2):101-8. DOI: 10.1080/00048670802607238
Source: PubMed


The aim of the present study was to review the dopamine theory of attention-deficit-hyperactivity disorder (ADHD), in light of recent use of noradrenergic therapies. A historical review of pharmacological theories of ADHD was conducted, including inverted-U, spatial working memory and neural circuit aspects. Pharmacological advances, including animal and human studies of dopaminergic and noradrenergic mechanisms at the prefrontal cortex (PFC), indicate that alpha-2A adrenoreceptor stimulation results in increased dendritic firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation result in reduction of delay-related firing to non-preferred directions, allowing representational control in the PFC. Recent studies of the COMT val/met gene and stimulant medication response may help explain variation in inverted-U responses in individuals. Further studies utilizing delay-related firing paradigms should be useful in the investigation of attentional syndromes, and responses to newer pharmacological treatments.

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    • "However, it appears that neither NE nor DA can act independently without affecting the other system. Both the NE and DA systems are required for proper operation of prefrontal functions because a selective impairment in either transmission within the PFC leads to disrupted working memory (Arnsten, 2004; Arnsten and Jin, 2014; Brozoski et al., 1979; Levy, 2009; Ramos and Arnsten, 2007; Vijayraghavan et al., 2007; Williams and Goldman-Rakic, 1995). Previous studies have also shown that both NE and DA levels undergo moderate and comparably sustained increases during a delayed alternation task in trained animals (Rossetti and Carboni, 2005), and DA may be taken up through the NE transporter (NET) in brain regions with low levels of DA transporter (DAT), such as PFC (Moron et al., 2002; Sesack et al., 1998). "
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    ABSTRACT: Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies.
    Full-text · Article · Jan 2016 · Brain research
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    • "COMT and PRODH enzymes are related to neurotransmitters, such as dopamine, noradrenaline, GABA, and glutamate, which play a role in the etiology of various psychiatric disorders323334. Hyperprolinemia causes microdeletions in chromosomal region 22q11[35,36], and deletion in this region was investigated in schizophrenia293031. It has been suggested that there may be an association between the PRODH enzyme and schizophrenia[37]. "
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    ABSTRACT: We investigated whether prolidase activity has a diagnostic test value in schizophrenia and assessed the relation between prolidase activity and sociodemographic-clinical characteristics of patients with schizophrenia. Fifty patients with schizophrenia (diagnosed as schizophrenia according to DSM-V criteria) and 50 healthy volunteers were included in this study. Case and control groups had a similar distribution in age, sex, body mass index (BMI), and smoking status. Serum prolidase activity was measured in both groups and was determined to be significantly higher in the patient group (509.706±41.918) compared to the control group (335.4±13.6; t=6.231; p=0.0001). A cut-off point of 392.65U/L prolidase was determined for diagnostic measures from the plotted ROC curve. The area under the ROC curve was 1.000, which was significant (p<0.0001). Higher values were assigned as the disease state. Both positive predictive value (PPV) and negative predictive value (NPV) were 100% at the cut-off point of 392.650U/L. The prolidase levels of the control group were all below the cut-off point. There were no statistically significant differences between the two groups with regard to age, gender, or BMI (p>0.05), and no correlation was found between mean prolidase activity and age of onset of the disease, family history, disease duration, number of hospitalizations, subtypes of schizophrenia, PANSS scores or sub-scores, CGI-S scores, S-A scale scores, and the antipsychotic treatment (p>0.05). The results of this study indicate that serum prolidase activity may be a useful diagnostic test for schizophrenia; however, further studies are needed to verify this.
    Full-text · Article · Dec 2015 · Neuroscience Letters
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    • "Moreover, decreased working memory (e.g. SWM) (Barkley, 1997; Gallagher and Blader, 2001; McLean et al., 2004; Dowson et al., 2004; Rodriguez-Jimenez et al., 2006; Levy, 2009) and difficulties in executive functioning (Seidman et al., 1998; Mercugliano, 1999; McLean et al., 2004; Rodriguez-Jimenez et al., 2006; Greene et al., 2008) are often reported. At a neurobiological level, due to the ameliorating effect of stimulant medications (e.g. "
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    ABSTRACT: Even though there is an impaired perceptual capacity in attention-deficit/hyperactivity disorder (ADHD) patients, psychophysiological alterations, such as impaired gating as indexed by prepulse inhibition (PPI) or suppression of P50 auditory event-related potentials, have not been found in patients with ADHD. Hence, potential relationships of psychophysiological measures of gating to psychopathology and cognitive performance remain unclear. The present study investigates two distinct operational measures of gating as well as cognitive performance within adult ADHD patients in order to assess the relationship of these measures to psychopathology. PPI, P50 suppression, cognitive performance, and psychopathologic symptoms were assessed in 26 ADHD patients and 26 healthy control subjects. ADHD patients compared to healthy control subjects exhibited impaired P50 suppression, performed worse in cognitive tasks, and reported more psychopathological symptoms, but were normal in the test of PPI. Thus, P50 gating deficits are not specific to schizophrenia-spectrum disorders. These findings highlight the differences between P50 gating and PPI as measures of the gating construct. In keeping with the lack of correlations between these two putative operational measures of gating seen in both humans and animals, adult ADHD patients exhibit deficient P50 suppression and poor cognitive performance, despite exhibiting normal levels of PPI.
    Full-text · Article · Sep 2012 · Psychiatry Research
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